Immunology

Innate
Instrinsically (always on)
Nonspecific
No memory
Limited diversity

Adaptive
Inducible when needed
Specific
Memory
SPECIFIC
Self-limiting ( important to turn it off
when its not needed)

* dont forget skin, pH , chemicals like

lyzosymes , compliment are all part of
innate
Innate and Adaptive work together
Innate turns on Adaptive by antigen presentation
Adaptive strengthens the innate by cytokines
Primary lymphoid: where B and T born : bone marrow and thymus
Secondary : where activated
- Spleen : blood borne pathogen
- Lymph node: tissue pathogen
- Malt: mucous

Cell types

Cells always present in tissue

1. Macrophage (monocyte in the blood)
2. Mast cells
3. Dendritic cells
Eosinophils
-Kill parasites
-also called in Type 1 hypersensitivity and have Histaminase ( break
down histamine from mast) and release more Leukotrienes
Mast cells + basophils in Type 1 hypersensitivity
Dendritic cells
-Langerhans cell in skin ( have Birbeck granules)

B and T cells
-

Carboxy terminus of receptors goes into the membrane

N terminus binds antigen

B cells
-Idiotype : Variable region binds antigen ( N terminus) = heavy and light chain
- Isotype : constant region that determines FUNCTION (C terminus) = heavy only
B cell

T cell

MATURE nave B cell: IgM and IgD on

same cell
- receptor valency 2 minimum
- receptor is flexible bc of HINGE region
formed from disulfide bonds
Can secrete = antibodies
Receptors bind everything
Bind it by themselves
Signal Transduction for cascade
Ig- and Ig- two on each side, CD19,
CD20
Heavy chain (VDJ) + Tdt
Light chain ( VJ)

T cell receptor ( alpha and beta)

-Valency 1
- not flexible bc no hinge
Receptors ALWAYS CELL BOUND
Receptors only bind PEPTIDES
Require antigen presenting cell
CD3
Beta chain (VDJ) + Tdt
Alpha chain ( VJ) + Tdt
Self limited by FAS (Activation
induced cell death)

Production of chains B and T cell receptor

Chain production
The recombinase ( RAG 1 and RAG2) rearrange genes
-VDJ a) D-J b) V-DJ
- VJ
Then transcription
Then Alternative splicing for the different isotypes ( after the antigen is
presented in the germinal center)
-If nave just get IgM first bc its the first one
Diversity
1. Random gene rearrangements VDJ, VJ
2. Tdt insert random bases
3. Random combo of light and heavy chain for B, and alpha and beta for T
-----4. ONLY B CELLS : SOMATIC HYPERMUTATION causing AFFINITY
MATURATION in the cells that activated in germinal center, therefore
secondary activation is strong
B cells
Heavy chain isotypes all on one chromosomes ( therefore 2 chances to
rearrange, one from each parent)
Light chain + on different chromosome ( 4 chances to rearrange)
ALLELIC EXCLUSION: Once rearranged turn off the other gene so only ONE
SPECIFICITY / CELL
Antigens for B and T cells
B cells can bind anything VS T cells only bind peptides
Thymus dependant antigens : peptides ( the B cells present these and
causes strong immune response bc T cells help = isotype switch + memory)

Thymus independent antigen

- Ex: polysaccharide capsule + LPS (gram -)
- T cells not no (no CD40 ligand)= NO ISOTYPE SWITCH
-NO MEMORY

Bcell development and selection

PRO- B: The cytoplasmic is the heavy chain waiting for the light chain to be
made
Negative selection in the Immature B cell when only surface IgM
- clonal deletion of those that bind to tight
Activated Blast is when ANTIGEN BINDS and causes proliferation in the
GERMINAL CENTER
-here somatic hypermutation
-isotype switching
The plasma cell is a dead end ( make Ig and then die in two weeks)
Memory cells when activated 2nd directly to memory cell transform

T cells development and selection

Everything before thymus DOUBLE NEGETIVE (NO CD4 OR CD8)

Cortex DOUBLE POSITIVE
Medulla commit to CD4 or CD8
Postive and negative selection in Cortex
-Positive: select those bind MHC ( done by epithelial cell)
-Negative: remove bind to tight to self

Major histocompatibility complex (MHC)/ HLA

HLA are on chromosome 6
CoDominant expression (mom and dads)
- B2 microglobulin isnt encoded with HLA but needed for function
MHC II have INVARIANT CHAIN so MHC II dont bind self
MHC I
MHC II
HLA- A, B, C
grade 1 ABC
HLA- DR, DP, DQ Dr DePide likes DQ
Alpha chain + B2 microglobulin
Alpha + Beta
alpha and beta present to T alpha and
beta
On all NUCLEATED
On APC cell
-not on RBC
CD 8 + T cell
CD 4+
Endogenous pathogen
Exogenous pathogen
the antigen degraded by proteasome
phagocytosis of antigen
tranposrt into ER by TAP
phagosome+ lysosome fuse +

combine with MHC 1 in ER

to golgi cell membrane

degrade antigen
MHC II made in ER sent via vesicle to
lysosome
Lysosome degrade INVARIANT
CHAIN, So antigen can bind

Acute Inflammation
1) cytokines increase selectins adhesion on endothelial cells
2) ROLLING : PMN bind E-Selectin on endothelial cells
3) ADHESION: the Integrin binds to ICAM on endothelial
-LAD : if CD18 missing, part of integrin
4) pseudopods sent in and extravagation into tissue following chemokine gradient
Chemokines for PMN : IL-8, C5a, LTB4
* APC picks up the antigen and then goes to the lymph node or spleen in order to
activate T cells (B cells activate here too)

Antigen Presentation In 2nd lymph tissue INTERACTIONS

T cells bind to MHC on APC (the CD4 or CD8 stabilize it)

CD3 send the intracellular signal
CO-stimulatory signal : CD28 ( T) = B7 (APC)
-without this causes ANERGY
-CTLA-4/ CD152 compete with CD28 for B7 to turn off T cell
- Superantigen : binds to the outside of TCR and causes it to join MHC II, leading to
activation of MANY T CELLS HIGH CYTOKINE EXCESSIVE pro inflammation
causing multiple organ failure
T cell types
THo gets diff signals and transforms to diff cells ( CD4+)
TH1
IL-12 from macrophage activate NK to secrete IFN-gamma= TH1
-Cell mediated response
-marcophages (IFN-gamma)
- CD8+ CTL ( IL-2)
-makes IL-2, IFN-gamma, TNF-
-IFN-gamma inhibits TH2
TH2
IL4 causes TH2 to be made
- Humoral response (antibodies)
- Produces IL4,5,6,10,13,TGF-
-IL-10 and IL-4 inhibit TH1
Treg
- Made when TGF-beta ( antinflammatory)
- Make il-10 to turn off TH1 cells
- CD25 surface marker, and FOXP3 transcription factor
T17
- Made when TGF-beta + IL-6

- Pro-inflammation when makes IL-17

CD8+ T/ cytotoxic T cells :
- Tumor cell, viral, transplanted tissue bc HLA dont match

Clincial : Leprosy
Mycobacterium leprae is intra macrophage pathogen therefore antibodies
dont work
Tuberculoid: Th1 response good, forms granuloma to wall off infection +
recover
Lepromatous : TH2 response bad, antibodies dont fix issue and further turn
down TH1. HYPERgammaglobulinemia

Humoral Immunity

Need T cells for isotype switching

-CD40 ligand (T) = CD40 B
- W/o CD40 L= X-linked Hyper- IgM Syndrome

Papain
- cut above hinge
-3 fragments
-2Fab + 1FC

Pepsin
-cut below hinge
- 2 fragments
-1F(ab)2 + 1 FC
-agglutinate +
precipitate

The J chain keeps antibodies together ( IgM and IgA)

IgM always first made even in allergic rxn ( 1st exposure)
IgA has secretory component that protected it form degradation in the
lumen
ADCC: Antiody dependant cell- mediated cytotoxicity
-IgG for NK cells
-IgE for Eosinophils in parasite infection

Compliment

Made in Liver
C3a, 4a, 5a anaphylatoxins (bind to mast cell and basophil to degranulation)
C5a chemotactic for PMN
C3b Opsin
MAC 5 9 * essential for Neisseria infection ( meningitis and gonorrhea)
Alternative (activated by pathogen) vs Classic IgM and IgG

Killing mechanisms

Marcophage : nitrogen oxygen species and oxygen radicals

CD8+ T cells
1. FAS ligand (T) = FAS on cell : tells cell to kill itself
2. Perforins form pore, release Granzymes into cell caspases activated
3. TNF alpha and beta induce apoptosis
NK cells: work with granzymes and perforin like CD8+
- Inhibited by MHC 1
* NK and CD8+ work at OPPOSITE TIMES
-CD8 on when high MHC I
-NK cells work when low MHC I ( inhibited by MHC I)
- therefore when things turn down MHC I to escape, they are killed by NK

L-selectin
(on lymphocytes)
Il-1, Il-6, TNF alpha
IL-10, TGF
CD2 on T cells (ICAM)
LFA-1 on T cell (integrin)
CD28 ( T)
CTLA-4 ( T)

- used to leave blood into 2nd lymphoid tissue via

HEV ( high endothelial venules)
Pro inflammatory
Anti inflammatory
Bind to LFA-3 on APC (integrin)
Bind to ICAM-1 on APC
Bind B7 on APC ( co-stimulatory signal)
Bind B7 ( compete with CD28 to downregulate T
cell)

Definitions:

Idiotype : variable region where antigen binds

Isotype: the constant region of antibody that determines FUNCTION
Epitope/ antigenic determinant: part of ANTIGEN that is recognized by
receptor
Avidity: increase with number binding site ( IgM highest pentamer, IgA 2nd)
Affinity: strength of binding ( IgG)
Mitogen: activate clones of B or T cells
-Poke weed : B cells

CLINICAL

Tdt used are a marker for ALL in B and T cells for early stage
-Tdt adds random bases WIHTOUT TEMPLATE

Protein A from Staph bind to Fc of IgG, prevent phagocytosis bc the

macrophage cant bind
Mycobacteria, Leishmania, Listeria Facultative intracellular pathogens
in macrophage therefore require TH1 response
Adenovius vaccine = ONLY LIVE NOT ATTENUATED vaccine given cause
intestinal IgA to be produced (hence all mucosal) therefore respiratory now
protected
CD21 receptor for EBV ( infect B cells) then T cells form downey cells
MHC II deficiency / Bare lymphocyte syndrome II
- mimic SCIDS and AIDS ( no CD4+ and low CD8+)
-differentiate from SCIDS bc react to mitogens here ( can
replicate but just low bc not activated)
-IgM mostly since no CD4 TH2

Syndromes

Omenn Syndrome : missense mutation RAG causes decrease function (A.R.)

o B cells missing
o T cell decreased
SCIDS: Rag 1 and 2 genes null mutation ( cant form chains)
o A.R.
o No B or T cells

Medbullets
SCIDS (no proliferation with mitogen)
X linked : IL-2 Receptor ( gamma chain) ( affect IL-2,4, 7)
A.R.: Adenosine deaminase deficiency
A.R. nonsense mutation Rag 1 and 2
* MHC II/ Bare lymphocyte mimic the SCIDS but proliferate with mitogen .
Atopy: allergic rxns etc
Burtons agammaglobinemia
-Normal Pro B cell., the Pro cant go further
Chronic Mucocutaneous Candidiasis
Inability for T cells to produce cytokines to combat Candida Infection
On skin, mouth, sometimes esophagus
Infant have diaper dermatitis
Need Fluconazole
Auto recessive or spontaneous auto dominant
IL-12 deficiency: diminished TH1 response therefore mycobacteria attack

Catalase + infect Chronic Granulomatous Disease

Staph aureus, Pseudomonas, E.coli, ASpergillus
NTD test, if diseased (-) test , dont turn blue
LAD:
CD18 on integrin LFA-1 ( beta chain)
HIV

Normal ratio 2:1 CD4 to CD8

In aids it reverses 1:2
CCR5 co receptor on the macrophage and dendritic cells
-the macrophage and dendritic ARE NOT killed by HIV
-act as reservoirs for the disease
Immune evasion
-Anitgenic drift of gp 120
-glycosylation of gp 120 ( like a mask)
-Tat inhibit cytokine synthesis
-Nef decrease MHC 1
Testing
1. ELISA: Antigen on plate, Add patients serum ( see if have Ig), then add
ant- human IgG and colour change +
2. Westenr Blot ( confirmatory) : Antigen on nitrocellulose
-Add patient serum ( antibodies)
-Add anti- human Ig ( radiolabelled)
* test for p24: capid
-gp 160 : envelope protein
-GP 120 : attatch
-gp 41: fusion and entry

CHediak- Higashi Syndrome

( LYST gene mutation) : lysosomal storage protein
PARTIAL ALBINISIM
Hypersensitivity Rxns
1. Early phase is degranulation : histamine, eosinophil chemoatractant, heparin
Late phase rxn: Leukotriens and prostaglandins made
Jobs Syndrome/ Hyper IgE
Th1 dont make enough IFN-gamma therefore PMN cant respond
Absesses that are without inflammation cold
Retain primary teeth, eczema

Questions: U wooooorld

Lupus

MHC1 works opposite from CD8+ T cells and NK

Turn CD8 + T ON
Turn NK OFF
Therefore CD8 and NK dont work at the same time
any carpopedal spasm = HYPOCALCEMIA ( in child think missing parathyroid
glands)
Wiskott- Aldrich : Eczema, recurrent infection, thrombocytopenia
-X-linked
-B and T cell deficiency
- WATER : W,A, thrombocytopenia purpura, eczema, recurrent
infection
ANA( anti nuclear antibodies) : sensitive, not specific
Anti-ds DNA is specific LUPUS
AntiSMith/ snRNPs is specific LUPUS
Anti-phopholipid antibody
-cause (+) VDRL (False positive) AND prolonged PTT
-venous and arterial thromboemobilisim leading to fetal loss
Delayed hypersensitivity is from the Th1 CD4+ T cells
PUS is caused by neutrophils
-Attracted by IL-8, C5a, LT B4

Bradykinin
Leukotriene C4

-vasodilation + permeability
-smooth muscle contraction
- PAIN
-vasoCONSTRICT + increase permeability
-bronchospasm

Majority of myasthenia gravis patients have thymus abnormality ( thymoma,

thymic hyperplasia): appear as anterior mediastinal mass (in front of the
veins)

Guillain-Barre: CD 8+ T cells attack the endoneureium + cause demyelination

PNS
Polymyositis: symmetric proximal muscle weakness CD8+ mediated
- increase CK creatnine kinase
- increase anti-Jo1 antibodies

Eosinophilic Myositis: eosiniophils infiltrate skeletal muscle (rare)

Sarcoidosis high CD4: CD8 ratio! (negative PPD even if they are + bc all the
cells are sequestered at the lungs)
Polymylagia rheumatic : bilateral stiffness in shoulder and pelvis. Fever,
weightloss, increase ESR. ASSOCIATED WITH TEMPORAL ARTERITIS
Transplants
Hyper Acute: preformed antibodies. Occurs as soon as organ attached to
vessels. Thrombosis ischemia and necrosis
-Type 2 hypersensitivity reaction
Acute: vasculitis of the vessel
Chronic: fibrosis of graft and blood vessel have smooth muscle proliferation
so obliterate
Graft VS Host
Bone marrow, liver transplant
CD4 and 8 donor attack the recipient bc the MHC dont match and
recognized as forgein
Organs affected most : skin (desquamation), liver (jaundice), GI
(bleeding in poop)

HIV

Gp120 binds to both CD4 + CCR5

Without CCR5 cant enter the cell ( a chemokine receptor )
-homozygous mutant = no infection with HIV
-heterozygous mutant = slow progression of disease
CCR5 is on macrophages and dendritic cells ( reservoir)
CxCR4 is on T cells
Nef decrease expression MHC1
Tat increase viral replication
Immunodeficiency
X linked agammaglobinemia : Burtons disease (only one where ONLY B
CELLS ALL MISSING AND NOTHING ELSE)
- tyrosine kinase not working
- B cells stop differentiating at Pre B cell
- Hypercellulairty in bone marrow with high PRE B CELL
- No immunoglobulins
C3 deficiency : no MAC then Neisseria infections ( meningitides and
gonorrhea)
ATM ( Ataxia Telengiectasis Mutated)
-ATM gene
-cause DNA double stand breaks
-ataxia, teleangiectasis, and sinopulmonary infection (IgA deficiency)
Chronic Granulomatous Disease: NADPH oxidase missing
-infection with CATALASE POSITIVE ( staph, pseudomonas, enteric
like E.coli, Klebsiella, Aspergillus)

- nitroblue tetrazolium test (-) if have it bc cant turn the test blue
without reactive oxygen species
- Catalase negative die bc the cells use H2O2 by myeloperoxidase to
form HOCL (hypochlorite/ bleach).
-Catalase + break down the H2O2 from its metabolisim.
Hyper IgM: isotype switching now occurring ( alternative splicing) when the
CD40 ligand on T cells is missing
LAD Leukocyte adhesion deficiency: CD18 which is part of the integrin on
leukocytes is missing. Cant ENTER TISSUE
- HIGH WBC BLOOD
- No puss in inflammation or abcess
- Umbilical cord delayed separation
- Poor wound healing
- CD18 is beta chain of integrin
- Bacterial infection, viral normal

Random
Cadherin: Calcium dependent adheres btw cells
T cells with CD4 and CD8 on them are IMMATURE CORTICAL T CELLS (in
cortex of thymus (in medulla they have chosen either CD4 or 8 then) called
DOUBLE POSITIVE
Tetanus toxin retrograde transport to CNS and prevents release of GABA and
glycine which are inhibitory transmitters
- Tetanus toxoid causes antibodies against the toxin
Thymic epithelial cells have role in POSITIVE SELECTION
o Express MHC and see if they bind
o If mind then + select
o If dont bind then apoptosis
Eosinophils
1. Parasite : Antibody dependant Cytotoxicity : ADCC : IgE bind parasite
and then bind eosinophil to relase its granules
2. Type 1 hypersensitivity: release histaminase, to decrease histamine
from mast cell. Also LT to promote inflammation
Eosinophils against ONLY HELMINTHS ( not giardia )
Give RHOGam 28 weeks gestation and immediate post partum so that the IgG
will bind the Rh+ fetal cells before the mothers body can bind it and make
antibodies against it
Antiapoptosis
Apoptosis
Bcl-2 Bcl-x ( L for live) = prevent
Bak, Bax, Bim
cytochrome c existing mitochondria via
bax
CD15 = neutrophils and Reedsternburg cells in Hodgkins

IFN- alpha and beta cause synthesis antiviral proteins that degrade intracellular
mRna and impair protein synthesis
IL-10 and TGF- beta decrease inflammation