Chronic Inflammation Seminar 1 Dr.

Shenker
- Case 1
o 65 year old male presents with
High fever chills, pain in flank, polyuria, pain when urinating, pyuria (pus in urine), cellular casts in
urine
Took antibiotics for 2-3 days and symptoms disappeared
o Over next 12 months experience same symptoms several times on top of
Fatigue and headaches
Difficulty voiding (slow onset, frequency, incontinence, suprapubic pain)
o Seeks medical attention:
Prostatic enlargement 3 lobes enlarged due to hyperplasia

- Due to abnormal hormone levels, this enlargement

compresses urethra causing pain
- Bladder will thicken as a result of increased workload
- However, the most serious complication is the inability
to flush completely retrograde infection up ureter and
eventually kidney (pyelonephritis)

Bacteuria
Proteinuria

- Slight hypertension due to fibrotic kidney (dec

perfusion = dec GFR renin-angiotensin system activation
cardiac output increases)
- Azotemia elevated blood urea nitrogen (BUN) due to
kidney not functioning correctly
resulting in urinary nitrogen accumulation (usually flushed out)

- All in all, started off with urinary tract infection

o Hyperplastic prostate NOT resolved, happens over and over again
Acute chronic inflammation
- Case 2
o 26 year old male
2 days of acute pain in floor of the mouth and right side of face
Temperature 101 degrees F
o 3 weeks ago had similar symptoms but disappeared
o For past year
Fullness in the region of right submandibular gland
Tender an swollen especially when eating possible gland blockage
Diagnose by making him salivate (w/ chewing gum)
Diagnose by radiograph floor-of-the-mouth view
Saliva coming out is normally sterile
Blockage retrograde infection (non-sterile)

- Case 3
o Patient presents for routine visit
o X-ray reveals excess cement pushed through apical foramen
Induced foreign-body inflammation (chronic, granulomatous [pepperoni-pizza])

- Case 4
o 65 year old man several month prior to death
Weight loss
Progressive respiratory disease
Productive cough
Blood-tinged mucopurulent sputum
o Lungs autopsied caseous necrosis most likely granulomatous inflammation (chronic due to TB)
Damage mostly from immune response NOT THE INFECTION
 - Case 5
o 48 year old man
o Had mandibular cuspid removed
o 1 day later, still bleeding with development of large ecchymotic area on face
o Sent to hospital
o Hospital findings:
Chronic alcohol bad for your liver
Pale & jaundiced due to accumulation of bilirubin b/c of liver dysfunction, cannot
breakdown RBC
Spider nevi due to liver dysunfunction impeding incoming blood from the portal
system, producing hypertension & backing blood up blood vessel
enlargement/vasodilated
Gynecomastia due to liver dysfunction & less than efficient breakdown of estrogen
Elevated prothrombin time due to liver dysfunction, blood clots take longer to form
Proteinemia, albuminemia (low levels) loss of fluid due to liver dysfunction thus
decreased production
o Ascites (swelling in peritoneal cavity) due to proteinemia
o Leg & feed swollen due to proteinemia
o Difficulty breathing due to fluid in abdomen inducing pressure, also fluid in
lungs
Sexual dysfunction
Testicular atrophy
Weak
Liver goes from NORMAL FATTY CHANGE CIRRHOSIS
 -note: collagen deposition around
sinusoid

-Trichrome stain (for collagen deposition = blue)

-Spider nevi = spider web = one central blood vessel w/ branches

(spider nevi left, normal right)

-Erythematous esophagus due to portal hypertension (backing up of blood near esophagus?)

(normal left, erythematous esophagus right)
Infectious Diseases Dr. Sciutto Lecture 1 Bacterial Infections
lowe respiratory infections
- Leading causes of death in high-income countries are mostly heart disease, cancer, stroke, dementia COPD
o Infection is relatively controlled however
- Leading causes of death in low-income countries are (also) heart disease, lower respiratory infections, HIV/AIDS,
perinatal conditions, stroke, diarrheal diseases, malaria
o Basically, infections (respiratory, GI) are a lot MORE COMMON in developing countries
- What is an infection?
o Invasion & multiplication of an organism in or on tissues of another organism
What determines the pathogenicity?
Infectious agent properties such as evasion of hosts system
Host response to infectious agent such as inflammation
What are some host defenses against infection?
Skin/epithelium - mechanical barrier. These desquamating cells prevent agents from
reaching underlying dermis. The surface is dry which prevents bacteria survival. The
low pH (~5) is not good for bacterial growth.
Respiratory nasal hair + mucosa = mechanical barrier. Mucociliary escalator traps
bacteria and pushes them backward toward the throat. Alveolar macrophages attack
bacteria that reaches lung.
o These can be compromised by smoking, cystic fibrosis, intubation trauma
GI low pH (gastric juice). Viscous mucus covering the gut (mechanical barrier). Lytic
pancreatic enzymes. Bile detergents. IgA antibodies. Emesis (vomiting) can also reduce
microbe infiltration. Mucosal integrity, indigenous microflora, and peristaltic
contraction all contribute to protection of gut
Genito-urinary tract sterile flushing of urine, low pH of urine, IgA secretion,
indigenous microflora (lactobacilli)
Mouth oral mucosa (mechanical barrier), high turnover rate of epithelium, salivary
antibacterial defense
Inflammatory/immune system
- Attributes of pathogenic agents
o Resist external & internal host defense systems
o Proliferate in host tissues
- How infectious agents cause disease
o Contact/enter host cells and cause cell death
o Release toxins
o Inflammatory/immune-mediated damage/mechanisms
- How infectious agents disseminate/spread (different bacteria can cause specific infections in different organs)
o Within tissues or structures / to adjacent tissue / tissue planes / lymph nodes / blood stream / other fluids
(saliva, urine) / placental fetal transmission
- Spectrum of inflammatory responses to infection (we should know some of this! in yellow highlighter)
o Suppurative/purulent inflammation abscess, pyogenic bacteria
o Granulomatous inflammation TB
o Chronic inflammation with scarring HBV (hepatitis B virus)
o Cythopathic-cytoproliferative inflammation HSV (herpes simplex virus) HPV (human papilloma virus)
o Necrotizing inflammation cutaneous infection with bacillus anthracis (anthrax)
- Infectious agents can include: bacteria, viruses, fungi, parasites, protozoa, prions
- Mechanism of bacterial virulence
o Immune evasion or immune response
o Adhesins (Lipoteichoic acid & M Protein bind to surface molecules to establish infection)
o Endotoxins (LPS on gram-negative bacteria)
o Exotoxins (AB toxins of anthrax & superantigens)
o Bacteriophage, plasmids, transposons (ENCODE virulence factors or resistance when bacteria conjugate)
DONT GET TOO HUNG UP ON THE BACTERIA & VIRUS NAMES FROM ABOVE FOCUS ON THE 3 DISEASES COMING UP!
Namely
- Syphilis sexually transmitted disease that has been increasing in prevalence
- Diphtheria classic example of exotoxin producing bacteria
- Streptococcal infection a prevalent infectious agent with several common pathologic manifestations
Syphilis the re-emerging disease (with HIV epidemic), >50 million people infected, 16,000 new cases/year in US
- Caused by Treponema pallidum gram-negative spirochete can ONLY be viewed with dark field microscopy OR
fluorescence microscopy
- Resistant to phagocytosis
- Does not produce toxins, does not cause direct lysis of cells
- The tissue damage is due to host immune response
- STD mucosal to mucosal transmission (risk of infection INCREASED with HIV)
o Meaning skin to skin contact okay, sex is a no-no
- Occupational hazard for dentists/physicians
o Because this organism is invasive and can come off of lesions (from pts) and penetrate intact mucous
membrane OR skin ABRASIONS!
- Three phases of syphilis primary, secondary, tertiary/latent
Primary Syphilis (go look up pics in the slides b/c I kinda dont want to put a buncha penises on this lol)
- Lesion is called chancre
o Appears 2-3 weeks after infection, lesion usually singular & highly contagious
o Raised ulcer with rolled border
o Painless
o Occurs at site of inoculation (98% genitalia, 2% oral/lip area common)
o Histologically

- Lots of T, B, plasma cells with some macrophages and giant cells

o These inflammatory cells will CUFF arteries (periarteritis)
o And the endothelial cells of the arteries appear to be
swollen (endarteritis)
o Eventually leads to lumen occlusion, reducing local blood
flow (endarteritis obliterans)
o This lack of blood ulceration
- Outcome: 2-6 weeks, heals sponatenously
o 50% pts secondary phase
Systemic spread (fever, malaise, rash)
Lesions mostly at distal sistes
Secondary Syphilis (may see lymphadenopathy, sore throat, malaise, headache, weight loss, fever, musculoskeletal pain)
- Appears 2-3 MONTHS after chancre healing, lesion usually multiple & lesions are still contagious
- Manifestations include:
o Macular rash
o About 30% patient mucous patches focal areas of exocytosis & spongiosis of ORAL mucosa
o Condylomata lata papillary lesions that resemble viral papillomas
o In immunocompromised (HIV/AIDS) patients lues maligna explosive and wide spread

- Histologically characterized by vasculitis due to local deposition of immune complexes (anti-treponemal antibodies
& treponemal antigens, may even result in transient arthritis or glomerulonephritis)
- Outcome: within weeks, lesions disappear but may recur 1-3 times
o Immunity develops
 o 30% pts tertiary phase (5-30 years LATENT period)
Tertiary Syphilis (can involve almost ANY organ system- most serious complications)
- This is an IMMUNE RESPONSE because NO ORGANISM ARE DETECTABLE, NOT CONTAGIOUS
o Obliterative endarteritis (endarteritis obliterans/ periarteritis/blood vessel damage induced tissue
destruction (same thing as described in primary syphilis)
- Cardiovascular syphilis (80%) usually affects ascending aorta & coronary ostia
o Endarteris obliterans on vaso vasora (muscle replaced by fibrous tissue pressure-induced aneurysm b/c
cannot stretch as well anymore)
- Neuro-syphilis (10%) 4 forms
o Meningovascular anterior spinal artery thrombosis & fibrosis paraplegia
o General paresis involves cerebral cortex, meninges, cerebral arteries atrophy of frontal and temporal
lobes mental and physical problems
o Tabes dorsalis arteritis atrophy of dorsal roots, de-myelinization of sensory fibers paresis
o Primary optic nerve atrophy blindness
- Benign tertiary syphilis (Gumma) non-contagious GRANULOMATOUS reactions with central area of COAGULATIVE
necrosis

o Surrounded by lymphocytes, plasma cells, giant cells, epitheloid cells, fibrous tissue
o Oral manifestation of gumma usually on palate & tongue
May perforate palate & destroy nasal septum
May enlarge tongue interstitial glossitis
Tongue papillae may atrophy luetic glossitis
Congenital Syphilis untreated women transmit this across placenta (not infectious)
- Early congenital syphilis - appears within 2 years after birth with lesions similar to secondary syphilis, then
progresses to tertiary (gummas, neuro-syphilis)
- Late congenital syphilis develops after 2 years of age with lesions same to tertiary syphilis

- Also peg-shaped incisor (Hutchinsons

incisors)
- Dome-shaped molars (Mulberry
molars) common but NOT ALWAYS
- Hutchinsons triad there
o Interstitial keratitis (corneal
inflammation)
o Deafness (CN VIII)
o Hutchinsons incisors

- Diagnosis (usually with either serological tests or microscopy [dark field or fluorescence])
o Low sensitivity to screen for ACTIVE infection
Rapid plasma regain (RPR)
Venereal disease research laboratory (VDRL)
o High sensitivity will ALWAYS BE POSITIVE AFTER infection
Fluorescent treponemal antibody absorption (FTA-ABS)
T.Pallidum hemaglutination assays (TPHA)
o Use in combination to differentiate between the phases!
- Treatment treat primary and secondary with penicillin to stop progression to tertiary
Diphtheria a life-threatening syndrome
- Caused by Corynebacterium diphtheria gram-positive rod-shaped humans are the ONLY host
o Spreads from person to person via aerosols or skin shedding
o Tissue damage due to EXOtoxin (A-B toxin) inhibition of protein synthesis (no translation = cell death)
Fortunately, controlled by vaccination & anti-toxin
- Signs and symptoms: lowgrade fever, headache, malaise, anorexia, sore throat, vomiting

o Mainly mucosal surfaces (patchy yellowish-white film adherent & gray film necrosis)
o Depending on membranes involved can:
Compromise airway
Lead to lymphadenopathy (bull neck)
In severe cases, paralysis, myocarditis and neurologic involvement
o Localized wound infection
o Asymptomatic carrier
- Diagnosis
o Culture specimen from underneath diphtheric membrane and nasal mucosa
o Confirm presence of microbe
- Treatment
o At clinical diagnosis (Dont wait for culture results or may be too late!)
Antitoxin + antibiotics (penicillin)
o 3 consecutive NEGATIVE cultures required to verify organism REMOVAL!
Streptococcal Infections

- Caused by strep gram-positive pyogenic cocci (chain-like appearance)

lead to suppurative infection of multiple tissues
o Streptococcus pneumonia lung, meninges infection
o Streptococcus mutans caries
- Has M-protein associated with disease causation (in S. pyogenes)
- But do know that penicillin works against even virulent streptococci
o We are going to talk about the common manifestations such as
pharyngitis/strep throat & impetigo, but do KNOW THAT other manifestations are
possible (see below)

- Suppurative complications: tonsillopharyngeal cellulitis/abscess, otitis media, sinusitis, necrotizing fasciitis,

streptococcal bacteremia, meningitis or brain abscess
- Nonsuppurative complications: acute rheumatic fever, acute glomerulonephritis, strep toxic shock syndrome (TSS)
Bacterial virulence factors of Streptococcus (these are NOT mentioned in lecture, but in the reading)
- Rapid multiplication
- Cell wall components
o M-protein alpha helical coiled-coil dimer that resists phagocytosis
o LTA for adherence to mucous membranes
- C5A peptidase cleaves complement C5A protein and destroy chemotactic signal
 - Extracellular products
o Streptolysin O and streoptolysin S hemolytic (blood cleaving) toxins
Streptolysin O is used as an indicator for recent infection
o Deoxyribonuclease A/B/C/D DNA cleaving
o Hyaluronidase hyaluronic acid (in connective tissue) cleaving
- Pyogenic exotoxins A/B/C responsible for causing fever & scarlet fever rash
o Also stimulate T cells to proliferate = superantigens increase susceptibility to endotoxic shock
o Also cause dysfunction of the reticuloendothelial system, produce cardiac and hepatic necrosis, depress
antibody synthesis
- Nucleases A/B/C/D liquefaction of pus
- Other enzymes (two most important)
o Streptokinase plasminogen plasmin digest fibrin
o Hyaluronidase (mentioned before)
Common examples of Strep infections (tonsillitis/pharyngitis, scarlet fever, impetigo, erysipelas)
Tonsillitis & Pharyngitis 25% caused by group A, Beta-hemolytic strep this manifestation is the most common BACTERIAL infection
- Human to human spread in humans
- Signs and symptoms

- Sudden onset sore throat, fever, dysphagia, tonsillar hyperplasia,

redness of the oropharynx and tonsils, palatal petechiae, cervical
lymphadenopathy, yellowish/purulent exudate (patch or confluent)
o Dont usually see rhinitis, laryngitis, bronchitis
- Diagnosis (often indistinguishable from viral pharyngitis so)
o Throat culture or rapid antigen detection test
o Presence of certain clinical features (conjunctivitis, cough,
hoarseness, ulcerative lesions, diarrhea) suggest VIRAL etiology and SHOULD
NOT BE TESTED!
o Early diagnoses needed to prevent rheumatic fever, acute
glomerulonephritis, or TSS
Scarlet Fever systemic infection caused by group A, Beta-hemolytic strep most common in children 3-12
- BEGINS as tonsillitis with pharyngitis
- Erythrogenic toxin from bacteria produces SKIN RASH attacks blood vessel
- Clinical features again, initially resembles tonsillitis & pharyngitis

2 days WHITE strawberry tongue (the seeds of strawberry are actually the fungiform papillae)
Fever develops and stays to 6 days
Facial erythematous rash
Body rash begins and is full blown in 24 hours (sunburn with goosebumps
appearance)

4 days RED strawberry tongue due to tongue desquamates

Transverse red streaks on body where pressure is Pastias lines
Rash clears in a week and skin desquamates in 8 weeks

Impetigo superficial skin infection caused by S. pyogenes & S. aureus most common in young children
- Most arise over previous trauma/dermatitis, pruritus and lymphadenopathy can also be seen
- Two presentations
o Fragile non-bullous vesicles erupt thick adherent AMBER crust (left next page)
o Longer lasting bullous vesicles erupt thin HONEY-colored crust (right more with S. AUREUS)
 - Diagnosis (usually clinically obvious, but cultures from skin can be used if not)
- Treatment (antibiotics - penicillin like always, but resistance becoming problematic)
o MISTREATMENT corticosteroids reduce crust but DOES NOT CLEAR red raw lesions afterwards
Erysipelas superficial skin infection caused by A, Beta-hemolytic strep (AKA: St. Anthonys Fire, Egyptian Healer, French
Hospital with Red Walls lol what?)
- Less commonly seen today, but can be confused with facial cellulitis from dental infection
- Clinical Features

- Primarily young and elderly patients

- Previous trauma a predisposing factor
- Cheeks, nose, eyelids reminiscent of butterfly lesion associated
with lupus erythematosus
o Characteristic orange-peel look
o Area is red, painful, swollen, indurated, warm, well-
circumscribed
- Systemic signs and symptoms may be present (fever, sore throat
and all that junk)
- Cultures usually NOT beneficial
- Treatment (penicillin or erythromycin)
o Lesion enlarges AFTER initial treatment (lysis of bac)
o Resolution in 48 hours
Complications abscess, gangrene, necrotizing fasciitis,
TSS, may recur
Additional information nonsuppurative complications of Strep
- Acute rheumatic fever
o Follows initial pharyngitis with a latent period of 2-3 weeks
Arthritis, carditis, chorea, subcutaneous nodules, erythema marginatum
o Possibly (not confirmed) due to antigenic cross-reactivity between strep antigens & heart tissues
o Or strep exotoxin directly toxic to tissue, Or antigen caused inflammation in heart
- Post-strep glomerulonephritis caused by specific nephritogenic strains of group A strep (type 12, 49)
o Possibly due to immune complex deposition within glomerulus
Sub-epithelial deposits of immunoglobulin can be seen with immunofluorescent staining
- Strep toxic shock syndrome (TSS) associated with M proteins of strep (type 1, 3)
o Also associated with strep pyogenic exotoxins A/B/C
o Also associated with strep super-antigen
Infectious Diseases Dr. Sciutto Lecture 2 Viral & Fungal Infections + Actinomycosis bacterial infection
- On top of bacteria, viruses & fungi can cause infections too
- Mechanism of viral virulence
o Inhibition of cellular metabolism, subverting them to viral needs (mitochondria, DNA, RNA, protein synth)
o Damage membrane integrity (such as downregulation of surface receptors, evading immune system)
o Cell lysis
o Presentation of viral proteins on cell surface immune destruction (HBV)
o Target host defense cells (HIV kills CD4+ cells)
o Destroy cells that others depend on (polio)
o Cellular transformation (HPV associated with cancer)
o Alteration of apoptotic pathways (can re-program cell so it does not undergo apoptosis when it should
Hepatitis B (A through G discovered with B and C most clinically significant)
- 10-100 times more infectious than HIV, 300,000 Americans infected per year
- Most common cause of cirrhosis and liver cancer, NOT ALCOHOL! (yay?)
- Present in all body fluids except stool
- Hardy virus survival on dry surfaces
o Can remain in blood for 6 months
- Transmission
o Perinatally, vertically (mother to child) or via horizontal (person to person) transmission during early
childhood
o Sexual contact (blood, semen, secretions)
o Occupational (in dentistry too) contact contaminated needles and syringes
o Household contact with a person suffering acute or chronic carrier
o Receipt of certain blood products & hemodialysis (transfusions, transplants)
o Over 30% patients with acute hepatitis B DO NOT HAVE IDENTIFIABLE RISK FACTORS
- Pathogenesis hepatocyte injury believe to result from damage to the virus infected cells by CD8+ T-cells

o Reasoning for this self-damage theory is that there are chronic carriers with no cell injury
o The run down:
HBV enters hepatocyte via receptor and starts to synthesize viral proteins
HBsAg, HBcAg, HBx, etc and undergoes self-replication
o HBsAg - @ hepatocyte cell SURFACE (thus the S) via MHC induces antigen-
specific cytotoxic T-cell response apoptosis via death signaling (Fas-Fas
ligand, TNF to their respective receptors)
Also secretes IFN-gamma activate secondary immune responses
- Three kinds of hepatitis: acute (icteric, anicteric), chronic (with or w/o cirrhosis), fulminant hepatitis (hepatic
necrosis)
Acute Hepatitis (20-25%) produces necrosis & inflammation of liver with four stages
o Incubation
o Pre-icteric
o Icteric (fever malaise, loss of appetite, vomiting)
o Convalescence (recovery)
 - Symptoms

- 50% of infected adults - jaundice/icteric, preceded by

mild fever, fatigue, malaise, loss of appetite, n/v
- Children and infants (and other 50% of adults)
anicteric (no jaundice)

- Viral components
o HBsAg (surface) first marker to appear in serum of pts with acute hep B (2 weeks to 2 months before
symptoms) & disappears during convalescence
Following disappearance, antibody to HBsAg appears complete recovery/life-long immunity
o HBcAg (core) antibody to HBcAg appears after anti-HBsAg DOES NOT CLEAR OR PROTECT FROM RE-
INFECTION REMAINS IN BLOOD, good marker for PREVIOUS HBV INFECTION!
o HBeAg appears closest to onset of clinical disease and disappears in 2 weeks marker for period of
intense viral replication & thus, MAXIMUM INFECTIVITY
Antibody to HBeAg appears shortly after removal of antigen can detectable for up to 2 years after
resolution the antigen-antibody complexes can cause extrahepatic diseases (glomerulonephritis,
arteritis, arthritis)
- Signs and symptoms expanded

o Ballooning degeneration diffuse swelling so cytoplasm looks empty

o Cholestasis/bile flow blockage bile plugs (canaliculi) and brown pigmentation of hepatocytes
o Cell death
Cytolysis necrotic cells drop out and scavenger macrophages aggregate @ site
Apoptosis hepatocytes shrink & become eosinohpilic w/ fragmented nuclei, eventually
phagocytosed by macrophages
o Inflammation is characteristic
Via Kupffer cells undergo hypertrophy & hyperplasia on top of lipofuscin can be seen
Fulminant Hepatitis (<1%) a massive hepatic necrosis

- Suggested causes (current unknown)

o Direct cytopathic effect by aggressive viral strain
o Enhanced immune response (massive release of immune complex & cytokine over-production)
- Symptoms
o Presents with acute hepatic failure
Jaundice, coagulopathy, bleeding, encephalopathy
Cerebral edema major cause of death
- Grossly the liver appears shrunken with necrotic areas muddy red, mushy with blotchy bile staining
o There may be very little inflammation at first
o Survival leads to massive influx of inflammation
Chronic Hepatitis (4%) if acute does not resolve within 6 months
- Risk factors
o Young age (mother to infant 90%, children 25%, adults 2-5%)
o Homosexual
o Gender (male 90% )
o Altered immune function
- Two types
o Chronic persistent often resolve

Mild form does not spread beyond portal triad, does not progress to serious disease
High HBsAg, low HBeAg (little viral replication)
Granular cytoplasm contains HBsAg accumulation Ground-glass hepatocytes
o Chronic active necrotizing & inflammatory cirrhosis, liver cancer

Symptoms fatigue, loss of weight, jaundice

Can spread beyond the portal triad region
Piecemeal necrosis (inflammation on border of portal tracts) hallmark of progressive disease
Bridging fibrosis predictor of rapid progression to cirrhosis
Cirrhosis dense collagenous septa, destroy the lobular architecture and divide liver into
hepatocellular nodules
Hepatocellular Carcinoma (HCC) common cancer that develops in 20% of cirrhosis patient 30-50 years AFTER infection
- Younger you get infected, more
likely to get this (since it takes 30-50 years
to onset, get it when you are 80, probably
not going to show up at all)
- Once symptoms appear, already
@ terminal stage
- Prevention:
o Avoid transmission
(sharing needles, etc)
o Vaccination
o IM anti-HBsAg after
birth (reduce infection by 95%)
- Supposed/Putative Mechanism of HCC
o Integration of viral DNA near oncogene or tumor suppressor gene (activate or deactivate respectively)
Can cause changes in cell cycle (growth, differentiation)
o Necrosis, cell death accelerated cell division to replace increases probability of mutation, DNA
damage, viral insertion
Less time for DNA repair
o Inflammation free radicals damage to DNA
Dental Implications of HBV
- Comprehensive history & prothrombin time (clot dysfunction indicator since clotting factors made in liver)
 o If acute suspected NO ELEVTIVE DENTAL TREATMENT until resolution, dont want no spread!
Wrapping it up
- Diagnosis enzyme immunoassay (EIA), PCR, liver function test
- Treatment immune modulators (IFN), antivirals
- Prevention (mentioned already) vaccination, HBsAg Ig after birth (95% reduction)

Human Papillomavirus most common human viral infection (75%-80% adults infected)
- Can only infect humans, thus HUMAN papillomavirus
- Spread by contact (hand to hand, sexually) or vertically (mother-child)
- Associated with mucosal & epithelial surfaces see all the pictures in slides, too many to include
o Cutaneous warts 4 forms of benign tumors (with the common histology shown)

Verruca vulgaris (common wart)

Mymecia (deep hyperkeratotic palmoplantar wart)
Superficial mosaic type plamoplantar wart
Verruca plana (flat wart)
o Epidermodysplasia verruciforms appears to have a genetic component
o Mucosal HPV lesions latent with no visible lesions
o Condylomata acuminata (genital warts) most common benign genital tumor
o Laryngeal papillomas removal required even though benign b/c might block respiratory tract
- Cytoproliferative response
- HPV and cancer - induces cancer by inactivating tumor suppressors p53 and pRb
o Associated with HPV 16, 18 (and possibly 31, 35)
o Vaccines now available
o Risk factors for cervical cancer early age @ first intercourse, multiple sexual partners, increased parity, a
male partner with multiple previous partners, presence of cancer associated HPV, presence of high-risk
(viral load) HPV, certain HLA and viral subtypes, exposure to oral contraceptives and nicotine, genital
infections (such as Chlamydia)
Dental Implications of HPV

- Oral manifestations: squamous papilloma (verruca vulgaris?),

condyloma acuminatum

Wrapping it up
- Diagnosis no serologic markers, papanicolaou cytologic tests/papersmears, DNA hybridization techniques
- Treatment removal by electrocauterization, cryosurgery, laser surgery
o Topical antiviral cidofovir
- Prevention vaccine (Gardasil, Cervarix) even with vaccine, still get pap smear b/c vaccine does not cover all strains
Infectious Mononucleosis common manifestation of Epstein-Barr Virus (EBV)
- A self-limited lympho-proliferative disorder characterized by fever, lymphadenopathy, hepatosplenomegaly, sore
throat, atypical activated T lymphocytes
- Spread through saliva kissing disease that affects 50% of adolescents and young adults
o Universal infection by age 4 in developing nations
- Establishes LATENT infection once infected, host for life
- Clinical Manifestation

o Infant and toddlers asymptomatic

o Children and young adults
2 weeks prodromal phase fatigue, malaise, anorexia
Symptomatic phase fever, sore throat, lymphadenopathy, hepatosplenomegaly, atypical
activated T lymphocytes
- Pathogenesis
o Infection of B cells and epithelial cells
Lytic (minority of the cells) releases virus
Latent (integrate host genome) polyclonal activation/proliferation of B cells
o It is actually the immune response that causes symptoms
Cytotoxic T cells and natural killer cells (expansive lymphocyte proliferation)
Lymphadenopathy T cell proliferation in lymph nodes
Splenomegaly expansion of activated T cells within follicles & red sinusoids
o Complications include thrombocytopenia, splenic rupture
Hepatomegaly impair liver function
Wrapping it up
- Diagnosis (from least specific to most specific)
o Lymphocytosis with atypical lymphocytes in the peripheral blood
o Positive heterophil antibody reaction (monospot test) Paul Bunnel antibody test
o Specific antibodies for EBC antigens
- Treatment palliative therapy, NSAIDS, non-aspirin anti-pyretics, no contact sports to prevent splenic rupture,
corticosteroids if airway obstruction due to lymphadenopathy (watch out for immunosuppression though)

Histoplasmosis (systemic) most common FUNGAL infection in US

- Caused by Histoplasma capsulatim
o Yeast-like phase
o Hyphal phase
- Spread by airborne spores
- Common in humid river basins
- Contraction based on spore number, host immune status, strain
- Pathogenesis
o Acute self-limited
Pulmonary infection, influenza-like symptoms (fever, headache, myalgia, nonproductive cough,
anorexia)
o Chronic rare. resembles TB
Primary affects lungs in elderly, emphysematous, immunocompromised pts
Predilection for white males
(Cough, weight loss, fever, dyspnea, chest pain, weakness, fatigue)
o Disseminated REALLY rare
SPREAD to EXTRA-pulmonary sites in elderly, immunosuppressed pts
 Affects many tissues including oral mucosa
o Tongue, palate, buccal mucosa (solitary, variably painful ulceration lasting
weeks) PICTURES NOT INCLUDED HERE B/C HARD TO DISTINGUISH FROM
CANCER would biopsy
- Histologically

o Diffuse macrophage infiltrate

o Multinucleated giant cells - granulomatous inflammation
o Causative agent can be seen with H&E, Grocott-Gomori stain, Periodic Acid Schiff stain
Wrapping it up
- Diagnosis histologic identification of organism, culture of organism, serologic antibody to an H. capsulatum yeast
form protein
- Treatment
o Acute palliative treatment
o Chronic & disseminated - antifungal (amphotericin B, ketoconazole, itraconazole)

Candidiasis (localized) most common ORAL infection

- Caused by Candidia Albicans
o Yeast phase
o Hyphal phase more invasive
- But part of normal oral flora in 50% people
o May be opportunistic infection! due to:
Immune host status (immunosuppression, etc)
Oral mucosal environment
Strain
- Manifestations in the Oral cavity
o Pseudomembranous
o Erythematous (other than acute atrophic, the other four are usually chronic & asymptomatic)
Acute atrophic
Central papillary atrophy
Chronic multifocal
Angular cheilitis (perleche)
Denture stomatitis
o Hyperplastic
o Mucocutaneous
Pseudomembranous Candidiasis/thrush creamy white cottage cheese-like, REMOVABLE plaques

- Burning sensation, foul taste

- Under lesion, mucosa may be normal or erythematous
- Caused by: antibiotics & immunosuppression
(Erythematous) Acute Atrophic Candidiasis antibiotic sore mouth

- Red macules
- Loss of filiform papillae bald tongue
- Feels as though scalded by hot drink
- Caused by: broad spectrum antibiotics

(Erythematous) Central Papillary Atrophic Candidiasis symmetric loss of filiform papillae from MIDLINE of tongue

- Often asymptomatic

(Erythematous) Chronic Multifocal Candidiasis similar to central papillary but AT MULTIPLE SITES

- These patients usually have central papillary atrophy

too on top of atrophy at hard and soft palate & angles of
mouth
- Kissing lesion
- Caused by: idiopathic, immunosuppression

(Erythematous) Angular Cheilitis (perleche) red fissure @ angles of mouth that can be a part of chronic multifocal or alone

- Irritated and raw feeling

- Seen in the elderly with increased skin folds where saliva can pool to favor growth
- Caused by: idiopathic, immunosuppression, loss of vertical dimension
o Sometimes Staph. aureus also involved in infection

(Erythematous) Denture Stomatitis (chronic atrophic candidiasis) erythema and sometimes petechiae

- Often asymptomatic
- The weird thing is! denture positive for candida but
MUCOSA NEGATIVE!
- Caused by: persistent denture wear w/o removal &
cleaning

Hyperplastic Candidiasis white plaques that are NOT REMOVABLE! similar to leukoplakia

- Often asymptomatic
- Resolves with antifungal treatment

Mucocutaneous Candidiasis recurrent/persistent SUPERFICIAL infection of skin, mucous membrane, and nails
- Appears similar to hyperplastic candidiasis but
- Indicative of underlying disease: immune-impairment, endocrine impairment, autoimmune disease
o Destruction of endocrine glands, treat with safe systemic antifungals
 - Histology

- Periodic acid Schiff (PAS) used in biopsy or exfoliative

cytologic preparation
- Presence of hyphae or pseudohyphae are necessary for
diagnosis (long string-like appearance)
- Thickened para keratin on surface
- Elongated rete ridges
- Chronic inflammatory infiltrates, microabscesses
Wrapping it up
- Diagnosis clinical signs, exfoliative cytologic examination (PAS), can do Sabouraud Agar slant culture (less practical)
- Treatment antifungal therapy, if doesnt respond: biopsy to rule out dysplasia, OSCC, lichen planus

Actinomycosis difficult to diagnose opportunistic BACTERIAL infection that usually initiates in oral cavity
- Caused most commonly by A. israelii, or A. viscosis
o Filamentous gram-positive bacteria part of the normal flora
o Usually not virulent, but can cause suppurative and granulomatous inflammation when granted entry via
lesions/damaged mucosa (caries, dental manipulation, oromaxillary trauma)
- Cervicofacial Actinomycosis
o Painless, indurated swelling that is a draining FISTULA intra-orally or on facial surface
o Causes acute & chronic inflammation, mixture of both cells (presence of abscess AND fibrosis)

- Actue suppurative adjacent to

organism
- Chronic granulomatous & fibrosis
around it
- Does not follow normal facial spaces
of lymphatics, lymph nodes uninvolved

- Also know that these

bacteria can form sulfur granules
(left) that can sometimes be
extruded from the sinus tracts
strongly indicative of
Actinomycosis

Wrapping it up
- Diagnosis
o Culture difficult due to other bacteria, improper growth, antibiotic therapy
Positive culture best for diagnosis, but difficult to obtain due to reasons above
o Presence of sulfur granules
Botryomycosis also has these but is rare
Detect via indirect fluorescence in sulfur granules
o Histologic examination/confirmation via colonies in lesional biopsies or aspirates
- Treatment
o Penicillin, tetracycline
o Course depends on stage
6 weeks for early
up to 1 year if deep and long-standing infection
o These are usually at HIGH DOSES to PENETRATE FIBROSIS
Infectious Diseases Seminar 2 Dr. Alawi
- Before we start, note that Dr. Alawi likes to use pictures of a similar (albeit different) disease. So dont really focus on
the clinical pictures UNLESS diagnostic
- Case 1: oral ulceration could be due to three things, trauma, infection, cancer so patient history is very important

- Case 2: oral lesion could possibly be syphilis, cancer, trauma among other things
o Try to have an idea of what the cause may be, THEN biopsy to rule out

o Rolled border, have reasons to believe that this is syphilis but not diagnostic until organism identification
Primary syphilis infectious
- Macular papular rash but still, not diagnostic until organism identification (could be chicken pox, drug reaction,
etc)
o Secondary syphilis still infectious

- Gumma granulomatous reaction with coagulative necrosis on the palate (perforation) & tongue (in the form of
leukoplakia)
o Tertiary syphilis not contagious

- Hutchinsons incisors in
o Congenital syphilis not contagious
- Hutchinsons triad (common in congenital syphilis but not always there)
o Interstitial keratitis (corneal inflammation)
o Deafness (CN VIII)
o Hutchinsons incisor
- Case 3: havent learned about this in lectures yet @ this point of seminar. so given straight to us:
o Primary herpetic gingivostomatitis (prior to this, may feel flu-like symptoms such as
fever/malaise/fatigue)
Manifest as small blisters, patients feel as if the mouth is on fire

- You cannot really treat herpes once you get it, only palliative care (magic mouth wash, diet [no acidic/spicy foods]
etc)
- The last picture here shows complete reversal but patient will always shed
o Reactivation can happen via stress, immunosuppression, sunlight

- Under the microscope, one would see herpetically altered cells which are cells with enlarged multiple nuclei

- This is recurrent herpes trigged by trauma of dental work post-traumatic

herpes
o Important to know that recurrent herpes can only occur on
KERATINIZED tissue, thus only possible on ATTACHED gingiva, hard palate, and
dorsal tongue (tongue not likely tho)
- Case 4: havent learned about this in lectures yet @ this point of seminar. so given straight to us:
o Aphthous stomatitis /canker sore do not confuse with herpes b/c these are ONLY on NON-KERATINIZED
surfaces (such as the alveolar mucosa and ventral tongue in the pictures below)

- Case 5: - chicken pox (varicella zoster virus)

o Oral manifestations are not common but can happen
o Also macular papular rash

- VZV in adults though, can be deadly shingles

- Once infected,
infected for life
- Can reside in
head and neck & trigeminal
ganglion
- Activation later
on in life (unlike herpes
simplex from before,
UV/sunlight does do this)
- Thus can manifest
as ANYWHERE THAT
TRIGEMINAL NERVE
INNERVATES
- V1 ophthalmic
can cause blindness due to
scarring and healing of the
eyes (this is the case in the
pictures to the left)
- V2, V3
- Antivirals may be used to pre-empt/prevent further additional lesions, but existing lesions wont be effected
 note that there are quite a few number of disease not covered in lecture but are in the book... decide if
Genetic Basis of Disease Dr. Sciutto Lecture 3 you want to spend a bunch of extra time for maybe 1-2 points lol
- Why do we, as dentists, care about genetic disease?
o Because a number of them result in changes in the oral cavity or will FIRST manifest in oral cavity
MEN 2B (Multiple Endocrine Neoplasia 2B) miRNAs - non-coding, single strand RNA that functions as
NEGATIVE regulators of gene
Mucosal neuroma on tongue and lips classic presentation - inhibit gene expression via repressing translation or cleavage of
Medullary thyroid cancer (2-3 yr) mRNA
- there is now evidence that they play a role in carcinogenesis
Pheochromocytoma - increase expression of oncogenes
Hypotonia, loose joints, long face (marfanoid) - reduce expression of suppressors
- examples: BCL2, RAS, MYC upregulation
- Outline we will look at
o Mendelian genetics single gene mutations
Missense point mutation, changes nucleotide
Nonsense premature stop
Frameshift changing the reading frame, completely different translation from original
o Non-Mendelian genetics read book for microRNA? (edit later after reading?)microRNA = miRNA (see above)
o Chromosomal abnormalities
Mendelian Genetics
- Autosomal recessive read book for cystic fibrosis (edit later after reading?)

o Often result in block of metabolic activity originally termed inborn errors of metabolism
Usually 50% enzyme in heterozygotes is enough

- But in purely recessive cases

- Not enough product from enzyme (no D E)
- Toxic intermediate (too much A, B, C)
- Toxic byproduct from alternate pathway (too much F, G)

o Phenylketonuria autosomal recessive defect in phenylalanine hydroxylase (normally converts

Cystic Fibrosis - autosomal recessive disease by phenylalanine to tyrosine)
mutationsin the CTFR gene encoding the CF Common in Skandinavians
transmembrane regulator
- main defect: CHLORIDE ion transport --> high salt Fair skin no melanin b/c tyrosine required
conc in sweat and luminal secretions in respiratory Eczema
and GI tracts
- results in cardiopulmonary complications & death
Severe mental retardation
- pulmonary infections common 2/3 cannot walk or talk
- possible bronchiectasis
- possible right sided heart failure
Seizure and neurologic abnormalities
- pancreatic insufficiency super common Need to restrict phenylalanine intake not too much protein!
- infertility CHARACTERISTIC IQ drops if off diet
- advances allow for survival, but increase
frequency of liver cirrhosis PKU mothers need to follow diet during pregnancy to avoid maternal PKU in their
children
Newborns are now screened
- Autosomal dominant
o Usually one parent affected (left chi square)
o Males and females affected equally
o Males and females transmit disease equally
o 50% chance of having affected offspring
 o Unlike autosomal recessive diseases where its associated the just an enzyme, autosomal dominant
Porphyria (can't find in book)
- acute porphyria is
involved w/ nervous
system
- cutaneous porphyria
is involved w/ skin
- these are disorders
of enzymes that normally
produce PORPHYRINS and HEMEo
o Anchondroplasia I think I dont have to include pictures of the little people/dwarfs
o Marfan Syndrome
diseases are more complex & often caused by mutations in wider variety of genes:
FH
- mutation in the gene encoding the LDL receptor
- develop hypercholesterolemia as a result of
impaired transport of LDL into the cells
= FH
- while heterozygotes have elevated serum levels of
cholesterol (risk of atherosclerosis & CAD)
- HOMOzygotes have an even greater serum level
of cholesterol and risk of ischemic heart disease
- cholesterols also deposits in tendon sheaths...
- read/edit porphyria, familialTermed = xanthomas
Osteogenesis Imperfecta
Brittle bones, easily broken
Collagen I defect harder to pack mutant fibrils into high order fibers
Dentinogenesis Imperfecta type I dentinogenesis imperfecta WITH osteogenesis imperfecta
- Enamel normal, defect in dentin opalescent teeth
Dentinogenesis Imperfecta shields type II dentinogenesis imperfect W/O osteo imperfecta
- Gene map locus 4q21.3 (DSPP dentin
sialophosphoprotein)
- Opalescent dentin and teeth
- Brown-blue or opalescent brown teeth
- Bulbous shaped crown
- Narrow roots, small or obliterated root
canals, absent pulp chambers
FGF-3 (fibroblast growth factor 3) defect becomes more active premature fusion of bone
Cartilage defects
Short limbs, trident hand, prominent brow and depressed bridge of nose
Maxillary hypoplasia, anterior overbite, small foramen magnum
Homozygous mutation NOT viable
Fibrillin 1 or 2 mutation the protein that binds a structural protein
Tall, thin stature with long limbs, fingers, toes
Narrow and/or sharp face (narrow mouth with a high palate, crowded teeth)
Off-center lenses in eye ectopia lentis
Scoliosis & loose joints
Decreased elasticity of lung tissue, blood vessels, heart valves
 Prominent stretch marks due to less elasticity & fast growth
Caved-in or pushed-out breastbone (pectus carinatum, pectus excavatum) rib overgrowth
Aortic dissection most serious complication due to less flexibility aneurysms (rupture prone)
- X-linked

- X-linked Expressivity in FEMALES

- Heterozygous carriers b/c of Mozaicism
o Lyonization
o RANDOM X-INACTIVATION (like in
cocalico cats)
o NOT RANDOM if mutation fatal (like in
ornithine transcarbamylase mutation)

o Amelogenesis Imperfecta 1E X-linked form in the 14 subtypes

Defect in enamel matrix deposition (hypoplastic)

Small teeth
Color yellow brown to brown
Males thin, hard smooth enamel microdontia (appears smaller than normal)
Females Lyonization vertical furrows with diff color schemes
Non-Mendelian Genetics
Mitochondrial Inheritance (mutations in mitochondria affect oxidative phosphorylation)
- Matrilineal all your mitochondria come from your mommy, from the EGG!
- Both sexes affected
- Mitochondria have own genome
- Severity depends on number of defective mitochondria inherited (heteroplasmy)
o Leber Hereditary Optic Neuropathy
Genomic Imprinting
- Epigenetic process changes in outcome NOT DUE to DNA sequence (such as packaging)
o Maternal vs paternal inheritance of an autosome
 o Huntington disease, neurofibromatosis, myotonic dystrophies
- Prader-Willi Syndrome vs. Angelman Syndrome

- Associated with chromosome 15q11-15q13

- Paternally expressed products SNRPN, NDN
- Maternally expressed products UBE3A
- Prader-Willi Syndrome deletion on chromosome 15 from
FATHER (UBE3A expressed)
o Hypotonia, obesity, small hands, mild retardation,
hypogonadism
- Angelman Syndrome same deletion on chromosome 15 from
MOTHER (SNRPN, NDN expressd)
o Ataxic gait puppet-like, inappropriate laughter,
severe retardation, seizures

Phenotype/Genotype Correlation
- Genetic heterogeneity
o Genocopy - different gene mutation causes same disease
Familial Alzheimers, breast cancer
- Variable Expressivity
o Varying DEGREES of disease with same gene mutation
Neurofibromatosis 1 (can have variable number of caf au lait, learning, skeletal malformations,
and cardiac defects)
- Allelic variation
o Mutation in same gene causes DIFFERENT diseases
RET gene mutation can cause:
MEN2A (exon 10, 11) pheochromocytoma, MTC
MEN2B (exon 15, 16) pheochromocytoma, MTC, neuromas
Or just familial medullary thyroid carcinoma (MTC) (exon 10-15)
- Penetrance
o % of patients with inherited mutation that develop disorder meaning some people DONT get disease!
Hereditary nonpolyposis colorectal cancer
Modifier genes & environment (carcinogens) can both impact the same mutation in the
same gene (either more or less severe outcome)
Usually occurs in autosomal dominant disorders
o Non-penetrance - individual is heterozygous & DOES NOT SHOW SIGNS of
disease
Presence of a mutation in a population
- Heterozygous advantage
o People who has the heterozygous expression has a survival advantage
Heterozygous sickle cell anemia resistant to malaria
Heterozygous cystic fibrosis resistance to tuberculosis
- Founder effect
o Sudden decrease in population leaves an increase in mutant among survivals the reason why some ethnic
groups have higher rate of genetic disease (intermarriage)
Tay Sachs disease
Tri-nucleotide repeat disease
- Expansion in the # of 3 nucleotide repeats
o (Low # of repeats normal)
o (High # of repeats over threshold disease)
o Huntingtons disease, Fragile X syndrome, Kennedy disease
Multifactorial Inheritance aka polygenic (number of genes together to give a certain trait)
- Genetic but no specific gene
 - Family has higher risk than population, but not mendelian
o Compare concordance between monozygotic (identical) & dizygotic (fraternal) twins
Monozygotic/identical twins both have disease when compared to dizygotic twins
Because monozygotic genetic makeup is identical, if one has a multifactorial disease, both will
have it
o Cleft Lip/Palate 1/700
Variable expressivity varying degrees (can have cleft lip, cleft palate, or cleft lip + palate)
RARa, TGF-B3, folic acid metabolism, fetal alcohol syndrome, malnutrition
Folate & B6 decrease cleft lip
Chromosomal Abnormalities 1/200 newborn have chromosomal abnormalities
- Background info
o DNA is packed into chromosomes and consists of
Centromere key landmark that divides chromosomes into two arms

- Metacentric centromere @ middle

- Submetacentric centromere closer to one end (arms of
different sizes)
- Acrocentric centromere is basically @ the end
p petite small arm
q long arm
G-band (Giemsa stain)
- 46 chromosomes in humans
o 22 pairs of autosomes
o 1 pair of sex chromosomes

- Spectral Karyotype (SKY)

o Each chromosome labeled with unique fluorescent signature
o Pseudocolor
o Visualize chromosomal abnormalities
o Comparative genomics
o Can easily, with color differences, see translocations
Mouse treated with ionizing radiation
SKY of bone marrow cells reveals 2 translocations T(2:14), T(2:19) on page 45 in slides
- Structural abnormalities
o Deletion, duplications, insertions
Deletion/microdeletion loss of a chromosomal segment so that the pt only has one copy of
that part of the chromosome
Williams Syndrome (microdeletion) deletion of 7q11.23

o Wide mouth, full lips, small chin, puffy eyes, starburst iris
o Wide spaced, small teeth
o Thick, curly hair
o Happy disposition
o Spatial learning deficit (D of y test make a big D out of small ys, wont be
able to see the D)
But normal verbal and pleasant socially
o Cardiac valve defects supravalvular aortic stenosis
o Enamel hypoplasia
Increased risk of caries hygiene and regular dental visits required
o Translocations exchange of chromosomal segments between non-paired chromosomes
Balanced reciprocal exchange, all genetic material maintained
Not a problem for carrier
Robertsonian balanced translocation w/ 2 ACROCENTRIC chromosomes fusing
Problem in gametogenesis lead to abnormal chromosome # in offspring
Aneuploidy
o Extra chromosomes
Trisomy 21, 18, 13 (other ones result in death)
Trisomy 21 = Down Syndrome (47 chromsomes)
- Increases w/ maternal age of conception
- Leading cause of mental retardation
- Epicanthic folds and flat facial profile
- Simian Crease (connected crease on palm)
- 40% have cardiac malformations
- Increased risk of leukemia, Alzheimers

Sex chromosomes
45X to 49XXXXY are viable
45X Turners Syndrome need other X for 2ndary
sexual characteristics (female w/ male features)
o Webbed neck
o Low posterior hairline
o Widespread nipples
o Growth retardation
o Failure to dev 2ndary sex characteristics
o High arched palate
o Aortic and kidney malformations
XXY, XXXY, XXXXY Klinefelter syndrome (male w/
female features)
o Male hypogonadism, testicular atrophy,
gynecomastia
o Increased body length
o Sterility
o Mild mental impairment
XYY, XYYY normal
XXX, XXXX normal (lyonization, x-inactivation)
o Loss of chromosomes
Monosomy Turners syndrome
Unbalanced non-reciprocal exchange
Patients appear monosomic or trisomic for segments
o Isochromosomes
o Inversions
o Ring chromosomes
Intro to Immunopathology Dr. Shenker Lecture 1
- Immunopathology (in subsequent lecture, will explore:)
o Hypersensitivity disease appropriate response against foreign substances that somehow becomes
unregulated
o Autoimmune disease response against self antigen, something that should NOT occur
o Immunodeficiency disease immune system not functioning properly congenital or acquired later in life (aka HIV)
o Transplant rejection (GVH) appropriate response that is not beneficial to the patient due to organ disease
o Immunoproliferative disorders pretty much involves tumors/cancers
- Innate vs. adaptive immunity BIGGEST DIFFERENCE IS SPECIFICITY
o Innate = nonspecific that utilizes PATTERN recognition receptors (such as TLR toll-like receptors)and PAMPs
Example: capable of telling a gram-negative bacteria from gram-positive phagocytes, complements, NK cells
Mechanical, chemical and microbiological barriers neutrophils and macrophages see antigens thru TLRs
Phagocytosis
Inflammation
each cell can differentiate diff antigens; highly regulated
o Adaptive/acquired = specific that utilizes specific ANTIGEN receptors
Example: capable of differentiating between DIFFERENT gram-negative bacteria
Humoral or antibody mediated OR
Cell mediated
o However, both innate & adaptive immunity are two-edged swords knock out immune
While they are required to maintain health or you get infectious diseases, even cancer system like to trt auto
Can also cause cell injury (the underlying cause of disease) immune disase,
Unique properties of the immune response 5 features suceptible to infxn
memory is the same immune response in innate
- Memory part of the adaptive immunity and NOT innate
- Active immunity can be
o Naturally acquired previous expd
o Artifically acquired vaccine
- Passive immunity can be
o Naturally acquired from mother to
child via IgA in milk
o Artifically acquired from snake
serum only lasts for as long as antibodies stay in the
body (30 days)

looking at immunoglobulins G and M , btu we couldve looked at antigen

specific B or antigen specific T cells and wouldve been same kinetics

- Specificity & adaptivity

- The types of antibodies produced are
adaptive and evolutionary
o Secondary response to a previous
antigen has higher avidity & specificity
- Response to a new antigen will have to go
through a primary response again

- Differentiates self from non-self

o By and large should NOT attack self-antigens
 - Dichotomy two immune systems
o Antibody/immunoglobulin-mediated immunity (HUMORAL) deals with extracellular microbes
Mainly associated with plasma cells & B lymphocytes
However, do note that the two systems are interconnected
Humoral immunity requires T-cells help for activation & immunoglobulin production
o Cell-mediated immunity deals with intracellular microbes
Mainly associated with T-cells
Humoral components HUMORAL = Ig, cytokines, complements
- Immunoglobulin/antibody products of B cells

-
Functions:
o Toxin neutralization (regardless of class of Ab)
Block catalytic site and eliminate a toxins activity
o Opsonization (ONLY IgM, IgG)
Bind bacteria to form ligands for the receptors on
phagocytes facilitative phagocytosis
o Cell lysis (ONLY IgM, IgG)
Activation of complement
o Agglutination (THEORETICALLY, all can do this most common
ones are IgA, IgM due to multiple subunits, more binding sites)
Can occur anywhere in the body, but more common @
areas of exposure (lungs b/c you can inhale bacteria), facilitates elimination
o Viral neutralization
Only good for extracellular phase of viral infection
o IgG 75% of serum Ig
Activates complement
As opsonins & ADCC (antibody dependent cell cytotoxicity)
Via Fc binding to macrophages, PMN, NK cells
Crosses placenta ONLY class that can do this
o IgA 2nd most common in serum primary function = agglutination--in secretions, which is a first line of defencse so causes agglut and disposal of antigens entering
Important for mucosal immunity: found in SECRETIONS (saliva, tears, mucus)
2 Forms monomeric found in serum (blood)
o Dimeric form important in agglutination (4 binding sites)
o IgM 3rd most common in serum
Activates complement
(Some Fc binding to cells)
Pentameric form important in agglutination (10 binding sites)
The monomeric form of these = the receptors on B-cells!
o IgD low serum levels not much known about its function
Antigen receptor on some B-cells
o IgE VERY low serum levelscause massive release of histamine
Allergic reactions high in those with seasonal allergy (too high = bad = hypersensitivity)
Parasitic diseases
Fc (epsilon) binding to mast cells & basophils fc heavy chain binding
o Antibody Diversity one foreign agent can have many epitopes, how do antibodies recognize these?
VDJ recombination V (variety gene), D(diversity gene), J(joining gene) genes are segmented
genes
Meaning that each gene can have multiple copies, so the combinations are basically
endless due to the permutations
On top of VDJ recombination, mutations also contribute to diversity
Lastly, both the heavy AND light chain go through similar processes, even more possibilities
- Complement proteins in this cascade exist in PRECURSOR forms
o Functions:
Direct lysis of cells
Opsonization
Generation of biologically active peptide fragment
o Pathways
There are two pathways of complement
 Classical pathway
1. IgG, IgM bind to bacteria
2. Activates complement
3. Activates C3a, C5a acute inflammation
a. PMN chemotaxis (requires C5, 6, 7 on top of C5a)
b. Opsonization (requires C3b)
The key to activating classical complement: C3 C3b (cleavage via C3 convertase)
o C3 convertase complex that requires IgG or IgM binding to antigen
Binding causes Fc changes and subsequent complex formation with
the recruitment of C1, C2, C4
Alternative pathway
Basically the same as classical WITHOUT step 1 (immunoglobulins not needed)
The key to alternative complement is also C3b
o C3 convertase (in this case) complex including the bacteria itself along with
P, B, D proteins (on top of some pre-formed C3b)
Complement derived peptides and their activity
C3b opsonization
C3a, C5a anaphylatoxins & stimulation of lysosomal release
C5a, C5, 6, 7 chemotaxis
C6-C9 membrane attack complex
C1, 4 viral neutralization
- Cytokines
o Mediators of cell-mediated immunity; also required for humoral immunity
o Produced by multiple cell types
o Act in three ways, autocrine, paracrine, endocrine
o Effects mediated by binding to specific receptors
o Effects are pleiotropic (overlaps, one cytokine multiple effects)
o Functions: (Shenker said we dont have to know the specific cytokines red ones = important ones?)
Cytokines are NOT ANTIGENIC SPECIFIC!!!
Mediate nonspecific inflammatory responses (IL-1, TNF-a, TNF-B, IFN-gamma, IL-6)
Regulate lymphocyte activation, growth, differentiation
Upregulation (IL-2, 4, 5, 12, 15) & Downregulation (TGF-B, IL-10)
Affect chemotaxis = chemokines
Stimulate hematopoiesis (CSF)
 Cellular Components
- Macrophages
o NO ANTIGEN SPECIFIC RECEPTORS but
TLR toll-like receptors
Class II MHC
o Functions:
Immune induction (antigen processing & presentation to T-cells in context of MHC II)
Immune regulation (cytokines) mostly pro-inflammatory cytokines (Shenker said he wont test
us on this, but no guarantee that other professors wont)
IL-1(B) activates vascular endothelium, activates lymphocytes
o Local tissue destruction, increases access of effector cells
o Leads to fever & production of IL-6
TNF-a activates vascular endothelium & permeability
o Leads to increased entry of IgG, complement
o Increased cells to tissues and increased fluid drainage to lymph node
o Leads to fever & metabolites shock
IL-6 lymphocyte activation, antibody production
o Leads to fever, acute-phase protein production
CXCL8 chemotactic factor (recruits PMN, basophils, T-cells)
IL-12 activates NK cells, induces differentiation of CD4 T cells TH1 cells
Immune effector cell (can respond to Ab & cytokines)
o Precursors are from bone marrow
Differentiation

- Microglia (CNS)
- Kupffer cells (liver)
- Alveolar macrophages (lung)
- Osteoclasts (bone)
- Activated macrophage (see pic)

- Dendritic Cells subtype of macrophages that are really good @ processing & presenting antigens to lymphocytes

o Langerhans type found at points of microbial entry (under epidermis,

interstitial of tissues)
o Follicular found in spleen, lymph nodes (filter areas)
o Functions:
Serve as APC (antigen presenting cell)
Express TLR (toll-like receptor)
Express MHC II
- Note that the dendritic cells mature and present antigen to nave T cells in
LYMPHOID tissue!
- Histocompatibility Molecules
MHC 1 has 3 loci o MHC (major histocompatibility) is the GENE; HLA (human leukocyte antigen) is the PROTEIN
- HLA A, B, C Originally identified as antigens responsible for graft rejection
Principle role of T-cell activation
- codominant expression of 6 proteins
Polymorphic no two people have same MHC (thus rejection)
MHC 2 has 1 loci Types (both types have clefts that can bind to antigenic epitopes)
- HLA D MHC Class I found in all nucleated cells and platelets
- codominant expression of 6 proteins also o Bind peptides derived from proteins synthesized IN CELLS such as intracellular
-------------------------------------------------------- viral proteins
Polymorphic: there are craploads of MHC MHC Class II found in professional APCs (antigen presenting cells)
gene forms, but only 6 ultimately get expressed o Bind, process, and present exogenous /extracellular substances
- so it's basically impossible for two humans to have the same set of MHCs
- we are all DIFFERENT and our immune responses respond DIFFERENTLY
- this is the basis for some autoimmune diseases that will be explored later
 - Lymphocytes (T and B cells)
o ALL mature lymphocytes express antigen SPECIFIC receptors
o 2 phases of development
Antigen independent (in bone marrow for B-cells, thymus for T-cells)
Antigen dependent clonal activation/expansion (in 2ndary lymphoid tissue such as lymph
nodes in the spleen & tonsils)
o Circulate between blood and lymphoid tissue
- T-cells (note TCR (T-Cell Receptors) are also rearranged like antibodies via segmented genes for diversity)
o alpha-beta TCR these recognize antigen complexed to MHC
The specificity of TCRs come from the alpha and beta chains
TCRs are stabilized by CD3 (all T-cells are CD3+)
CD4 bind to MHC II these are the master regulator of immune response (3 subtypes)

REMEMBER: - TH1 facilitates cell-mediated immunity/DTH (delayed-

Alpha + Beta type hypersensitivity)
subunits are o Induced via IFN-gamma, IL-12
- TH2 facilitates humoral immunity
the source
o Induced via IL-4
of SPECIFICITY!! - TH17 facilitates inflammation
o Induced via TGF-B, IL-6, IL-1, IL-23
- CD4 binding to MHC II requires TWO SIGNALS (to avoid
attacking self)
o 1. TCR to antigen (stabilized by CD4)
o 2. CD28 binding

CD8 bind to MHC I thus ANY cell can activate CD8 T-cells

- T-regulatory suppressors/brakes of the immune

response
- CTL cytotoxic T cell
- CD8 binding to MHC I (probably) requires more than one
signal (not discovered yet)
o Important note: most of these are CTL will
KILL the antigen present cells

o gamma-delta TCR sentinels that protect against microbes ; ARE NOT ANTIGEN SPECIFIC
Recognize peptides, lipids, NO REQUIREMENT FOR MHC
Found @ epithelial and mucosal surfaces
- B-cells (note the lymphocyte antigen specific receptors on these are mostly IgM, some IgD)
o Mainly becomes:
Memory B-cells
Plasma cells produce antibodies
Can also go through a process called class switching
 o From production of IgM to production of IgG/IgA/IgB with the SAME
specificity (this requires cytokines from CD4+ T-cells)

- Natural Killer Cells/LGL (large granular lymphocytes these granules are preformed)

o Share lymphocyte lineage

o No TCR not antigen specific!
o 10-15% of blood lymphocyte part of immune SURVEILLANCE
o Part of the innate response
o Cytotoxic (induces apoptosis) via
Direct contact
Antibody (ADCC) antibody bind antigen, NK bind to antibody
(via Fc)
o These are activated by stress-induced proteins, viral proteins
o These are inhibited by MHC class I molecules!!!
o These release perforin (bind to target cell and forms pores for) granzyme to enter & activate apoptosis
Lymphoid Tissue provides environment for lymphocyte maturation, immune responses, and network for circulation
- Primary lymphoid tissue antigen INDEPENDENT maturation
o Thymus, bone marrow
- Secondary lymphoid tissue antigen DEPENDENT maturation
o Encapsulated lymph nodes
o Non-encapsulated diffuse & solitary mucosa associated lymphoid tissue (MALT), GALT (gastric-associated),
BALT (bronchia-associated)

- Acute inflammation exudate lymphatic drainage = contact w/ antigen

(for antigen DEPENDENT maturation)
- B cells: reside and proliferate in GERMINAL centers
- T cells: reside and proliferate in pericortical areas (everywhere else)
- Entrance = afferent lymph vessels
- Exit = efferent lymph vessels (products of immune responses leave here)
o Some products leave via blood vessels as well
Stimulators of the Immune system
- Antigens proteins and glycoproteins are better antigens, but almost anything can induce immune response
- Haptens substances too small to induce response by themselves but are reactive & capable of binding to host
proteins to induce immune response
- Adjuvants in vaccines
o Aluminum hydroxide, aluminum phosphate, calcium phosphate
o These do two things
1. Induce inflammation so they can actually get to lymph nodes to induce response
2. Keep antigens from being eliminated (prolong response to produce immunity)
- Polyclonal cell activators similar to antigens
o Antigens activate SPECIFIC B, T cells
o Polyclonal cell activators TRICK immune system and bypass specificity, activating a wide array of cells
Results in lots of cytokines loss of control disease state
- Superantigens- the opposite of polyclonal cell activators
o These ARE antigens that interact w/ HLA
o They DO NOT allow APC to present the antigen (inhibition of secondary signal CD28)
So lymphocytes activates but DIES by apoptosis
Knocking out part of immune system so you can NEVER respond to those antigens again
Regulation of the Immune response
- Intrinsic
o Antigen elimination
o T-suppressor cells produce anti-inflammatory cytokines
o T-helper cells
o MHC controls WHAT you can respond to
o Macrophages controls induction of response
o Negative feedback
o Anti-idiotypes every B, T cell receptor has a unique sequence and can themselves be antigens
Antibodies bind to these to DAMPEN response
- Extrinsic
o Drugs interference with proliferation, metabolism will interfere with immune response
o Hormones
o Nutrition malnourishment hard pressed to mount immune response due to metabolic demand
o CNS - stress can affect immune response
o Microbial factors can produce substances that can interfere with immune system such as superantigens
need confirmation:
type 1 - mast cell
type 2 - macrophages? neutrophils?
type 3 - neutrophils
type 4 - not neutrophils, think TB
Hypersensitivity Lecture 1 Dr. Shenker Lecture 2
- These are response that may be detrimental, particularly when exaggerated or against otherwise innocuous
antigens
- Classification now based on the immune mechanisms that mediate the damage/disease to the host
o Immediate or antibody mediated hypersensitivity
Type I anaphylaxis (IgE)
Type II immune cytotoxic reactions (IgG, IgM antigen cell/tissue bound)
Type III immune complex (IgG, IgM antigen SOLUBLE)
ALL 3 involve Ab
o DIFFER according to class of Ab involved, location of Ag, and mechanism
of tissue injury
o Cell-mediated hypersensitivity
Type IV delayed type hypersensitivity (DTH) or T-cell mediated
Involves T-cells, macrophages, lymphokines/cytokines
Type 1 Hypersensitivity Anaphylactic Reactions (involves mast cells --> histamine)
- Involve contact of antigen w/ antibody bound to membrane Fc receptors of tissue mast cells or circulating
basophils
- Results in cellular degranulation & release of inflammatory mediators
o May be TARGETED to organs, such as allergic rhinitis (nasal mucosa), conjunctivitis (ocular mucosa),
dermatitis (skin dermis), generalized (systemic), fatal (anaphylactic shock)
- Terminology
o Atopy describes individuals with increased production of IgE (1000x more than normal). Tend to
suffer from allergic diseases such as asthma, eczema, hay fever, uticaria, food allergy
o Reaginic antibody antibodies (IgE) responsible for allergic responses
o Allergen antigens that induce allergic (hyper IgE) responses

- Sequence of events
1. Requires an initial exposure to antigen
a. Sensitization then occurs
i. Sensitization refers to antibodies (IgE, some IgG) binding to Fc receptors on mast cells
and basophils
1. These antibodies are referred to as homocytotropic
ii. Note that this process does nothing - no cells are injured @ this point
2. Second exposure to antigen
a. These sensitized cells are triggered via Ag-Ab reaction @ the surface
b. Anaphylactic shock occurs @ RE-exposure to an Ag that one is already sensitized
i. (Ag binds to IgE on mast cells)
ii. As a result, series of events are set in motion such as the EXPLOSIVE release of chemical
mediators responsible for clinical signs and symptoms of anaphylaxis
1. Mediators of Anaphylaxis
a. Primary mediators
 i. Biogenic amines: histamine increases vascular
permeability, vasodilation, bronchospasm, increased
secretion of mucus from glands
ii. Enzymes (proteases, hydrolases) cause tissue damage,
generate kinins & activate complement (contribute to
mast cell degranulation)
iii. Proteoglycans (heparin) serve to package & store other
mediators
b. Secondary mediators
i. Lipid derived
1. Leukotrienes potent vasoactive &
SPASMogenic agent, also chemotactic for
neutrophils
a. ECF-A (EOSINOPHIL chemotactic
factor) self explanatory
2. Prostaglandin bronchospasm & mucus
secretion
3. Platelet activating factor platelet aggregation,
release of histamine & bronchospasm
ii. Cytokines participate in late phase response

1. There are two kinetics for Type I

a. Immediate (rapid)
b. Late-phase (in a few hours)
2. The clinical manifestation depends on WHERE/how antigen is deposited
o Locally
Atopic dermatitis (exposure @ skin): hives, urticarial,
angioedema
Allergic rhinitis /hay fever (exposure @ inhalation)
Conjunctivitis
Allergic gastroenteritis (exposure @ ingestion)
Asthma (also exposure @ inhalation)
o Systemic
Anaphylaxis (exposure spread via blood)
o Common allergens
Proteins (foreign serum, vaccine)
Plant pollens (rye grass, ragweed, timothy grass, birch trees)
Drugs (penicillin, sulfonamides, local anesthetics, salicylates)
Foods (nuts, seafood, eggs, peas, beans, milk)
Insects (bee venom, wasp venom, ant venom, cockroach calyx,
dust mites)
Mold spores, animal hair/dander, latex
- Summary in a few words for Type I hypersensitivity anaphylaxis
o Mechanism: hyper IgE production mast cells mediator release
o Lesion due to: vascular dilation, vascular permeability & edema, smooth muscle contraction, mucus
production
Clinical Examples of Anaphylaxis
- Atopic dermatitis

o Urticaria & angioedema common disorder

o Antigens pollens, foods, drugs, insect, venom (basically same in most cases of Type I)
o Urticaria (wheals/hives) pruritic (itchiness), slightly elevated areas on the skin
Redder or paler than surrounding skin (basically edema of SUPERFICAL dermis)
Lesions appear rapidly and fade within hours (until antigen elimination)
o Angioedema closely related, DEEPER edema of both dermis & subcutaneous fat
Seen in lips, tongue, eyes
DO NOT CONFUSE WITH HEREDITARY ANGIONEUROTIC EDEMA (a C1 inhibitor deficiency)
- Allergic Rhinitis/conjunctivitis (hay fever)

o Affects 20% of population

o Antigens pollens, fungi, animals, dust mites (same as most castes)
o Morphologic changes
Mucosal edema, redness (vasodilation), mucus secretions, nerve irritation
Secretions contains NUMEROUS EOSINOPHILS
Nasal polyps may form in severe chronic cases
o Also may cause serous otitis media
o These may lead to symptoms of congestion, sneezing, pruritus, rhinorrhea, lacrimation
o May be seasonal (pollens)
o May be perennial (dust mite, animal dander)
o May be occupational (bakers yeast)
- Allergic gastroenteritis reactions to ingested allergens (within minutes to an hour)
o Perioral erythema, lip swelling, oral irritation, tongue swelling, pharynx swelling
Nausea, vomiting may lead to anaphylaxis
- Bronchial asthma (extrinsic) can have a number of causes, such as Type I hypersensitivity (more pics in lec pdf)
o Most common type of asthma
o Antigens (same again): environmental antigens, dusts, pollens, animal danders, foods
o Hyper-reactive airways leading to bronchoconstriction
o Morphologic changes
Overdistended lungs, occlusion of bronchioles with thick mucus plugs (from secretions)
Edema (due to vasodilation), increased submucosal glands, hypertrophy of bronchial wall
muscle, eosinophils
You will see neutrophils & macrophages b/c asthma is a chronic disease but
neutrophils & macrophages DO NOT CONTRIBUTE to disease
 o Pts present with wheezy dyspnea or chronic non-productive cough/shortness of breath on exercise

- Systemic Anaphylaxis characterized by widespread EDEMA, RESPIRATORY DISTRESS, VASCULAR SHOCK

o Itching, hives, skin erythema are rapid, INITIAL symptoms
o Contraction of respiratory bronchioles respiratory distress
o Laryngeal edema hoarseness (b/c vocal cords are located here), possibly obstruction
o GI vomiting, abdominal cramps, diarrhea
o Patient may go into shock within 1 hr b/c of HYPOtension (vasodiilatory actions of histamine)
o Below is a table summarizing the above

Summary of manifestations
Urticaria & angioedema
Laryngeal edema
Dyspnea and wheezing
Dizziness and hypotension
GI symptoms
Rhinitis

Cardiovascular!!
Tachycardia
Bradycardia
Hypotension/shock
Arrhythmias
Chest pain
 - Anaphylaxis may also induce hyperinflation of the lungs
o Capable of inhaling but CANNOT EXHALE (filled with AIR, not fluid)
<--large alveolar
spaces
<--stretched alveolar
septa
<--would require
normal lung for
comparison

- Treatment
o Acute emergency: remember ABC
Cricothyroidotomy intubate @ cricothyroid MEMBRANE
o Pharmacologic
Epinephrine (drug of choice for acute emergencies) IM
Vasoconstriction (a1) reverse histamines dilation
Bronchodilation & blockage of degranulation (b2)
Theophylline(a methyl xanthine) for bronchodilation
The goal of these two drugs increase cAMP
Adenylate cyclase (AC) UPregulated by epinephrine = more cAMP! (more synthesis)
Phosphodiesterase (PDE) INHIBITED by theophylline = more cAMP! (less breakdown)

Corticosteroids (??-reccurent for management purposes, NOT FOR EMERGENCIES)

Antihistamines (after stabilization NOT FOR EMERGENCIES)
o Prevention
Avoid antigen (take complete history!)
Avoid parenteral (administration other than oral) of drugs (especially penicillin)
Cromolyn sodium
Hyposensitization/allergen immunotherapy/desensitization making body more tolerant
Inject small suballergic doses of Ag
To generate blocking antibodies
To generate T-suppressor cells
Administer monovalent Ag
- Supplemental information (via lecture notes)
o Eosinophils in anaphylaxis
Localize & terminate rxn
Have Fc receptors for IgE, IgG possibly aid in removal of Ag
o ADCC via IgE
o Protective effects of anaphylaxis
To parasites patients with parasitic infections in GI have elevated IgE that develop diarrhea
as a result, help in clearing GI of parasites
Type 2 Hypersensitivity Immune Cytotoxic Reactions/Ab-Dependent Cytotoxic Reaction
 - Caused by IgG or IgM
o Reactions with antigens that is cell or tissue BOUND
o Once Ag and Ab bound on the surface of a cell the cell is destroyed via 3 mechanisms
Activation of complement cell lysis
Phagocytosis with or without complement
ADCC (antibody dependent cell mediated cytotoxicity) results in either lysis or inactivation
via Fc receptors on mostly NK cells
Clinical Examples of Immune Cytotoxic Reactions
- Mismatched blood transfusion

- Mechanism antibody mediated agglutination and lysis

of RBC
- Clinical manifestations
o Mild fever, chills
o Severe acute kidney failure or complete
vascular collapse and death
o Disseminated intravascular coagulation (DIC)
small clots consuming coagulation proteins so that normal coagulation
cannot happen abnormal bleeding

- Hemolytic anemia (not mentioned in lecture, but in online notes)

o Mechanism - increased rate of destruction of RBC by antibody or complement
o Clinical manifestations
Warm type associated with IgG
Extravascular hemolysis in the spleen
Cell lysis and agglutination in peripheral blood
Erythrophagocytosis of sensitized RBC in bone marrow
Cold type (below 32C) associated with IgM9
Agglutination in peripheral blood
o Increases viscosity Raynauds phenomenon
Severe Raynauds @ extremities may cause necrosis
At higher temperatures, intravascular hemolysis due to complement activation
- Hemolytic Disease of the Newborn (Erythroblastosis fetalis)

- Mechanism mothers antibody (anti D)

and complement mediated damage to fetal RBC
- This can only happen with RH (-) mothers
with RH (+) fetuses
- First pregnancy = sensitization, but baby
will be normal
- Second pregnancy = hypersensitive
response, baby will display clinical symptoms below
- Clinical manifestations
o Hemolysis increased
bilirubin (product of heme breakdown): jaundice, kernicterus
(CNS damage due to bilirubin)
o Profound anemia: heart failure,
enlarged liver/spleen, generalized swelling and respiratory
distress, hydrops fetalis (accumulation of fluid in at least 2
fetal compartments) pictures on next page
o Treatment (before mixing of fetal and maternal blood)
Rhogam consists of IgG antibodies capable of crossing placenta
These are antibodies against anti-D (anti-RhD) that mediates damage to fetal RBC
Transfusion completely replace fetal blood
o Treatment (after mixing of fetal and maternal blood (?)) not sure
Phototherapy degrade bilirubin
 o This is a slide of liver cells trying to help out bone marrow in producing more RBC due to profound
anemia
o Thus, these cells seen in the slide ARE NOT inflammatory cells, but RBCs
- Autoimmune Thrombocytopenia Purpura (not mentioned in lecture, but in online notes)
o Characteristic feature low platelet count + presence of megakaryocytes in bone marrow
o Clinical manifestations cutaneous signs of thrombocytopenia
Petechiae, purpura, mucosal bleeding
Major problem risk of bleeding into vital organs like the brain
Hypersensitivity Lecture 2 Dr. Shenker Lecture 3
Type 3 Hypersensitivity Immune Complex Mediated Hypersensitivity (Dr. Ali - three rhymes with free = free circulating complex)
- Caused by IgG or IgM (capable of complement
activation)
o Reactions with antigens that are
SOLUBLE resulting immune complex become
deposited in vessels or extracellular space
- This injury is not caused by complexes
themselves but rather due to host (complement
activation) which results in attraction & accumulation of
PMNs
- Infectious agents
- Bacteria(strep, T. pallidum): glomerulonephritis
- Virus(hep B): polyarteritis nodosa
- Fungi(actinomycetes): Farmers lung
- Drugs of chemicals
o Foreign serum serum sickness such
as GMN, pneumonitis
o Heroin glomerulonephritis

- Immune Complex Formation

- 3 types of complexes that can form that

depends on the amount of antigen in the body
1. Formed at Ag-Ab equivalence large
insoluble complexes that precipitate out & cleared via
phagocytosis
2. Formed in Ab excess small soluble
complexes
3. Formed in Ag excess small soluble
complexes
- The small and soluble ones are what causes
Type III hypersensitivity

Pathogenesis of Systemic Immune Complex Disease

Serum Sickness in cases such as in the elimination of snake venom
- Pathogenesis
o Due to immune complex formation
These soluble and circulating complexes localize in areas of turbulent flow (bifurcations) & areas
of fenestration (filtration tissues such as kidneys)
o Histopathology: necrosis/necrotizing vasculitis, fibrinoid necrosis, microthrombi, ischemia
- Clinical signs and symptoms
o Skin: macular popular (left) or purpuric lesionshemorage is cause of redness
o Joints: pain, swelling
o Renal: protein and blood in urinedestruciton of glomeruli
o Fever

after hemmorage in these diseases, antigens in the blood so its a multiorgan disease usually
 - Summary of sequence (FOLLOW THE FIRST PICTURE IN THIS LECTURE)
- Formation & localization of Ag-Ab complexes (soluble ones) give rise to complement and platlet aggregation

o Fixation & activation of complement (classical)

Chemotactic C5a attracts neutrophils
Damage to platelets and anaphylatoxin generation (C3a, C5a)
vasculitis is classic presentation Release to vasoactive amines vascular permeability increase edema
o The edema causes localization of complexes in vessel walls further complement & chemotaxis
PMN infiltration release of lysosomal enzymes b/c of frustrated phagocytosis
Damage to adjacent cells and tissues neutrophils are the CULPRIT
o Platelet aggregation (along with activation of Hageman factor) further contributes to damage by causing
ischemia form microthrombi and potentially lead to infart
Hageman factor can also activate kinins, allows for more vasodilation and edema, which allows
for further PMN deposition inside vascular walls

NOTE
HALLMARK
IS VASCULITIS
bc neutrophil relasing
lysozymes

- This summary of sequence also happens in the kidney (such as poststrep glomerulonephritis see below)

bc protein get pushed to sides of BV and blood cant be transported

no cuffing like in inflammation

 - Again, this summary of sequence can also happen in the lungs more involved with alveolar macrophages (such as
hypersensitivity pneumonitis see below)

- Immunofluorescence (left = kidney, right = lung)

c3b
or IgG can be
stained and would
give positive
reasing here
if flurochrome is on it

lumpy bumpy appearance

Irregularities b/c complexes are randomly deposited

- Immunofluorescence works by having an Ab to bind the Ag of interest (in this case, the soluble Ab-Ag complexes) primary immunoassay
flurochrome on Ab or on Ag o THEN have ANOTHER Ab (fixed with fluorochrome) bind to the new complex Ab-(Ab-Ag) from above secondary immunoassay
o Also note that we dont have to stain for soluble Ab-Ag complex secnodary: an antibody that binds to the
We can stain for C3b, marker for complement activation antibody that is bound to the antigen-can be used to detect autoantibodies
present in the serum
to detect for formation of immune complex, antigen could be C3b or Ig itself
Note that all these reactions are the same, with the only difference being the SITE
Arthus Reaction - when Type III Hypersensitivity happens in the skin @ site of injection
f pt get injection of serum (a drug) and they were already immune to that serum (had antibodies to it), they will develop immune
complexes-get
local vasculitis and necrosis at site of injection

see damage to the BV

not much damage in epi

o Basically the same reaction

Immune complex formation w/ antibody that has diffused out of capillaries
Form close to site of injection
Activation of complement & release of inflammatory mediators
Eventually PMN release of enzymes vasculitis
Platelets accumulate vessel occlusion
 Treatment:
Antibiotics to eliminate residual
bacteria
Anti-hypertensive meds/diuretics
to control edema and HTN
Low salt to minimize edema and
HTN
Most cases resolve with
conservative care
antigens
Poststreptococcal glomerulonephritis via types 12, 4, 1 group A B-hemolytic streptococci
- Pathogenesis 1-4 weeks following infection of pharynx or skin (impetigo) occurs when disease is subsiding, only residual Ag left
o Immune complex mediated (high Ab titers = Ab excess when most bacterial debris already eliminated)
o Hypercellularity of glomerulus kidney show granular immunofluorescence can see distortion and destruction
- Clinical manifestations hematuria, red cell casts, proteinuria, mild hypertension, oliguria, malaise, fever
because perfusion of kidney is dropping, so GFR drops, and kidney always responds to drop
o Leads to necrosis of glomerulus is GFR by raisingCO
o See pictures above of kidney/glomerulus
Hypersensitivity pneumonitidies extrinsic allergic alveolitis (where the antigen is inhaled) involved with alveolar
macrophages rather than PMNs
because this antigen is aerosol, Signs and symptoms: Farmer's Lung
while it is soluble, it wont go Flu like syndrome (fever,
into the blood, so it'll only affect
- Farmers lung (Micropolyspora faeni) chills, malaise, cought, chest Pathoagenesis:
the - Pigeon breeders lung (Droppings) tightntess, dyspnea IgG mediated
lung and no other organs (like Develops within hours of Complement activation
skin or kidney) - Humidifier/AC pneumonitis (Thermophilic actinomycetes) exposoure to antigen on vessel walls in lungs
antigen is inhaled, immune Symptoms resolve within 12 Stimulation of alveolar
complexes form in alveolar
- Mushroom pickers lung (M. faeni) hrs to several days following macrophaes to release
space and activate complement - Detergent workers lung (Bacillus subtilus enzyme) removal of trigger chemotactic factors for
which Recurs with re-exposure PMNs (IL-8)
brings in MACROPHAGES, o See pictures above of lungs/alveolar septa Treatment: antigen avoidance -release enzymes that
which cause destruction in and corticosteroid therapy destroy the lungs
lungs
Type 4 Hypersensitivity Delay Type Hypersensitivity (DTH)
- This step is CELL-MEDIATED as opposed to the first 3 types (antibody mediated)
o Involves sensitized T-cells, macrophages, lymphocyte, NOT MEDIATED BY PMNS/NEUTROPHILS
Also involves cytokines , proinflamm mediatiors, and macrophages (activated via TH1 (activated by cytokines) secretion
- 2 main forms we are going to talk about of IFN gamma
o Contact Dermatitis classic ex created by hapten--form neoantigen when in cutaneous route in body
granuloma wont form without T cells
or if no cytokines o Persistent Intracellular Infection (viral, bacterial)
o Although graft rejection falls within this category, we are going to explore this later
Contact Dermatitis
1. Usually with small molecular weight haptens or metal ions that can diffuse into epidermis, bind to skin proteins,
and create neoantigens (neoantigen can then prime or sensitize individual to a second exposure)
a. Haptens can include detergents/soaps, cleaning products, cosmetics/makeup, deodorant, clothing/shoes,
formaldehyde/other chemicals, rubber/latex, metals (nickel), jewelry, perfume/fragrances, weeds and
plants (poison ivy/oak), medicinal lotions
2. These neoantigens are taken up by dendritic cells of the skin (Langerhans cells), migrate into dermis, enter
lymphatics to lymph nodes where they present antigen to T-helper cells (CD4+) TH1 DERIVED CYTOKINE ACTIVATE MACROPHAGES = KEY TO DTH
3. The activation of T-helper cells (CD4+) results in generation of effector T cells (TH1, TH17), CTL (cytotoxic release proteases RESP BURST
also inc inflamm mediators
lymphocytes), and memory cells also activate macrophages via interferon-gamma (IFN-gamma) IL-1, IL6, TNF
a. These will emigrate back into blood @ arrive @ site of hapten deposition after clonal selection can happen over 2 exposures or 1 long one
takes 48 hrs from b. Histologically, will see a lot of T-cells around vessels (CUFFING, NOT vasculitis)
when they arrive
to once they are 4. The CD4+ T-cells that arrive back @ the site will have to be activated by the dendritic cell via antigen presentation
activated and move
where antigen is
a. The time for activation + time for traveling to site is what makes this a DELAYED response memory T cells go to epidermis at site of contact
bc BV are in the dermis
5. The activated T-cells then make cytokines that attracts macrophages TNF-A is KEY CYTOKINE
THIS IS A VERY o These will cause vesiculated & edematous lesions
SPECIFIC RXN
BUT ONCE YOU o Persistence causes lesion to become indurated slough off (elimination of Ag)
wet, weeping look
GET CYTOKINES - Clinical signs and symptoms (pictures of rash in lecture slides, pretty obvious so not going to include)
AND MACROPHAGES often refurred to as papular,
IT LOSES SPECIFICCITY o Skin lesion or rash at site of exposure vesicular reaction
--DRIVEN BY TH1 CD4 cells
Itching/pruritus, erythema papula are little raised areas on the
key to this reaction is the recruitment of
skin, usually are solid
chemokines recruit macrophages Tenderness of skin in exposed area vesicles (viral) and bulla macrophages, which release proteases and
to site of action inflammatory cytokines that
Papules, vesicles, bullae (blisters) (immunologic reactions) are fluid
filled blisters create a respiratory burst (O2 used by
local tissue descrution and inc
adhesion molec are TNF alpha and TNF B
May involve oozing, draining, or crusting tend to be oozing or draining macrophages for NADPH and making
ROS)-since this is causing injury and
may blister off and ulcerate
May become indurated, thickened, scaly, raw because blisters are full of cells, not is NOT A PROTECTIVE RESPONSE-its
DTH. if it was killing things that were harming
o Microscopically just exudate, they will thicken and
harden the body, it would be cell
Epidermal edema due to attachment breakdown mediated immunity
REACTION IS THE SAME FOR IMMUNITY
Spongiosis development followed by papules/vesicles/bullae/blisters AND DTH
Will then eventually slough off, eliminating antigen in the process
Pictures of microscopic sections are on the next page

ype 4 is "delayed" because sensitization occurs just like any other, exposed to antigen and you get a cellular immune response, and the
subsequent interaction with antigen is with MEMORY cells-these cells have to be reactivated on site (where they encounter the antigen) -this takes
a few days (as opposed to antibodies which are activated right away)
TB test-if you tested positive, it takes a few days to see the lesion-this is DTH

cytokine therapy is becoming common-either to cause a response or using analogs to dampen a response
there is typical immune response to the antigen-its taken up by macrophages/APC, its broken down and then presented on the surface on MHC2,
this activates CD4 cells (Th1 cells in particular), these create cytokines that activate other T cells and macrophages, recruit macrophages and
superactivate them
 everyone does not react to poison ivy-how you react/what you react to is governed by MHC-MHC is four loci in your genome, MHC1 are ABC, MHC
two ways tissues will be destroyed: 1. activation of CD4 cells, 2 is HLAD, inherited as one haplotype (inhert all the loci together) from mom and one from dad-and both are expressed. genomic pool is polymorphic
especially TH1 class, which produce cytokines that for these loci, there are dozens of genes we can inherit, so none of us are antigenically identical. the MHCs make these antigen pits that tend to bind
recruit inflammatory cells (neutrophils and macrophages-but certain antigens and not others-so you could inherit an antigen pit tht doesnt bind the neoantigen created by poison ivy that well, so you dont get a
mostly macrophages in this reaction), and the reaction
macrophages cause tissue injuries by releasing their if you've never been exposed to catechol before, its going to take 7-10 days to respond, and during that time the dendritic cell has processed the
lysosomal enzymes antigen and releases some singnals that cause very minor changes to vascular permeability, but not much else happens-and if you didnt have long
contact with the poison ivy, by the time the T cells are made 7-10 days later, the epithelium that contacted the poison ivy probably sloughed off so
second mechanism of tissue injury: cytotoxic the antigen isnt there any more-so nothing happens during 1st exposure
(CD8) T cells-antigen specific, they the second time, you are sensitized and have memory cells, so they go to the site of exposure very quickly
interact with antigen synthesized by the target cell contact dermatitis is primarily CD4 TH1, cytotoxic T cells dont contribute that much
and presented in context of MHC1
(instead of antigen presented on MHC2 of stained section for
APC) -CD8 then makes mediators like presence of T cells-al the
perforators and granzymes, which then kill the circles are T
host cell cells, can see that they
are cuffing the BV and
HAPTENS are usually plant derived moving into
we develop vesicles and papules, lesion is red and has fluid filled vessicles which are called spongiotic the epidermis
vesicles-there is edema in the
epidermis
reaction starts because T cells arrive at site in the dermis, first thing you'll see, as the T cells come in, they
surround the blood vesselsperivascular cuffing-BVs are NOT damaged (unlike type 3 HS). eventually cells there are inflammatory
accumulate into epidermis, and you start to see cells-are round
epidermal edema-can see space between epidermal cells-this is called spongiosis-cells are starting to seperate cellsmacrophages and
we start to develop fluid filled vesicle and as disease progresses, this vesicle gets larger lymphocytes, not
neutrophils

vesicles eventually coalesce,

forming larger vesicles
these are irritation, isn't life
threatening, but you lose the
epidermis

can become life threatening

because when the antigen is
widespread, immune system is
going to keep
working till it gets rid of it, no
matter the damage it does to the
host
this damage was done by a drug
that accumulates in subcutaneous
drugs, epithelium kept sloughing
off, and this makes pts
susceptible to secondary
infection-that's why you dont
scratch
this pt is also at risk for
dehydration
aka persistent intracellular infection
DTH Associated with Chronic Infection (such as TB, but can be viral, bacterial, fungal, protozoa)
- Pathogenesis of TB (caused by Mycobacterium Tuberculosis that generally involves lungs but may affect any organ)

1. Upon inhalation, TB is taken up by alveolar macrophages, but they are resistant to killing due to their complex
lipid walls
2. Because they can survive in macrophages, they proliferate in macrophages
a. Will eventually burst out and release contents, taken up by even more macrophages, cyclic nature
3. Failure of bacterial elimination causes sensitization of CD4+ T cells

leprosy is a related bacterium that causes a related disease with skin lesions
involves T cells activated by MHC on APCs-NOT a neoantigen, its an actual bacterium being displayed-activates TH1 CD4 cells, which make
cytokines that lead to recruitment and activation of macrophages and other round cells-cytotoxic T cells can also play a role in this
T cells usually get rid of intracellular bacteria, but we can't get rid of this one, and so it becomes a DTH-same mechanism that usually causes
immunity is causing DTH instead
 a. As soon as this happens, you are positive for TB (doesnt mean there is an active infection, just means
that you have been exposed before and mounted an immune response)
b. BCG attenuated form of TB used as vaccine in some countries will also give you positive reading
4. Effector T cells are mobilized (TH1) and produce cytokines (IFN-gamma) to activate macrophages & recruit
other crap
a. There are also tests for TB that measures IFN-gamma such as the QuantiFERON-TB test
5. Langhans giant cells, B lymphocytes, T lymphocytes, macrophages, epitheloid cells (superactivated
macrophages), fibroblast (collagen production) all come together to form granuloma or tubercles
a. MAY see SOME PMNs, but this phenomenon is NOT CAUSED BY PMNs
o Outcomes of infection (battle between host and invader) depends on
Number of organisms present
Ability of these organisms to grow & prevent being killed (virulence factors)
Ability of macrophages to kill

- Granuloma/tubercle double edged sword hallmark of this disease is formation of granuloma, which
o GOOD walling infection off = resistance to disease forms by cytokines from CD4 cells, macrophages and
persistance of bacteria-serves to
o BAD caseation/caseous necrosis - will never be lung tissue again/loss of function wall of infection-but, when this forms in the lung, it forms
- Know that hard tubercles bacteria is alive but LATENT instead of parenchymal tissue, so you dont have normal
alveoli-hurts the host
- Know that soft tubercles have undergone NECROSIS
- Clinical signs and symptoms
o A bad cough that lasts 3 weeks or longer, weight loss, coughing up blood or mucus, weakness or fatigue,
fever, chills
- Treatment
Type IV Hypersensiivity: Tuberculosis
o Antibiotics: rifampin or isoniazid Etiology: M. tuberculosis hominis
o Although drug resistant strains a bigger problem now Pathogenesis: DTH leading to
formation of granulomas (tubercles);
initially involves lung, but other
tissues may be affected
Signs and symptoms:
A bad cough that lasts 3 weeks or
longer, weight loss, coughing up
blood or mucus, weakness or fatigue,
fever and chills
Tx: antibiotics (e.g.
rifampin/isoniazid), drug resistant
strains

can use rifpam but there are resistive strains

can spread thru conjunctiva, inhalation, abrasion
 - Ghon complex - The lesions consist of a calcified focus of infection near the hilar area and an associated lymph node
- Secondary/cavitary TB re-infection of TB that is more widespread may see cavitations (cavities in lung)
- Miliary TB or disseminated TB, pattern of spread similar to millet seeds
Lastly, know that LEPROSY is similar to TB, but with skin manifestations
 3
Hypersensitivity Seminar 2= Dr. Ali
- Case 1: penicillin-induced anaphylaxis (Type 1)

- Case 2: pemphigus vulgaris (Type 2) vesiculobullous manifestations (main goal is diagnosis b/c a lot diseases
present w/ same symptoms)
o History taking is important! antibiotics DID NOT work so not bacterial infection
Steroids worked so immune-related!
o So biopsy once you have a differential diagnosis of 2-3 diseases! remember to biopsy the vesicles/bullae
that ARE NOT ruptured/ulcerated (for epithelium analysis)

- Case 3: BMMP (benign mucous membrane pemphigoid) (Type 2?) also a vesiculobullous manifestations (main
goal is diagnosis b/c a lot diseases present w/ same symptoms)
So while PEMPHIGUS has a SUPRA-BASILAR cleavage
PEMPHIGOD has a SUB-BASILAR/EPITHELIAL cleavage
- Case 4: Systemic lupus erythematosus (SLE) (Type 3)

- Case 5: contact dermatitis (Type 4)

Note that one of the most important concept in this lecture is that ALOT of these autoimmune diseases functions via
hypersensitivity mechanisms
- It is of upmost importance to memorize that even though a lot of these diseases mimic TYPE 3 (soluble complex), the
damage is NOT ALWAYS DUE TO PMNs
 Such as:
SLE - in skin (lymphocytic), everywhere else (PMN) no autoimmune diseases involve mechanisms like Type 1 sensitivity (can't develop allergies to yourself, but do involve
mechanisms like Type 2, 3, 4
RA - lymphocytic
Hashimoto's - not sure?

Autoimmunity Lecture 1 Dr. Shenker Lecture 4 (I didnt highlight antigens in green, but do know ALL of them imo)
- Autoimmune disease horror autotoxicus
1. Immune reactions involving T-cells OR antibody directed against self/auto-antigens which lead to tissue
injury and clinical manifestations of disease
2. May be organ specific/fixed to tissues (localized antigen) or involve multiple organs/systems (widespread
once we break tolerance and get an
deposition of antigen or immune complexes via being soluble/circulates) autoimmune disease, the disease will
kidney, skin, joint etc if systemic
So clinical manifestations depends on organ/tissue injured by immune system have an autoimmune reaction only where
antigen is being
Thyroid disease, diabetes, SLE the most common autoimmune diseases produced-but if its in a place like the
thyroid which make hormones, there will
3. Collectively, autoimmune diseases afflict 2-8% of US population be clinical manifestations in other places
75% women! (genetic or hormonal factors?) as well
where the hormone works
th
immun tolerance to self: 4 largest cause of disability among women in US
so autoimmune disease is not common
Specific repression of the- Immunologic Tolerance generally individuals display self-tolerance to their own antigens
immune response to 1. Central tolerance associated with antigen INDEPENDENT maturation if these developing
autoantigens Clonal deletion/negative selection of self-reactive T and B cells that respond to autoantigens cells are exposed to
ANY antigen, instead
Properties: During this earlier phase of maturation, there SHOULD BE NO EXPOSURE to anything of becoming activated,
acquired or learned foreign so anything that reacts @ this point is reacting against self (self-primary they
phenomenon so if u put a bac in this stage it will
Immature lymphocytes are more lymphoid (thymus, bone marrow) tissues)dev tolerance to it
die and never appear
susceptible to induction of One transcription factor (AIRE) in the thymus induce the expression of peripheral self-antigens again in
Immunologic tolerance to self the thymus, further aids in central tolerance
exhibits the Mutations in AIRE autoimmune diseases
same properties as those of
adaptive
2. Peripheral tolerance associated with antigen DEPENDENT maturation (b/c central tolerance isnt perfect
immunity (inducibility, specificity and and some self-reactive cells escape deletion)autoreactive lymphocytes gain
access to the peripheral circulation
memory) so peripheral
Both central and peripheral - Anergy lack of the SECOND signal (CD28 with B7) mech stops this
mechanisms
required for response
exist to induce and and maintain
tolerance - Suppression by regulatory T-cells
to self - Activation-induced death self antigen recognition
leads to apoptosis

3. SEQUESTERED SELF ANTIGEN

- Mechanism of Autoimmunity why do reactions to self happen?

1. Many of unknown etiology
2. Most autoimmune diseases have complex patterns of susceptibility most are multifactorial-genetic, immuno-regulatory breakdown, environment
Genetic predisposition
HLA alleles that are associated with different HLA proteins are the
types of diseases-so, if you inherit the B27 HLA HLA genes (disease associated) products of the MHC
allel, you're 87 times more likely to get
ankylosing spondylitits-but the risk of the disease o Normally functions to regulate immune response & negative selection of T- genes-make up the MHC
complexes-during normal
is .001, so 87 times more isnt that much more cells (central tolerance) immunity, they govern what
could be that different MHC alleles serve as we can respond to, also
binding sites for different infectious agent--also Hormones (such as estrogen) play a role in eliminating
drugs
goodpasture, mS, graves, uveulitis
Environment (such as taking drugs like procainamide) autoreactive B cells and T
cells during development
Infection (such as EBV) virus other genes besides MHC
also play a role
Mutations in immuno-regulatory genes (Fas, AIRE, CTLA-4 dont have to know these)
3. Breaking of Immunologic Tolerance
Mutation of T/B cell receptors when proliferating, if a mutation makes the receptor BETTER, will
be positively selected (but may mutate into a receptor that recognizes auto-antigens)
Deletion/altered T-SUPPRESSOR cell function
Non-specific ACTIVATION of T-helper cells or effector cells such as with polyclonal cell
activators (PCA)
Altered self
Via hapten binding, mutation, infection, degradation (due to inflammation)
Antigen mimicry cross reaction with self-Ag that are close in conformation to foreign Ag
Maturation antigens associated with secondary sexual characteristics
These antigens are not present in early life & appears w/ onset of maturation
Sometimes tolerance for these are weak leads to disease
 Sequestered antigen usually sequestered intracellularly no need to be tolerant b/c not
vascular however, cell damage leakage autoimmunity
4. Immune-mediated Mechanisms of Tissue Destruction how are tissues destroyed in autoimmunity?
Cell-mediated injury DTH such as Diabetes Mellitus
Same as type 4 hypersensitivity but just with self-antigens
o Going to involve the same cells (T-cells cytokines macrophages, CTL)
Antibody mediated
Immune cytotoxic reactions such as Pemphigus vulgaris
o Same as type 2 hypersensitivity but just with self-antigens on cells/tissues
Going to involve complement lysis, opsonization phagocytosis,
and ADCC
Immune complex reactions such as SLE
sometimes, the antibody can mimic the ligand-this o Same as type3 hypersensitivity but just with self-antigens that are soluble
will cause the signal to go through when the signal
Going to involve complement PMN-mediated damage (like
actually isnt needed, and there is no feedback loop,
so the signal wont stop vasculitis) these can also become multi-organd due to solubility &
ex: TSH produced by pituitary usually causes deposition in lungs, kidneys, heart, skin
thyroid to make T3 and T4, feedback loop will
eventually cause TSH to stop, antibody will mimic Receptor stimulation via autoantibodies such as Graves disease no tissue destruction
the effects of TSH, but there will be no feedback Receptor blockade via autoantibodies such as Myasthenia gravis no tissue destruction
loop to stop production to thyroid grows and grows
o No injury but an interference w/ function
Pernicious anemia receptor bloackade
- Antigen instrinsic factor protein produced in gut, facilitates absorption of vit B12, important for making DNA
- Pathogenesis autoantibody
1. Autoantibody binds to IF, so IF cannot bind to vitamin B12 (required to facilitate B12 absorption)
- Clinical symptoms
1. Malabsorption of vitamin B12 (required for DNA synthesis!!)
and nuclear development
2. Megaloblastic anemia
aka RBC arent being made properly

- Bone marrow hypercellular with megakaryocytes (functions to produce

platelets b/c anemic)
- PMNs are hypersegmented (6+ lobes compared to the normal 3-4)
- RBC oval, egg shaped

intrinsic factor binds to B12, this complex binds to Cubam, a receptor in the gut epithelial lining-this allows B12 to be moved
across the gut lining
the autoantibody binds to intrinsic factor, so it can't bind to B12 and that can't bind to Cubam-receptor blockade
there can also be a secondary antibody that binds to Cubam instead and so the B12 still can't bind

3. Reduced hematocrit
Autoimmune hemolytic anemia
- Antigen neoantigens on RBC (drugs)
- Pathogenesis autoantibody (IgG, IgM) removal and destruction of RBC
1. Via complement activation (C3b) lysis and/or phagocytosis
- Clinical sympptoms
1. Jaundice, splenomegaly
Warm agglutinins (IgG) cause hemolysis & opsonization @ body temp
Cold agglutinins (IgM) lower affinity, only react with RBC @ below 30 C happen in extremities

- May cause Raynauds phenomenon caused by cold anti IgM

when temp in fingertips drop below 30 degrees, the IgM antibodies bind to
1. Episodic, pallor/blanching, cyanosis RBC, causing agglutination, which block the
2. (Fingers, toes, ear, nose) micro capillaries and blocks the blood flow-first the hands turn white because
there's not enough blood flow, and then
blue and tissues become depleted of oxygen-when you start warming the
hands up, the agglutination will clear and this
stops the disease

Tx: RBC transfusion, steroids, immunosuppresants--not antigen specific-pt is susceptible to many

other diseases

you could keep transfusing but if antibody is still

being produced the RBCs will keep getting
destroyed

these antibodies also interact with RBC that dont have the hapten from the drug (if it was just against the hapten RBC, it would be
hypersensitivity)-now, they attack the RBCs that dont have the hapten either (just normal RBC)-this makes it autoimmunity
the RBCs will keep being destroyed, even if the hapten goes away, because the antibodies are also against the normal RBCs-will keep
being destroyed until that antibody goes away
 ssociated with platelets-antibody binds to platelets and they are
removed in spleen following agglutination--type 3 platlet associated agglutination
Autoimmune thrombocytopenia
- Antigen membrane glycoprotein IIb/IIIa complex (on platelets)
- Pathogenesis autoantibody (IgG, IgM) removal, destruction & agglutination of platelets
- Clinical symptoms

- Low platelet count bone marrow will be trying to compensate and make more platlets
- Megakaryocytes compensation for loss of platelets
- Petechiae, purpura, mucosal bleeding (also risk of bleeding into vital
organs)

Myasthenia Gravis

- Antigen acetylcholine RECEPTOR at post-synaptic muscle

membrane
- Pathogenesis autoantibody decreasing # of functional receptors
1. Either via receptor occupation
2. Or receptor internalization
3. Or destruction via complement (in online notes)
- Clinical symptoms
1. Disorders of neuromuscular transmission
2. Abnormal fatigability of skeletal muscle
o Pharyngeal affects swallowing & eating
o Respiratory causes distress & paralysis
o Ophthalmic transient double vision (diplopia)
& ptosis
- Treatment
1. Anti-cholinesterase prolong half life of Ach, get maximum benefit from the few remaining receptors
2. Immunsuppression (severe cases) prednisolone, azathioprine
Graves Disease
- Antigen TSH receptor
- Pathogenesis IgG autoantibody named TSI SIMULATES/MIMICS TSH
Because its IgG can cross placenta & cause disease in fetus
2. Normally TSH (from pituitary) stimulates thyroid to produce T3, T4
When T3, T4 levels are HIGH negative feedback to stop TSH secretion
3. In Graves TSI autoantibody stimulates thyroid to produce T3, T4
When T3, T4 levels are HIGH negative feedback to stop TSH secretion but FAILS because TSH
IS NOT CAUSING THE HIGH LEVELS, TSI IS THE CULPRIT!
Thus, Graves characteristic trait low TSH, high T3, T4
- Clinical symptoms

- Basically thyrotoxicosis any symptoms of

hyperthyroidism:
1. Goiter the enlargement is due to
excessive glandular element, the goiter in Graves =
functional
2. Exopathlmos protruding eyes
3. Wt. loss, excitable, nystagmus, tremors,
hot clammy skin, muscle wasting, dyspnea, tachycardia
Hashimoto Thyroiditis
- Antigen thyroglobulin (thyroid peroxidase, think of as T3, T4)
- Pathogenesis autoantibody (Type 2, 3 hyp mechanism) & T-cell infiltration/DTH (Type 4 hyp mechanism) of thyroid
1. Low thyroglobulin, high TSH (but no matter how high, the new thyroglobulin going to get destroyed)

mixed reaction-autoantibody that can react with product of

thyroid gland OR with the enzyme that makes it-can cause
type 2 or LOCAL type 3 reaction

autoimmune rxn to thyroid

this also has goitreous enlargement of thryoid, but its not due to increase in FUNCTIONAL thyroid mass-unlike
graves, these people have high TSH, low thyroglobulin--> high TSH because the product of the thyroid gland
that TSH is responsible for causing production of is being destroyed by antibodies, so the thyroglobulin can't
trigger the feedback loop that stops the production of TSH, and the thyroid itself is being destroyed so the
pituitary is trying to stimulate the remaining tissue more to compensate-so, manifestations are going to be
HYPOthyroidism
Thyroid diffusely enlarged in most will see germinal centers of lymphoid cells, not functional
cases; sometimes local enlargement tissue
occurs Graves involves autoantibody which stimulates production of
Extensive infiltration of parenchyma by more functional thyroid tissue-hyperthyroidism symptoms
lymphocytes and plasma cells with well Hashimoto involves autoantibody destroying the thyroid and
developed germinal centers recruiting cell mediated immune cells-hypothyroidism
Atrophic follicles lined by epithelial cells symptoms
with abundant, eosinophilic and
granular cytoplasm LOWERED MET
Treatment: - Clinical Symptoms
- Thyroid hormone replacement therapy
thyroid will be enlarged, but not 1. Basically any symptoms of hypothyroidism:
because there is more glandular Goiter the enlargement is due to inflammation,
tissue like in Graves-the the goiter in Hashimoto = nonfunctional
enlargement is because there are Fatigue, cold, wt. gain, depression, myxedema,
more inflammatory and immune
cells inside the thyroid-T cells, accumulation of glycosaminoglycans (puffy face and hands, thickened skin,
neutrophils, macrophages-as a hoarse voice, cardiac enlargement, macroglossia)
result, tissue is being destroyed
and knock out immune response
Rheumatic Fever
- Antigen cross reacting Ab (antigenic mimicry) antistrep Ab
- Pathogenesis
1. Carditis caused by Type 2 hyp response (antigen associated with myocardial cells & valves)
Results from cross reacting Ab
2-3 weeks following B-hemolytic streptococcal pharyngitis
o 5-15 yr olds
o Recurrent 25-35
- Clinical symptoms

1.Acute (chest pain, palpitations, dyspnea)

Carditis myocardial granuloma (Aschoff bodies = diagnostic!) contains Anitschkow cells rubbing sound
Fibrinous pericarditis fibrosis and adhesion develop with characteristic rub and ECG changes
2. Chronic
aterpillar nuclei-are
Valvulitis mitral valve develops vegetation and incompetence murmur Anischkow cells
Myocarditis chamber dilatation & CHF ag react with ab on mitral valve
Goodpasture Syndrome
- Antigen basement membrane component: a3-chain of type 4 collagen
- Pathogenesis autoAb (IgG) via Type 2 hyp mechanism hyper-cellularity of PMNs/neutrophils nd since GFR is down,
1. Possibly due to viral infection or chemical exposure kidney automatically
- Clinical symptoms (2 organs that suffer that most = kidney, lung) responds by increasing
renin-angiotensin and
aldosterone, causing
hypertension

antibodies will interact with

basement membrane,
activate complement, recruit
neutrophils-neutrophils
(Lung presents with hemorrhage too, with similar linear/smooth IF stain, see lecture slides page 36) cause most of the problems
1. Glomerulonephritis and association with hemorrhage renal failure, may require dialysis
2. Lung hemorrhage; may be massive and fatal
Insulin Dependent Diabetes Mellitus One
- Antigen pancreatic B-cells, OR insulin in subset of pts
- Pathogenesis T-cell infiltrate (accumulation of lymphocyte + macrophages in pancreas causes damage)
1. Autoantibodies present but not disease causing/destructive
- Clinical symptoms
1. Insulin deficiency accumulation of glucose & fatty acids hyperosmolality & hyperketonuria
 2. Polyuria (peeing everything out b/c cannot be utilized), polydypsia, wt. loss, fatigue, visual disturbances

- This is termed insulitis inflammation of the islet cells

- Complications include acidosis, loss of electrolytes, dehydration lead to coma & death (see page 38 of lec slides)
1. Others to note: PERIDONTAL DISEASE, ATHEROSCLEROSIS, nodular glomerulosclerosis, hyaline
arteriosclerosis, infections (pyelonephritis), eyes
Sjorgren Syndrome more prevalent in woman (9:1 f/m)
- Antigen cytoskeletal protein (alpha-fodrin)
1. Highly likely associated with viruses (EBV, Hep C)
- Pathogenesis T cells (CD4) infiltration & fibrosis of lacrimal & salivary gland (leads to non-functional enlargement)

- Autoantibodies present but not disease causing/destructive

- Primary (with connective tissue diseases like SLE, RA) vs secondary (without connective
tissue diseases)

- Clinical symptoms afflicts older women (50-60) parotid enlargement: but not with functional
tissue-with fibrotic tissue
- Xerostomia difficulty swallowing solid food, decreased taste, cracks & fissure, dryness of
buccal mucosa, parotid gland enlargement, dry and fissured tongue
- Keratoconjunctivitis sicca (dry eyes) blurred vision, burning, itching
shows
- Diagnosis lip, minor salivary glands biopsy (lymphocytic infiltrate = CD4, CD8, macrophages)

no glandular elements
Multiple Sclerosis (in online notes, not in lecture slides)
- Antigen myelin sheath that surrounds and insulates axons
- Pathogenesis Lymphocytic infiltration (CD4, CD8, macrophages) & demyelination (formation of plaques)
- Clinical symptoms
1. Early: paresthesia, retrobulbar neuritis, mild sensory symptoms in limb or cerebellar incoordination
2. End stage: undsteadiness of gait, incontinence, paralysis

CT diseases: involves immune complexes, complement,

neutrophils and platelets-looks like serum
sickness (antibody reacting to free foreign
antigen in the blood, antibody-antigen
complex is soluble)-antigen is an autoantigen
 not sure if scleroderma is Type 3 (txtbook
classifies differently)
- Scleroderma - progressive FIBROSIS of
skin, GI tract, and other tissues as a result
of FIBROBLAST activation by
Connective Tissue Diseases/Collagen Diseases
- Injury to components of blood vessel WALL (collagen, elastin, proteoglycans) CYTOKINES via T cells
1. Fibrinoid necrosis of arteries and arterioles - Polyarteritis nodosa - necrotizing
2. Vasculitis and obstruction inflammation of the walls of blood vessel
- Pathogenesis (similar to type 3) immune complexes, complement, PMN, plateletsmost likely from the deposit of immune
- Examples SLE, RA, scleroderma, polyarteritis nodosa (read in textbook) complexes
Systemic Lupus Erythematosus (SLE)
- Antigen
1. Most common Ag are called ANA Anti Nuclear Antibodies: dsDNA, ssDNA, Sm, RNA, histones the cause
of multi-organ disease
These are usually intracellular, UV damage to cells causes these sequestered antigens to be
released thus, this is type 3 hyp mechanism; ALWAYS present in lupus
2. Specific cells: lymphocytes, erythrocytes, platelets
This is type 2 hyp mechanism; SOMETIMES present in lupus
3. Other antigens (due to genetics, damage) RFs, thyroglobulin, coagulant components, phospholipids
- Pathogenesis immune complex formation due to photosensitivity/light damage
1. Etiology/cause of autoimmunity can be due to many things like infection (viruses like EBV), hormone
(estrogen), drugs (procainamide), stress, genetics (HLA), impaired ability to repair DNA breaks

- Clinical symptoms
other important
1. Skin and mucocutaneous lesions: malar rash (butterfly region, flexor surfaces), photosensitivity,
manifestations: erythematous/maculopapular plaques & ulcers, oral ulcers (may appear lichenoid w/ white striae)
- renal - capillary loops & 2. Arthritis, renal (proteinuria, HT, insufficiency), lung, serositis (pericarditis, pleuritis), CNS (seizures,
glomeruli thickened psychosis), hematologic (anemia, leukopenia, thrombocytopenia, lymphopenia) & constitutional signs
- serosal membranes - (fatigue, fever, myalgia, wt. loss) these are due to the soluble immune complex deposition
serous effusions or - The Mechanism Explained in SKIN
fibrinous exudation/ 1. Exposure to UV light causes
2. Damage to epithelial cells which leads to
opacification
3. Release of INTRACELLULAR DNA (usually sequestered)
- cardiovascular - 4. This causes sensitization & formation of small complexes which
myocarditis, associated with Activates complement
Libman Sacks endocarditis5. Cells are then brought in perivascular cuffing & vasculitis/fibrinoid necrosis can be seen
before steroid invention (these The curveball
are vegetations on heart valves) ONLY SKIN manifestation the infiltrate is MONONUCLEAR LYMPHOCYTES/chronic
inflammatory cells
o Also in the skin, the DNA antigen tends to accumulate @ epidermal & dermal
junction can be seen clearly with irregular/granular stain from indirect IF
Everywhere else (such as the kidney) the infiltrate is NEUTROPHILS but will still see same granular
- Another characteristic of SLE
IF even in kidney
1. LE cells an artifact that can only be seen AFTER storage/a period of time
Basically a neutrophil PHAGOCYTOSIS of a denatured cell (denatured/broken due to
venipuncture during blood drawing)
 meaning cannot be type 2

Chronic Discoid Lupus

- Antigen ANA (same as SLE)
- Pathogenesis immune complex formation (same as SLE)
- Clinical symptoms a self-limiting disease, NOT SYSTEMIC
o Lesions CONFINED TO SKIN (areas exposed to sun light) erythematous plaques on face and scalp
Rheumatoid Arthritis destruction of smaller joints (fingers, knees common)
- Antigen IgG (abnormal glycosylation); basically antigen is the antibody (IgG) itself!
- Pathogenesis autoAb (RF rheumatoid factor) immune complex Type 3 hyp-like rxn thats restricted to joints
o Pannus formation: vasculitis, edema, inflammatory infiltrate (chronic, round cells as opposed to PMNs:
basically T-cells, macrophages, and their cytokines)
Inflammatory cells release enzymes digest bone + cartilage
- Clinical symptoms
o Inflammation of synovium membrane lining/nonsuppurative proliferative synovitis causes pain,
stiffness, warmth, redness, swelling
o Rheumatoid subcutaneous nodules on extensor surfaces & others (25% pts) pathognomonic
Central focus of fibrinoid necrosis surrounded by macrophages which is in turn surrounded by
granulation tissue
Can also be seen in viscera including that of the lungs, spleen, pericardium aorta, heart valves
o Effect on TMJ is a possible!
Diseases of the Skin and Mucous Membranes Dr. Alawi Lecture 1 (highly rec to look in book for pictures)
- Background information (everything will make sense later!)
o Etiology/differential diagnosis what it could be
Traumatic, idiopathic
Immune mediated, autoimmune, infectious, neoplastic, genetic
o Cell attachments, desmosome & hemidesmosome
- Desmosome attaches epithelial cells to adjacent epithelial cells
- Hemidesmosome attaches epithelial cells to adjacent basement
membrane (these only occur near the basal cells closest to basement membrane)

o Keratinized surface vs non-keratinized surface

Keratinized oral mucosa hard palate, attached gingiva, dorsal tongue
Non-keratinized oral mucosa everywhere else
These are some diseases that only manifest on either keratinized or non-keratinized
o Important for diagnosis
HOWEVER, if a patient is immunosuppressed (such as HIV pts) then this rule does not
apply
- Desquamative gingivitis/peeling gums (KNOW THIS FOR EXAM) the green ones in the table = typical differential dx
o Nonspecific a lot of diseases can present with this, thus not really diagnostic
o Erythematous & ulcerated
Pemphigus Mucous Bullous Erosive lichen Lichenoid Lupus
vulgaris membrane pemphigold planus mucositis erythematosus
pemphigold
Primary herpetic Erythema Chronic ulcerative Graft vs. host Epidermolysis Linear IgA disease
gingivostomatitis multiform stomatitis diseases bullosa acquisita
- Immunofluorescence (IF)
o Direct IF uses patient TISSUE that should have autoantibody
Followed by a second antibody (with fluorophore) that recognizes human antibody (such as IgG)
constant region
o Indirect IF uses patient SERUM that should have circulating autoantibody on animal tissue
Followed by a second antibody (with fluorophore) that recognizes human antibody (such as IgG)
constant region
Pemphigus vulgaris (presents with desquamative gingivitis)
- What is it?

- Older patients, no sex predilection

- Fragile vesicles or bullae that rupture leaves behind painful & denude
areas/ulcerations (vesicle is smaller than bullae)
- Affects skin & mucous membrane
o Dysphonia (altered speech), dysphagia (difficulty eating)

- Mechanism autoimmune
o IgG auto-antibodies against desmoglein 3 self-antigen in desmosomes
Characterized as a type II hypersensitivity sort of reaction
- Microscopically (biopsy MUST include adjacent normal tissue)

- Suprabasiliar cleavage cleavage above basal cells

- Acantholysis epithelial cells no longer attached to each other, losing cell-cell adhesion
- Tzanck cells individual cells floating around (epithelial cell)
- Inflammation
- Tombstone appearance b/c hemidesmosomes still functioning
 - Diagnosis

- IF (either direct or indirect)

o Chicken wire characteristic appearance, possibly pathognomonic
- ELISA estimate antibody titers
- Positive Nikolsky sign (old tech) trigger blister with mild trauma

Treatment
- Long term corticosteroids
- Alternate therapies
- Rarely completely resolve
- But mortality usually due to complications of treatment

Benign Mucous Membrane Pemphigoid (Cicatricial pemphigoid) (BMMP) (presents with desquamative gingivitis)
- What is it?
- Mainly in older women
- Usually limited to mucous membrane (oral gingiva, eye, esophagus, larynx, genitals)
skin uncommon!
- Intact vesicles and bullae may be seen
- Lesions heal WITH scarring
- Ocular lesions may lead to blindness so ophthalmology consult is MANDATORY
Blindness due to symblepharon formation repeated scar that
attaches eyelid to the eye itself ankyloblepharon (fixed globe)
- Mechanism - autoimmune
o IgG auto-antibodies against MANY antigens (but all of these antigens are associated with hemidesmosome
& basement membrane)
Existence of a disease spectrum
- Microscopically sub-basilar or
- Subepithelial cleavage - @ interface of epithelium and connective tissue
o Other diseases can cause subepitheilial cleavage too, so not pathognomonic
Bullous pemphigoid (see next section)
Dermatitis herpetiformis, epidermolysis bullosa acquisita, bullous
systemic lupus, linear IgG disease, chronic bullous dermatosis of childhood
- No acantholysis (desmosomes intact)

- Diagnosis
- IF (ONLY DIRECT b/c not enough circulating auto-antibodies around)
- Linear band (represents where the autoantibodies (IgG) and complement component
(C3) are)
Treatment
- Topical or systemic steroid therapy

Because Pemphigus vulgaris & BMMP are very similar clinically here is a table to help you differentiate
Pemphigus vulgaris BMM Pemphigoid
Circulating Antibodies Yes No
Location of Antigen Desmosome Hemidesmosome
Location of Blisters INTRA-epithelial SUB-epithelial
Surfaces affected Mucosa + Skin MAINLY mucosa
Nikolsky Sign +++ + (will take forever to induce)
Treatment Systemic medication Topical/systemic medication
Prognosis Fair-good Good-excellent
Bullous Pemphigoid
- What is it?
o Similar to BMMP clinically
o The difference is that skin involvement is commonplace while oral (& other mucous membrane)
involvement is rare
o Lesions heal WITHOUT scarring
 - Mechanism autoimmune
o IgG auto-antibodies against antigens in hemidesmosome & basement membrane like BMMP (but
supposedly DIFFERENT proteins are attacked)
- Microscopically
o Same (subepithelial cleavage)
- Diagnosis
o IF (BOTH direct & indirect will work UNLIKE BMMP)
Same (linear band)
Lichen Planus (erosive form presents with desquamative gingivitis)
- What is it? wickham's striae: that's how you know that it's lichen planus

- Middle ages, F>M

- Skin lesions as purple, pruritic, polygonal papules usually to the flexor (inner) surfaces
of extremities
- Oral manifestation has two forms
o Reticular more common, usually asymptomatic (if symptomatic, will see
white & lace-like lines called Wickhams striae)
History of waxing and waning (lesions come and go)
o Erosive symptomatic/more bothersome (ulcerated mucosa with borders of
Wickhams striae IF restricted to gingiva = desquamative gingivitis)
Associated with Hepatitis C
- Although other disease may also present with Lichen Planus-like lesions
o Lichenoid mucositis (contact allergy, drug allergy)
o Chronic ulcerative stomatitis
o Systemic conditions like Lupus & graft vs. host diseases
- Mechanism
o Type IV reaction immune-mediated
- Microscopically
ORAL LP
- Saw-tooth rete pegs
- Lichenoid appearance dense & band-like lymphocytic infiltrate immediately
subjacent to epithelium (darker cells @ bottom half of pic)
- Basal cell layer exhibits hydropic degeneration
- Epithelial cells exhibits degeneration colloid bodies (arrow) all in lower levels of epi

- Treatment
o Asymptomatic no treatment
o Erosive or symptomatic topical corticosteroid (fluocinonide/Lidex or clobetasol/Temovate)
Should resolve within 2-3 weeks with therapy
Lichenoid mucositis/dermatitis (presents with desquamative gingivitis

- Lichen planus-like lesions INDUCED via

o Drugs (ibuprofen)
Toothpaste, mouthwash
o Cinnamon
o Restorative material (amalgam)
- Microscopic
o Same as LP (dense & band-like lymphocyte infiltrate subjacent to epithelium)
BUT! lymphocytes also seen surrounding blood vessels (deeper
infiltrate) (arrow)

Lupus Erythematous didnt talk about in lecture but in online notes

- What is it?
o Multi-system disease (joints, kidneys, heart, lungs, skin, mucous membrane)
We are going to focus on the skin & oral manifestations in:
Systemic lupus erythematosus (SLE) & chronic cutaneous lupus erythematosus (CCLE)
 - Mechanism
o Auto-antibodies against various antigens including nuclear antigens, double-stranded DNA and
Ribonucleoproteins (Smith antigen) 10-30% of SLE
Other forms of LE should be negative for Smith antigen
Type III hypersensitivity reaction
- Microscopically
o Auto-antibodies along the basement membrane in a granular-linear pattern w/ IF
Perhaps similar to pemphigoid
- Systemic lupus erythematosus (SLE)
o Butterfly rash over bridge of the nose lupus - presence of LE cells:
o Sunlight worsens lesions photosensitivity
macrophage or neutrophil that engulfed
o Any mucosal surface may be affected
Oral lesions in 5-25% of patients often non-specific in appearance denatured materials of another cell
Clinically, oral lesions are never diagnostic
Can only diagnose with known history or clinical + lab findings
- Chronic cutaneous lupus erythematosus (CCLE) or discoid lupus
o Predilection for sun-exposed areas such as the face
o Mainly affects skin
o Will eventually heal with scarring
Oral lesions resemble erosive lichen planus (central redness w/ Wickhams striae border)
Oral lesions usually seen WITH skin lesions though
Recurrent Aphthous Stomatitis/Canker Sores
- What is it?
o Etiology unknown (possibly allergy, genetic, predisposition, infectious agents, trauma, stress, hormones,
nutritional deficiencies, hermatologic abnormalities)
o Three types minor (most common), major (Suttons disease), herpetiform
o Usually only on NON-keratinized tissue (everywhere EXCEPT hard palate, attached gingiva, dorsal tongue)
- Mechanism not really known but immunologic
o Increased % of CD8+ T cells
o Decreased % of CD4+ T cells
- Minor (80% most common)

- No sex predilection
- Again, non-keratinized mucosa
o Small, painful, superficial, yellow-grey ulcer surrounded by erythematous halo
But lesions are NOT pathognomonic
- Heal without scarring in 7-10 days
o Treatment: not needed
- Microscopically: Non-specific so biopsy usually NOT indicated
- Major (10%)
o On non-keratinized mucosa BUT MAY EXTEND ONTO KERATINIZED (typically larger than 1 cm in diameter)
Ulcers are very painful/debilitating & may extend deep
o Heal with scarring in 7-21 days (w/ variable recurrence rate)
Treatment: palliative, usually treat with topical corticosteroids w or w/o local anesthetic rinse
Avoid acidic drinks/foods
If cannot eat due to pain, drink high nutrient shakes such as Ensure, Boost
- Herpetiform (least common but can present with hundreds of lesions at a time)

- F > M, oftentimes in adulthood

- This CAN be on BOTH keratinize & non-keratinized basically multiple lesions that does
NOT follow rules
- Heal without scarring in 7-10 days (w/ closely spaced recurrence)
o Treatment: palliative

- Note that apthous lesions may be associated with Behcets syndrome, SLE, inflamed bowel syndrome, nutrient
deficiency
o Behcets Syndrome
What is it?
 Etiology unknown but a chronic inflammatory disease
Recurrent aphthous stomatitis of oral and pharyngeal mucosa
o Oral manifestation in 99% pts and typically precedes other sites
Ulcers of the genitals
Skin lesions
Severe ocular inflammation
Joints, GI, CNS affected
Diagnosis MUST have 6+ aphthae that recurred at least 3 times in 1 year AND
Two (or more) of the following:
o Ocular lesions
o Skin lesions
o Positive pathergy test (similar to tuberculin-like skin reaction)
Herpes Infections
- DNA-based (unlike RNA-based HIV) virus family includes 8 members, we are going to focus on:
o HSV-1 (our main focus)
Mainly affects oral, facial ocular areas
Infection via saliva or active lesions
o HSV-2
Mainly affects genital area
Infection via sexual contact or birth canal
- However, know that this is NOT an immune-mediated disease but infectious process
o We discuss this here because it can resemble other diseases here such as aphthous
- Primary Herpetic Gingivostomatitis/Acute Herpetic Gingivostomatitis (presents with desquamative gingivitis)
o What is it?
Small minority are symptomatic (20%)
Fever, loss of appetite, irritability, malaise, swollen lymph nodes (cervical
lymphadenopathy)
Outbreak of painful ulcers in perioral region most debilitating
o Difficulty eating malnourishment
Commonly contracted during childhood and college
Infected via saliva with an abrupt onset
Adult onset
o Pharyngitis and tonsillitis
o Few cases with oral lesions
Constitutional signs and symptoms multiple small 1-3 mm fluid-filled vesicles that
rupture, becoming ulcers

- Keratinized and non-keratinized may be affected

- Desquamative gingivitis fiery red, enlarged, painful
- Acute lasts for 5-7 days
- Symptoms subside in 2 weeks

o Microscopically biopsy reveals

- Acantholysis virus affects epithelial cells

o Tzanck cells
- Herpetically altered cells
o Cell nuclei are large, glassy
o Oftentimes multinucleated

o Treatment: supportive and symptomatic therapy only usually resolve on its own
No medications can cure, only palliative
DO NOT USE TOPICAL CORTICOSTEROIDS can exacerbate problem since this is an
immune response to viral infection
Steroids diminish lymphocyte response virus proliferation and spread (this is often
the case seen in AIDS pts/transplant pts)
After primary infection, the virus establishes latency
- HSV-1 in the trigeminal ganglia
- HSV-2 in the sacral nerve root ganglia (S2-S5)
- Reactivation induced by various stimuli
o Very common in immunocompromised pts
o Acute UV exposure only known proven trigger experimentally

- Secondary Herpes/Recurrent Herpes (Cold Sore, Fever Blister)

o What is it?
- Occurs usually @ site of primary inoculation (commonly on vermillion border herpes
labialis)
- Existence of prodromal signs and symptoms (S&S BEFORE onset of lesion) pts known
when theyre going to break out
o Burning, itching, tingling, redness
o Unlike primary, no systemic symptoms
- Lesions start as erythematous papules vesicles ulceration
o Variable recurrence
o Maximum shedding @ first 24 hours but may last up to 5 days
- RESTRITED ONLY to keratinized tissue (attached gingiva, hard palate, dorsal tongue
[rare])
o Heals within 7-10 day w/ or w/o treatment

o Diagnosis
Viral culture (not practical)
Biopsy similar to primary
Acantholysis Tzanck cells
Multinucleated giant cells
Eosinophilic intranuclear inclusion bodies
o Treatment: no complete effective therapy
Antivirals (only work during prodromal phase, will not work if lesions breakout)
Prophylaxis
Again, NO STEROIDS for the same reason
- Herpes Zoster/Shingles
o What is it?

- Reactivation of varicella zoster virus/human herpesvirus (NOT SIMPLEX)-3/chickenpox

virus)
- Prodromal pain (~4 days before onset) involving dermatome, fever, malaise, headache
o Dermatome = area of epithelium innervated by sensory nerve
- Lesions after prodromal S&S = vesicles that follow distribution of nerve
o The area of inoculation determines where virus lie dormant
o Head/neck trigeminal, thus can affect all 3 branches
o Ocular involvement (V1) may lead to blindness
Tip of nose involvement warrant IMMEDIATE ophthalmology
consult b/c nasociliary nerve is of the V1 branch
- Healing with scarring
- Keratinized and non-keratinized mucosa (lesions stop @ midline b/c of bilateral
innervation)
o Microscopically HZ and HSV are similar so
Diagnosis instead of biopsy, clinical presentation usually enough to diagnose
o Treatment: only to prevent new lesions from developing, but whats already there is there
Palliative
Antiviral (acyclovir)
Erythema multiforme (presets with desquamative gingivitis)
- What is it?
o Etiology unknown but a self-limiting disease (usually resolve by itself)
 o 50% have known triggering agent
Infections HSV
Medications sulfonamides, barbiturates, antibiotics (penicillin, vancomyin)
o 3 forms: minor, major (Steven Johnsons Syndrome), toxic epidermal necrolysis (Lyells disease)
o Existence of prodromal S&S 1 week prior to lesion onset fever, malaise, headache, sore throat
- Minor most common (young adults, M>F)
- Limited to oral mucosa and skin
- Target-like skin lesions = pathognomonic
- Manifestation on lips blood-filled blister ruptures hemorrhagic
crusted lips

o Microscopically (biopsy) non-specific, clinical presentation needed for diagnosis

But biopsy/smear useful in ruling out primary herpetic gingivostomatitis (multinucleated cells)
o Treatment supportive/palliative (steroids usage is controversial)
- Major/Steven Johnsons more severe (young adults, M>F)
o Usually triggered by medication
o Lesions manifest @ skin, oral AND ocular, genital lesions
o Treatment: usually with systemic steroids after elimination of triggering agent
- Toxic Epidermal Necrolysis/Lyells life-threatening (older adults, F>M)
o Trigged by medication
o Characterized by diffuse sloughing of skin & mucous membrane
Immune Deficiency 1 Dr. Shenker Lecture 5 (can happen as a result of defects @ ANY steps of maturation/differentiation)
- If primary immune deficiency inherited or congenital
o T-cell defects affects cell-mediated immunity
Susceptible to intracellular
Viruses (CMV, herpes, measles), fungi (histoplasmosis, candida, pneumocystis carinii,
cryptosporidiosis), bacteria
o B-cell defects affects humoral immunity either from abnormal differentiation or secretion of
immunoglobulin
Susceptible to pyogenic bacteria
Such as streptococcus, hemophilus, Neisseria
o Complement defects
Susceptible to pyogenic bacteria
o Phagocytic defects
Susceptible to pyogenic bacteria
- If secondary immune deficiency infection, malnutrition, aging, immunosuppression, chemotherapy (stops clonal
expansion)
o Increases susceptibility to infection and cancer such as lymphomas, skin/lip carcinomas
- Methods for Clinical Evaluation of the Immune System (bunch of tests not elaborated here see online lec notes)
Primary deficiency:
Mucocutaneous candidiasis (either due to T-cell defect OR ANTIBIOTIC therapy) more pictures on page 5 in lecture slides

-What is it?
o Chronic refractory disease afflicting mucous membranes, skin,
hair, and nails
o Caused by fungi: Candida such as C. albicans
- Clinical symptoms
o Oropharyngeal candidiasis/thrush in the
immunocompromised such as newborns, people on antibiotics, people on
corticosteroids, or deficiencies in T-cells
o Typical lesions are raised white pseudomembranes on
mucosal surfaces that bleed when scraped away
Thymic Hypoplasia: DiGeorge Syndrome (due to deficiencies in T-cell MATURATION)
- What is it?
o Immune deficiency due to congenital thymic defect an intrauterine accident
Lymphoid tissue lack T-cells, no circulating T-cells in blood
- Clinical symptoms
- Vulnerable to viral, fungal, protozoal, intracellular bacteria infections due to
lack of cytokines!
- Other developmental abnormalities such as hypertelorism (inc distance
between two body parts)
- Parathyroid HYPOplasia (hypocalcemic tetany)
- Midline developmental abnormalities such as cleft lip
Treatment: thymic transplant

X-linked (more often in males) Agammaglobulinemia (Bruton Disease) (due to failure of PRE-B-cells to DIFFERENTIATE into
mature)
- What is it?
o Mutation in tyrosine kinase no Ig-light chain made
o Absence of mature B cells no gamma globulin in blood
Reduced B cells in circulation
Lack of germinal centers (where B cells mature) in lymphoid tissue
o Also no plasma cells
- Clinical symptoms
 o Recurrent pyogenic bacterial infection haemophilus influenza, streptococcus pneumonia, staphyloccus
aureus
Acute and chronic pharyngitis, sinulsitis, otitis media bronchitis, pneumonia
o Most viruses & fungus handled normally except for viruses echovirus, enterovirus, fungus
pneumocystis carinii, protozoa giardia lamblia (infection of intestine malabsorption)
- Treatment: passive immunization with pooled human serum
Common Variable Immune Deficiency (Acquired or late onset agammaglobulinemia) (due to inability of B-cells to
differentiate into plasma cells mature B cells & germinal centers PRESENT, but NO DIFFERENTIATION)
- What is it?
o Inability for mature B-cells to differentiate may be due to
B-cell defects, T-HELPER defects, T-SUPPRESOR defects so
Few to no B-cells no plasma cells low to no immunoglobulins
o Absence of plasma cells, hypogammaglobulinemia
Impaired antibody response to infection & vaccination
- Clinical symptoms
o Increased susceptibility to infection (similar to Bruton disease pyogenic)
o Increased risk to autoimmune disease?
Isolated or Selective IgA Deficiency (due to block in terminal DIFFERENTIATION of IgA secreting B-cells to plasma cells, basically
loss of B-cell ability to class switch into IgA producer)
- What is it?
o No serum and secretory IgA produced (usually @ mucous membrane lining of mouth, airway, GI tract)
o Normal IgM, IgG levels
- Clinical symptoms
o Most asymptomatic
o Weakened mucosal defenses recurrent sinopulmonary infections & diarrhea
Hyper IgM Syndrome (due to failure in B-cell heavy chain class switching)
- What is it?
o Enzyme deficiency associated with class switching & T-cell contact
o NO IgG, IgA, IgE
- Clinical symptoms
o Recurrent pyogenic infections
o Increased susceptibility to INTRACELLULAR pathogens implies T-cell deficit too
Severe Combined Immune Deficiency/Swiss type (due to defects in BOTH humoral (B) & cell-mediated (T) immunity)
- What is it?
o Types of Swiss type agammaglobulinema
X-linked mutations in cytokine receptors
Adenosine deaminase (ADA) deficiency
MHC class II expression deficiency
o Lymphoid tissue atrophic
o No serum IgG
- Clinical symptoms usually presents with marked lymphopenia
o Susceptible to everything, viruses, fungi, protozoans
Recurrent opportunistic infections, may be fatal
Candida, pneumocystis, CMV, pseudomonas
- Treatment: bone marrow transplant
o In infants, maternal immunoglobulin from placenta crossing & breast milk will work for a bit
o But 6 months into the disease, these kids will develop symptoms death
o If detected early, can do bone marrow transplant
Secondary deficiency:
- Result of other disease states:
o Cushings (too much steroids), renal/hepatic dysfunction (accumulation of toxins), infection (bac, viral)
- Result of therapy for other conditions:
o Anti-inflammatory, x-ray/chemo, immunosuppressive therapy for transplantation/autoimmune diseases
- Immuno-inhibitory drugs
o Cytotoxic (alkylating agents, x-irradiation, anti-lymphocyte serum [causes complement lysis])
o Cyclosporine A interfere with T-cell signaling
o Anti-inflammatory steroids
o Anti-metabolites like azathioprine
Abnormalities of Immune Function in AIDS
- What is it?

- Lymphopenia
- Decreased T-cell function
- Altered monocyte/macrophage function
o Basically, as T-cell numbers drop, clinical
symptoms increase

- Clinical symptoms the big four

o Oral Hairy Leukoplakia due to VIRAL infection (EBV, also called human herpesvirus 4)
Unlike candida, white plaques cannot be wiped off
Hyperkeratosis, epithelial hyperplasia

o Kaposi sarcoma cancer of blood vessel also associated with virus (human herpesvirus 8)
o Aggressive periodontitis

o Candidiasis
Pseudomembranous candiasis & erythematous candidiasis most common
Hyperplastic candidiasis, angular cheilitis possible but not as common
Transplant Rejection 1 Dr. Shenker Lecture 6
- Transplantation is very important for patients with end-stage organ disease
o The principle genetic system in humans that determines success or failure of transplants is the HLA
complex
The target on the graft to which the recipients immune system response are the products of HLA
complex histocompatibility antigens
- Types of donor
o Living donor grafts limited to kidney & bone marrow b/c any other organs are vital for living
o Cadaverous grafts
- Types of grafts
o Autografts from same person (just from one point to another, like skin grafts)
o Isografts/syngeneic graft from genetically identical person (such as identical twin)
o Allografts/allogeneic/homograft from genetically dissimilar individuals of the same species
o Xenografts/heterograft not the same species
o A note about cornea transplants
Rarely rejected due to being a privileged site may survive even though not ideal match
- Transplant Rejection the Target Antigens
o Major histocompatibility antigens requires tissue typing (ideally want all antigens to match)
o Minor histocompatibility antigens called minor b/c we dont know much about it
But the reason why rejection may still occur even though majors are matched
o Blood group antigens ABO
- Histocompatibility molecules MHC; HLA
o Originally identified as antigens responsible for graft rejection
But they have the role in T-cell activation (MHC restriction)
Two types:
o MHC class I heterodimer w/ beta microgloblin
o MHC class II heterodimer
o Polymorphic
There are 4 closely linked HLA loci which code for 4 classes of HLA antigen
HLA-A, B, C responsible for MHC I
HLA-D (w/ 3 subtypes) responsible for MHC II
Each of these have hundreds of genotypical alleles
For example, there are 119 possibilities for A, 245 for B, 71 for C, so on so forth
o Haplotype group of genes that are inherited together as a SET (think of HLA-D as just one gene)

- So you either inherit a OR b from the mother & c OR d from the father
o In the end
25% siblings will be IDENTICAL in HLA
50% siblings will be PARTIALLY identical
25% siblings will share NO IDENTITCAL HLAs
Graft Rejections on the lecture slides (page 13) the picture will just confuse you, Shenker said to think of it this way:
- The difference in rejection lies in the source of the antigen presenting cells
o Antigen-presenting cell FROM THE graft
o Antigen-presenting cell FROM THE recipient
- But in the end, most rejection due to T-cells (CD4, CD8) and (possibly) cytokines & macrophages, starting in the
endothelium
Types of Rejection FROM host
o Hyperacute rejection occurs IMMEDIATELY
Due to PREFORMED antibodies to HLA
Due to multiparous women (multiple pregnancies with different partners, exposed to
different antigens via fetus)
Due to previous blood transfusions/grafts
o Acute cellular rejection occurs within DAYS to WEEKS
Due to T-cell response (CD4 T-cells, cytokines, macrophages, CTL)
Can be controlled via immunotherapy/suppression drugs
o Chronic rejection occurs in MONTHS to YEARS
Due to CD4 T-cells, cytokines, macrophages, CTL, FIBROSIS (collagen deposition loss of fxn)
o Acute humoral rejection (xenografts) an antibody mediated reaction against endothelial cells
Very rare b/c most rejections are due to T-cells & macrophages
Pretty much affects endothelium similar to hyperacute, but just slower
Hyperacute rejection
- Primary target HLA class I (does he mean MHC I?) on vascular endothelial cells
o Mediated by antibody & complement
Destruction of endothelial cells (vasculitis), edema, characteristic local hemorrhage (red in pics
below)
Activatio of coagulation-thrombotic occlusion
Organ becomes cyanotic (no air) and hemorrhagic (pic)

Acute rejection
- Primary target
o CD4 T-cells respond to MHC I
o CD8 T-cells respond to MHC I
o Maybe Ab
Interstitial infiltrate of mononuclear cells (LOTS of purple dots WITHOUT fibrosis)
Edema
Interstitial hemorrhage due to CD8 mediated endothelitis
- Normally responds to immunosuppression therapy
IF NOT TOLD that this is transplant rejection will be impossible to tell
BUT, if TOLD that this is transplant rejection, know that purple dots + no fibrosis = ACUTE rejection!

Chronic rejection

- Occurs when theres the greatest HLA disparity

- Episodes of acute rejection chronic/delayed rejection
o Vascular pathology intimal smooth muscle proliferation, ECM synthesis
and fibrosis leads to obstruction and ischemia
o Interstitial fibrosis
o Cellular infiltrate (T-cell, macrophages just like acute)
- Progressive LOSS of function
- DOES NOT respond well to immunosuppression therapy
Graft vs. Host Disease (GvHD) rejection in reverse (graft rejects host)
- T-cells FROM DONOR respond to HLA of recipient a huge complication of BONE MARROW TRANSPLANTS
- (recipient now carries the donors immune system and are producing cells that are of donors origin)
o Involves epithelial cell necrosis:
Skin rash (desquamation)
GI tract bloody diarrhea, nausea, vomiting
Liver destruction of bile duct leading to cholestasis, jaundice
Lung interstitial pneumonia
o Mediated by CD4/CD8 T-cells and NK cells derived FROM DONOR thus mononuclear infiltrate
Methods for Increasing Graft Survival
- Minimize HLA disparity
o MHC I
o MHC II
o Minor HLA
- Immunosuppressive therapy (this isnt pharm but probably will be a few questions on the test about this stuff)
o Antimetabolites inhibit DNA synthesis
Azathioprine (Imuran), Mycophenolate mofetil
o Corticosteroids interfere w/ T-cell function & possibly cytotoxic to T-cells
Prednisone, Solumedrol
o Calcineurin inhibitiors interfere w/ T-cell SIGNALING, preventing activation
Cyclosporine (emulsion), Tacrilomus (FK506)
o Anti-lymphocyte antibodies T-cell antibody that utilizes complement or toxic cargo for kill
(but the antibodies themselves can be antigens, causes serum sickness)
o Cytokine inhibitors
o Newer immunosuppresants
Rapamycin interferes w/ phosphorylation and lymphocyte activation G1 arrest
Deoxyspergulin
- There are complications with immune suppression
o Non-specific increases susceptibility to opportunistic infections
o Increased risk of developing CANCER
EBV-induced lymphomas
Human papillomavirus-induced squamous cell carcinomas
Kaposi sarcoma