DISEASE

Complement
Deficiency

CAUSE/COMPLICATIONS

Hereditary
Angioneurotic
Edema (HANE)

Paroxysmal
Nocturnal
Hemoglobinuria

-C1, C4, C2 crucial for clearing

apoptotic cells (F &
autoimmune nephritis)
-terminal component defect
usually results in infections
listed above (both gram neg.)
terminal complex doesnt affect
gram +
-Hereditary Angioneurotic
Edema results from vascular
activation by complement
and kinins caused by
deficiency of C1 esterase
inhibitor (a protein found in
plasma)
- Paroxysmal Nocturnal
Hemoglobinuria
hemolytic episodes,
increased cancer risk, due to
deficiency of DAF and CD59
(cell-associated inhibitor of
C3 convertases or
membrane attack
complexes, respectively)
Lyse own cells in times of
hypoxia

Tx?
Activated
Protein C
(drotrecogi
n)
restricted
to severe
sepsis with
high risk of
death

EXAMPLE

Result: Disseminated Intravascular Coagulation

This is rapid, this picture taken 24 hrs after onset.

Diffuse hemorrhage such as this is known

as pupura fulminans (fulminans means
fast)

Angioneurotic edema:

DISEASE
Circulatory
Shock

CAUSE/COMPLICATIONS

Tx?

EXAMPLE

-hypotension (less than

60mmHg)
-Tachycardia
-Oliguria (loss urine
production)
-altered mental status
-peripherial hypoperfusion and
hypoxia

Systemic lupus
erythematosis

90% of individuals w/C1q

deficiency end up with SLE.
Many kinds & many causes
involved (multifactorial), other
kinds of lupus can bring on SLE
Wiki:
http://en.wikipedia.org/wiki/S
ystemic_lupus_erythematosus
T cell dependent antibody
mediated

ANA test: Antibodies to RNA,

DNA, proteins, lipids (to
apoptotic blebs presented by
DC).
Broad response
glomerulonephritis
Risks:
-Early classical pathway
complement component
deficiency
-gender
-HLA haplotype
-Ability to clear apoptotic cells
before they become necrotic
Type II, III, & IV
Hypersensitivities (difficult to
know what precipitates)

Immune
suppressants
Analgesics
Disease
modifying
antirheumatics
Hydroxychloroq
uinone (malaria
drug) to maybe
(?) inhibit
antigen
processing
and/or
DNA/RNA
induced
TLR9/TLR7
activation

Classic butterfly rash

Cytotoxic
agents (kill T
cells B cells)
Experimental:
monoclonal B
cell depletion

Analogous to H.flu vaccine design

DISEASE
DIC

CAUSE/COMPLICATIONS

(see
Compliment
Def. 1st entry)

Tx?
Tx
underlying
illness

EXAMPLE
(See Compliment def. 1st entry) can be
caused by other (sepsis) We got this
picture for example of DIC and
Complement Deficiency

Plasma
substitutio
n (clotting
factors)
Platelets depleted b/c so many
clots have formed

Platelet
infusion
Protein C
(see above)

Chediak-Higashi
Syndrome

CHS is an autosomal recessive

disorder of all lysosomal
granule containing cells with
clinical features involving the
hematological and neurological
system
-All cells containing lysosomes
have giant granules.
-In neutrophils large granules
result from abnormal fusion
of azurophilic and specific
granules; granule fusion with
phagosomes is impaired.
-Neutrophils of CHS patients
fail to orient themselves
during chemotaxis resulting in
impaired recruitment into
tissues
-Mutated gene: LYST = protein
involved in vacuolar
formation and transport of
proteins
-mild mental retardation
-peripheral nerve defects
-later onset of lymphoma-like,
lymphoproliferative diseases
due to defects in cytotoxic T
cells, typically viral EBV

Not always this extreme, can look like

frost/highlight hair dye job
Typical infections:
S. Aureus, Group A Streptococci

DISEASE
Chronic
Granulomatous
Disease

CAUSE/COMPLICATIONS
-CGD is a caused by genetic
defect in one of the four
subunits of the NADPH
oxidase.
-70% are due to an X-linked
defect in gp91 phox
-Other forms are autosomal
recessive

-Invasive infections due to all

types catalase-positive
bacteria and fungi
Staphylococcus aureus,
Pseudomonas, Nocardia,
Aspergillus, etc
-Why not catalase-negative
ones? They make their own
H2O2 and without catalase
they cant break it down when
quarantined in
phagolysosome.
-Lymphadenopathy and

hepatosplenomegaly
(enlarged lymph nodes, liver
and spleen), eczema and
diarrhea
-Recurrent infections of lungs,
bones, skin, lymph nodes,
gums (gingivitis)
-Chronic granulomatous
tissue inflammation,
particularly in the gut, in
attempt to wall-off infection
that cannot be cleared
completely
-Usual age of onset <6
months, but may be later

Tx?

EXAMPLE

DISEASE
Adult
Respiratory
Distress
Syndrome
(ARDS)

CAUSE/COMPLICATIONS
Diffuse pulmonary
parenchymal injury associated
w/non-cardiogenic pulmonary
edema
(this can occur from sepsis
edema)
Alveolar walls become lined
with hyaline membranes
(fibrin)
Mortality 60%
Diffuse alveolar damage

Dx:
In clinical practice the
diagnosis is based on:
-Severe sepsis or other
disease known to be
associated with DIC
-Vascular thromboses
and/or diffuse bleeding
-Platelet count less than
100,000/ml
(thrombocytopenia)
and/or rapid, progressive
decline of the platelet
count
-Prolongation of clotting
assay times
-Presence of fibrin split
products
-Low levels of coagulation
inhibitors (Antithrombin
III, Protein C)

Tx?

EXAMPLE

DISEASE
Leprosy

CAUSE/COMPLICATIONS
-see slide
-Th2 cell response in
lepratomous
leprosy=worse than no
response at all!
(Th1, TNF, IFNgamma
necessary for granuloma)

DiGeorge
Syndrome
(a combined
immunodeficien
cy)

Chromosome 22q11
microdeletion
developmental defects of
heart, parathyroid and
thymus the T cell defect
is usually mild but is
severe in ~5-10%
Typical- thymus missing

Tx?

EXAMPLE

DISEASE

CAUSE/COMPLICATIONS

Tx?

EXAMPLE
Severe:

Thrush due to severe form, lack of T cells

Bare
lymphocyte
syndrome
(a combined
immunodeficien
cy)

-Lack of MHC class II

expression or loading of
peptides in MHC class I
by TAP,
-results in CD4 or CD8 T
cell defects, respectively
-rare recessive genetic T
cell deficiency w/ marked
reduced expression of
MHC

Bone
marrow
transplant

Chronic respiratory infections

End up with lots viral infections

-clinically similar to SCID

Severe
Combined
Immunodeficien
cy (SCID)

SCID = T cell deficiency

with or without
accompanying B cell
and/or NK cell
deficiency
X-linked recessive
(most common) T
and NK cells low or
absent defect in c,
the common cytokine
receptor subunit for
IL-2, IL-4, IL-7, IL-15
receptors
Autosomal recessive
T and B cells low or
absent and NK cell
numbers normal
most often due to RAG
defect
Autosomal recessive
T cells low, normal
numbers of B and NK
cells IL-7 receptor

Bone
marrow
transplant
Some
successful
cases of
gene
therapy,
but caused
leukemia,
too in some
so not
standard
practice
(see
biochem
fall 08)

Varicella infection

DISEASE

CAUSE/COMPLICATIONS
defect

ADA-SCID

Chromosome 20

Leukocyte
Adhesion
Deficiency (LAD)

See example. Have

trouble w/ANY kind of
bacteria
Note: any trouble
w/neutrophils will give
you trouble w/gums

Tx?

Injection of
conjugate
bovine ADA
(PEG-ADA).
Bone
marrow
transplan
tation.
Retroviral
gene
therapy

Circulatin
g T-Cells
Retroviral
gene
therapy

Hematop
oetic
Stem
Cells
Lethal if
not treated
w/marrow
transplant

EXAMPLE

DISEASE
B cell
malignancies
Clonal tumors

CAUSE/COMPLICATIONS
See chart
V(J)D rearrangements
may give rise to some.
Burkitts lymphoma
due to chromosome 8
& 14 translocation

T cell
malignancies

May also result from

somatic
rearrangements

Tx?

EXAMPLE

DISEASE
Chronic
Inflammatory
Diseases

CAUSE/COMPLICATIONS

Reponse to M.
tuberculosis

Chronic inflammation can

also lead to fibrotic tissue
changes

Tx?
Varies
w/disease

EXAMPLE

Children
get BCG live
attenuated
tuberculosi
s vaccine as
they are
more
susceptible

See other entry for leprosy picture

Typically more
mononuclear cells than
neutrophils
Continued recruitment of
macrophages = tissue
damage
Sarcoidosis not sure of cause: note that
it does not have caseous necrosis
NOTE: Without Th1, cannot form a

granuloma and necrosis can spread to

adjacent tissues. This happens in
immunocompromised patients with
AIDS and children.

DISEASE

CAUSE/COMPLICATIONS

Relapsing Fever

Bacterial infection
(spirochete)
Other relapsing infections
are acquired from other
Borrelia species, such as
Borrelia hermsii or Borrelia
parkeri, which can be
spread from rodents, and
serve as a reservoir for the
infection, via a tick vector.
Borrelia hermsii and
Borrelia recurrentis cause
very similar diseases
although the disease
associated with Borrelia
hermsii has more relapses
and is responsible for more
fatalities, while the disease
caused by B. recurrentis has
longer febrile and afebrile
intervals and a longer
incubation period.
Tick-borne relapsing fever is
found primarily in Africa,
Spain, Saudi Arabia, Asia,
and certain areas in the
Western U.S. and Canada.
(wikipedia)

Tx?

EXAMPLE

DISEASE
X-linked
agammaglobuli
nemia

CAUSE/COMPLICATIONS

Tx?

EXAMPLE

Give
pooled IVIG
($$$$$)

Defect in CD40 ligand means:

cannot make antibodies

few B cells (arrested devo)
Btk, a tyrosine kinase, is on
the X chromosome
Infection with extracellular
bact, capsulated bacterial
pathogens and viral
mucosal pathogens

X-linked Hyper
IgM Syndrome

Defect in CD40 ligand

Early onset disorder

No class switch, no memory, no affinity

maturation, no germinal centers

Autosomal recessive more

rare

Common
Variable
Immunodeficien
cy

Later onset

Selective IgA deficiency

Give
pooled IVIG
($$$$$)

IgG usually LOW

(see slide)

Antibody
production
disorders

Antibody mediated
opsonization & viral
neutralization is lost

Give
pooled IVIG
($$$$$)

Infection with capsulated bacterial

pathogens and viral mucosal pathogens
Esp. recurrent & chronic respiratory and
GI tract infections with extracellular
capsulated bacteria (e.g. Strep. pneum) &
certain viral pathogens (e.g.
enteroviruses)

Asplenia

Surgical removal
Functional asplenia (sickle
cell anemia)

Susceptible to gram (+) sepsis, especially

encapsulated bacteria

DISEASE
Congenital
Neutropenia/cy
clic neutropenia

CAUSE/COMPLICATIONS

Genetic
susceptibility to
Mycobacterial
disease

Th1 defect in activating

macrophages

Myasthenia
Gravis

Ach Receptor antibodies in

over 70% of patients

Tx?

EXAMPLE

Genetic defect in neutrophil

elastase

Can involve opportunistic

mycobacteria

Can be neonatal from

maternal Ab crossing
placenta
Often presents in the eyes
first.
Muscle weakness with
prominent fatigue
Normal normal nerve
conduction

Anti-AchE
Treat
immunolog
ical
Careful
over overRx because
Ach
receptors
may
become
desensitize
d

Normal vesicle release

Watch Tensilon test:

http://www.youtube.com/watch?v=k7YX9
kuWrxA

Type II Hypersensitivity

Botulism

2+

Block Ca action of vesicle

release = synaptic
transmission at NMJ
(presynaptic problem)
EM of nerve normal,
conduction normal, muscle
excitability normal, MEPP
normal size=presynaptic
Both botulism toxin &
tetanus toxin mess with
SNARE proteins, which

Mechanical
ventilation
(months)
until body
clears toxin

BOTOX

botulism paralysis

DISEASE

CAUSE/COMPLICATIONS

Tx?

tether vesicles for release:

Tetanus Toxoid

Blocks central inhibitory

synapses (reflexes stimulate
opposing muscle groups)
Retrograde transport both
botulism toxin & tetanus
toxin:

Hyperkalemic
Periodic
Paralysis

Example of channelopathy
(of which there are many)
Gain of function mutation in
sodium channel (impaired
inactivation)

EXAMPLE
ingestion of toxin. Honey in infants
(infection) or toxin in improperly canned
foods that arent sweet/salty/acidic
enough to kill clostridial bact note that
tomatoes are no longer bred to be acidic
enough for canning w/o pressure cooker)

Very
difficult Tx,
better to
vaccinate

Glucose or
other
carbohydrates
can be given
during an attack
and may reduce
the severity. [1]

Intravenous
calcium
decreases
activity of
sodium
channels. It may
stop sudden
attacks.[1]

Diuretics such
as furosemide
may be needed
to stop sudden
attacks.[1]
acetazolamide
and thiazide
diuretics such

See videos on quarter horse model

DISEASE

CAUSE/COMPLICATIONS

Tx?

EXAMPLE

as
chlorothiazide
are also
effective.[1]

Intravenous
glucose and
insulin
stimulates
potassium
uptake into the
cell by the Na-K
ATPase and may
reduce
weakness
without a loss
of total body
potassium.[1]

A highcarbohydrate
diet may be
recommended.

-wiki

Myotonia
Congenita

Thompsons
diseases=autosomal
dominant (more severe)
Beckers=autosomal
recessive (more severe)
Perceived as a cramp
(seconds-minutes)
Warm-up phenomenon
Muscle is hyperexcitable
Dominant negative effect,
CLC-1 (Chloride channel)

Goat model
http://www.youtube.com/watch?v=we9_
CdNPuJg

DISEASE
Graves Disease

CAUSE/COMPLICATIONS
Graves disease is a thyroid
disorder characterized by
goiter, exophthalmos,
orange-peel skin, and
hyperthyroidism. It is
caused by an antibodymediated auto-immune
reaction.
Antigen=Thyroid
Stimulating Hormone
Receptor
It actually mimics the
hormone=HYPERTHYROIDIS
M
Graves disease is known for its
enlarged thyroid and eye
problems. Thyroid-associated
ophthalmopathy is one of the most
typical symptoms of Graves
disease. It is known by a variety of
terms, the most common being
Graves ophthalmopathy. Thyroid
eye disease is an inflammatory
condition, which affects the orbital
contents including the extraocular
muscles and orbital fat. It is almost
always associated with Graves
disease but may rarely be seen in
Hashimotos thyroiditis, primary
hypothyroidism, or thyroid cancer.
The ocular manifestations that are
relatively specific to Graves
disease include soft tissue
inflammation, proptosis
(protrusion of one or both globes
of the eyes), corneal exposure, and
optic nerve compression.
-wiki

Tx?
Thyroid
meds
Surgery

Treat eye
disease

EXAMPLE

DISEASE
Hashimotos
Thyroiditis

CAUSE/COMPLICATIONS
Autoimmune
T cells attack thyroid, so
Type IV Hypersensitivity
The family history of thyroid
disorders is common, with
the HLA-DR5 gene most
strongly implicated
conferring a relative risk of
3 in the UK. In addition
Hashimoto's thyroiditis may
be associated with CTLA-4
gene since the CTLA-4
antigen acts as an inhibitor
to T-Cell activation.

Tx?
Thyroid
hormone
replacemen
t

EXAMPLE
Figure legend:
From the top:
Side view of a
thyroid enlarged
by Hashimoto's
thyroiditis.
Thyroid scan
revealing the
enlarged thyroid.
Gross
appearance of
the thyroid
involved by the
Hashimoto's
thyroiditis. Low
power
microscropic
view of a section
of a thyroid
involved by the
Hashimoto's
thyroiditis. The
thyroid follicles
are surronded by
the lymphoid
cells which have
formed a
germinal center.
Mid-power
microscropic
view showing
the lymphoid
infiltrate. High
power
microscropic
view of the
thyroid showing
intimate
contacts
between the
thyrocytes and
the lymphoid
cells.

DISEASE
Multiple
sclerosis
(MS)

CAUSE/COMPLICATIONS

Tx?

EXAMPLE

Type IV Hypersensitivity
Multiple sclerosis
(abbreviated MS, also
known as disseminated
sclerosis or
encephalomyelitis
disseminata) is an
autoimmune condition in
which the immune system
attacks the central nervous
system, leading to
[1]
demyelination.
-wiki
Specifically T cells cross
blood brain barrier. Affect
oligodendrocytes
Symptoms increase with 2-4
degrees temperature
change

Guillain Barre
Syndrome

LPS of Campylobacter jejuni

resembles gangliosides on
myelin sheath
Cross rxn from antibodies,
loss on myelination
T-cell independent B cell
antibodies (so if you get rid
of infection & let B1 cells
die off=rxn goes away)
There are few to no
memory cells
Acute onset 7-9 days,
typically post-infection
Symmetrical, motor more
than sensory
Dx=slowed conduction

Supportive
Plasmaphor
esis
IV immune
globulin

This is an example of molecular mimicry

(immunology course)

DISEASE

CAUSE/COMPLICATIONS

Tx?

EXAMPLE

velocity
Symptoms increase with
elevated temp.
Type IV Hypersensitivity (T
Cell)

Addisons
Disease

Chronic adrenal
insufficiency

(adrenal
insufficiency)

Can result from endocrine

Autoimmunity (usually Type
II or IV Hypersensitivity)

Replace
hormones

United States President John F. Kennedy was

one of the best-known Addison's disease
sufferers. He was possibly one of the first
[10]
Addisonians to survive major surgery. There
was substantial secrecy surrounding his health
during his years as president, and the 25th
amendment to the U.S. constitution was
introduced at least in part as a result of this
[11]
secrecy.

Rheumatoid
Arthritis

TNF/IL-1
antagonist

Injury by type IV & type III

hypersensitivity

B7-CD28
antagonist
(blocks
IL12, IL1,
IL6, IL23)
$$$$$$$
methotrexa
te

DISEASE

Autoimmune
Lymphoprolifer
ative Syndrome
(ALPS)

CAUSE/COMPLICATIONS

Fas/fas ligand gene, cant

clear lymphocytes selected
against in nodes

Tx?
Make sure
TB (-)

EXAMPLE

Risk for
mycobacter
ia
Marrow
transplant

Autosomal dominant

Congenital
Adrenal
Hyperplasia

Step to make cortisol is

blocked, but can still
make androgens.
Feedback inhibition is
blocked, so get a buildup of androgens.
A small percentage of
patients have intersex
characteristics.

Post-mortem examination of a newborn

showing adrenal hyperplasia. The enormous
adrenal glands are indicated by arrows (the
kidneys can be seen below them). wiki

DISEASE
Pheochromocyt
oma

CAUSE/COMPLICATIONS

Tx?
Surgical
removal,
Alpha
blockade
followed by
a beta
blockade

EXAMPLE

Cushing
Syndrome

This is Cushings DISEASE NOT Syndrome

Case example of Cushings Syndrome &
more pictures:
http://www.kevinmd.com/blog/2005/03/
medical-mystery-revealed.html
Kartageners
Syndrome
(Primary Ciliary
Dyskinesia)

congenital disease
chronic sinusitis
infertility
bronchiectasis
situs inversus
90% outer/inner

No cure

Trouble with non-muscle motility (cilia)

DISEASE

CAUSE/COMPLICATIONS

Tx?

EXAMPLE

dynein defect

Velo-CardioFacial Syndrome
(VCSF)

180 kinds
Often: Tetralogy of
Fallot (hole btwn.
ventricles)

Surgery for
some of
the defects

Often cleft pallet

Claudin protein defect
(tight junctions)
nd

2 most common
inherited syndrome
Fifths Disease

Human parvo virus

B19, by the time you
get rash too late.
Problem for pregnant
woman
Cold-like symptoms,
contagious before rash

Characteristic facial features: almond

eyes, elongated face, long nose, small
nostrils

DISEASE

CAUSE/COMPLICATIONS

Petechiae

A petechia (pronounced
[ptiki]), plural petechiae
(ptiki) is a small (1-2mm)
red or purple spot on the
body, caused by a minor
hemorrhage (broken
[1]
capillary blood vessels) .

Cytomegalovir
us (CMV)

Most problematic for

Post-transplant
patients

Tx?

CMV) infection of a lung pneumocyte. The

central cell displays the dramatically
enlarged nuclei characteristic of CMV.

Herpes virus
Esp. Salivary glands
Congenital CMV passed
to fetus

Epstein-Barr
Virus (EBV)

Human Herpes virus 4

Usually asymptomatic,
but can cause
infectious
mononucleosis
(glandular fever or
kissing disease)
Fatigue, sore throat,
fever

EXAMPLE

Rest

DISEASE

CAUSE/COMPLICATIONS

Food
Poisoning
(staphylococca
l enterotoxins)

Super antigens

Cystic Fibrosis
(CF)

Mutation in epithelial
chloride channel
(defective or absent)

Tx?

EXAMPLE

Steroids/an
tiinflammato
ry drugs, IV
& inhaled
antibiotics,
nebulizers,
flutter,
digestive
enzymes,
osmotic
therapy
(hypertonic
7% NaCl) to
replete
lung
epithelium,
expectoran
ts?

CFTR:

Suppression of
adaptive response.

Can be single point

mutation that causes a
stop codon in CFTR
protein.
Constellation of
phenotypic & lab
results
Excess Cl in sweat
Now newborn screen
2 mutant CFTR alleles
Down regulation of CFTR,
lack of CFTR on surface,
Sodium is
hyperabsorbed, water
follows passively
mucus packs down cilia &
cant beat to clear
mucus.
In sweat gland, no
alternative channels
(only CFTR)
Exocrine pancreatic
dysfunction

up &
coming
potentiator
s, gene
therapy?
Alternative
Cl
channels??
Need to get
CFTR
function up
to 50%
function

F=Phenylalanine mutation 508 common

others include misfolding, many others
CFTR is ATP-binding cassette transporter
Activated by on cAMP dependent protein
kinase

DISEASE

CAUSE/COMPLICATIONS

Autoimmune
Blood
Cytopenias

Type II Hypersensitivity
Rh hemolytic anemia
Transfusion reactions
(e.g., ABO incompatibility)
Autoimmune (or
isoimmune maternalfetal) hemolytic anemia
note that ABO is IgM
mediated which doesnt
usually cross placenta & is
milder than IgG rxn
Autoimmune
thrombocytopenia and
leukopenia also occur

Tx?

EXAMPLE

DISEASE

CAUSE/COMPLICATIONS

Tx?

EXAMPLE

Atrial
Fibrillation (Afib)F

Timothy
Syndrome

Timothy syndrome is a rare

autosomal dominant
disorder characterized by
physical malformations, as
well as neurological and
developmental defects,
including heart QTprolongation, heart
arrhythmias, structural
heart defects, syndactyly
(webbing of fingers and
toes) and autism spectrum
disorders.

syndatyly

Timothy syndrome often

ends in early death.

Long Q-T
Syndrome

Defective inactivation of Na
channels increased risk
arrythmogenesis

Genetic LQTS can arise from

mutation to one of several
genes. These mutations tend
to prolong the duration of
the ventricular action
potential (APD), thus
lengthening the QT interval.

http://en.wikipedia.org/wiki/Long_QT_sy
ndrome

DISEASE

Malignant
Hyperthermia

CAUSE/COMPLICATIONS
Halothane & other inhaled
anesthetics
Triggers more than normal
calcium release in muscles

Tx?
Prevention

EXAMPLE

Dantrolene
(muscle
relaxant)

Muscle defect, linked to RyR

CICR amplification not turned
off soon enough sustained
contraction, very high Ca
levels

http://opa.faseb.org/pages/PublicEducato
rs/mh/

McArdles
Disease

See slide

Klippel-Feil
Syndrome

Bilateral reflex

Cant use glycogen

DISEASE

CAUSE/COMPLICATIONS

APECED
(autoimmune
polyendocrino
pathy
candidiasisectodermal
dystrophy)

Aire deficiency (gene

responsible for thymus
being able to express
proteins from other
tissues)

IPEX

Very rare X-linked

autoimmunity

(immunodysre
gulation
polyendocrino
pathyenteropathy Xlinked
syndrome)

Neutropenia

EXAMPLE

APECED Fingernails

Gene: FOXP3
Deficient in T Regulatory
Cells which are one of
the bodys 4 major
checkpoints in antiautoimmunity.
Early age onset of this
disease in males causes
severe enlargement of
the secondary lymphoid
organs, insulin
dependent diabetes,
eczema, food allergies,
and infections

Phagocyte
deficiencies

Tx?

Common: iatrogenic
Rare: genetic or
autoimmune
Mother can make
antibodies to fetus
neutrophils & baby is
born neutropenic

Limited
success
with
marrow
transplant

Are confined to bubbles:

Mom visits her baby after scrubbing in.

DISEASE

Inappropriate
activation of
NLRs

CAUSE/COMPLICATIONS

NLR3P mutations cause

autosomal dominant
autoinflammtory

(various
diseases, see
example slide)

HIV/AIDS

Tx?
Expensive,
daily
recombina
nt IL-1
antagonist
injections

See slide for mechanisms

HAART

Note that T cell activation is

important for incorporation
of proviral DNA into host
genome AND viral replication

Proteases,
integrases
being
targeted

Intestines get T cell depleted

st
1
Note also, that only when
virus bind to receptor does it
reveal epitopes to which
neutralizing Ab would bind.
Detect w/PCR or RTPCR
Myriad of co-infections
Combined immunodeficiency
when T cells less than
200/microL blood
CCR5 mutation=resistance
Relative resistance from
certain HLA types & CCL3L
(binds to CCR5)

EXAMPLE

DISEASE

Poliomyelitis

CAUSE/COMPLICATIONS
Fecal oral viral infection,
typically water borne

Tx?
Live
attenuated
vaccine

EXAMPLE

Paralysis

Also now
Salk
(inactivated
virus)
vaccine
used in
developed
world

Measles

Viral infection respiratory

system spread via aerosol
transmission or contact
with fluid from nose/mouth
infected person

Live
attenuated
vaccine

The classical symptoms of

measles include a four day
fever, the three Cscough,
coryza (runny nose) and
conjunctivitis (red eyes).
The fever may reach up to
40 Celsius (104
Fahrenheit).

Mumphs
(epidemic
parotitis)

rash
Viral thru respiratory
secretions
Painful swelling of the
salivary glands (classically
the parotid gland) is the
[2]
most typical presentation.
Painful testicular swelling
and rash may also occur.
The symptoms are generally
not severe in children. In
teenage males and men,

Classic measles rash

Live
attenuated
vaccine
Painkillers
if infected

Swelling of salivary & parotid glands

DISEASE

CAUSE/COMPLICATIONS

Tx?

complications such as
infertility or subfertility are
more common, although
still rare in absolute
[3][4][5]
terms.

Rubella
(aka German
Measles)

Rubella virus, transmitted in

respiratory secretions, urine
of infected persons ONLY
(no reservoir)

Live
attenuated
vaccine

children recover more

quickly than adults & not
very severe
Infection of the mother by
Rubella virus during
pregnancy can be serious; if
the mother is infected
within the first 20 weeks of
pregnancy, the child may be
born with congenital rubella
syndrome (CRS), which
entails a range of serious
incurable illnesses.
Spontaneous abortion
occurs in up to 20% of
[1]
cases.

Rotavirus

Most common childhood

diarrheal disease
Can be devastating in
developing countries (die of
dehydration)
Rotavirus is transmitted by
the faecal-oral route. It
infects cells that line the
small intestine and
produces an enterotoxin,
which induces
gastroenteritis, leading to
severe diarrhea

Live
attenuated
vaccine
ORS

EXAMPLE

DISEASE

CAUSE/COMPLICATIONS

Yellow Fever

Mosquito transmission
(also called yellow jack, or
sometimes black vomit or
American Plague) is an
[1]
acute viral disease. It is an
important cause of
hemorrhagic illness in many
African and South American
countries despite existence
of an effective vaccine. The
yellow refers to the
jaundice symptoms that
affect some patients.

Rabies
(aka
Hydrophobia)

Bite of infected mammal:

bats, monkeys, raccoons,
foxes, skunks, cattle,
wolves, dogs, mongoose or
cats provide the greatest
risk to humans.
less risk: domestic farm
animals, groundhogs,
weasels, bears and other
wild carnivores.
Almost no risk: Rodents
(mice, squirrels etc) are
seldom infected.
In the beginning stages of
rabies, the symptoms are
malaise, headache, and
fever, while in later stages it
includes acute pain, violent
movements, uncontrolled
excitements, depressions,
and the inability to swallow
water (hence the name
hydrophobia). In the final
stages, the patient begins to
have periods of mania and
lethargy, and coma. Death
generally occurs due to
respiratory insufficiency.

Tx?
Live
attenuated
vaccine
Symptomat
ic support

Live
attenuated
vaccine

EXAMPLE

DISEASE

CAUSE/COMPLICATIONS

Pertussis

Highly contagious, airborne

discharge mucous
membranes

(Whooping
Cough)

Bacterium Bordatella
pertussis
If not treated in first 24 hrs
death risk increases 90%
One of leading causes of
vaccine preventable death
in world

Tx?
Whole org.
vaccine

EXAMPLE

DTP or
DTap
(developed
world)
Stand for
diphtheria,
tetanus, &
pertussis
DTP can
cause
fever, pain
at site,
irritability,
crying

Diptheria

Diphtheria (Greek
(diphthera)pair of
leather scrolls") is an upper
respiratory tract illness
characterized by sore
throat, low fever, and an
adherent membrane (a
pseudomembrane) on the
tonsils, pharynx, and/or
[1]
nasal cavity. A milder
form of diphtheria can be
restricted to the skin. It is
caused by Corynebacterium
diphtheriae, an aerobic
[2]
Gram-positive bacterium.
Diphtheria causes the
progressive deterioration of
myelin sheaths in the
central and peripheral
nervous system leading to
degenerating motor control
and loss of sensation.
Diphtheria is a contagious
disease spread by direct
physical contact or
breathing the aerosolized
secretions of infected

Characteristic bull neck

DISEASE

CAUSE/COMPLICATIONS

Tx?

EXAMPLE

individuals.

RNA viral infection spread

via airborne respiratory
secretions

Influenza
(flu)

Whole
vaccine

there is also a less widely

used live-attenuated,
intranasal flu vaccine)

Hepatitis A

Hepatitis B

fecal-oral route via food

contamination
(Parham text error
hepatitis A vaccine is an
inactivated whole virus
vaccine not a subunit
vaccine)

sexual transmission
body fluid contact

Inactivated
whole virus
vaccine

Subunit
single
protein
HBsAg
made in
yeast
vaccine

Ascites & extreme complications of hep B

infected liver

DISEASE

CAUSE/COMPLICATIONS

Tx?

EXAMPLE
http://en.wikipedia.org/wiki/Hepatitis#Ty
pes

gram negative coccobacillus

Conjugate
vaccine

Think DIC, cellulitis, vaculitis

Hepatitis (C-G)
Haemophilus
influenzae
type b

Allergies

Essential elimination of H.
influenzae meningitis since
introduction of conjugate
vaccine
Reduction in S. pneumoniae
and N. meningitidis invasive
disease

incidence rising in
developed world,
may have genetic
predisposition to make Th2
and IgE in response to
harmless proteins
Type I Hypersensitivity

Shown is perioribital cellulitis

Eye cultures showed HIb and strep
pneumo

Various
Anti
inflammator
y meds
Allergy shots
for some
For
anaphylaxis=
epinephrine

Pencillin common hapten for anaphylaxis

DISEASE

Penicillininduced
hemolytic
anemia

CAUSE/COMPLICATIONS

Tx?

EXAMPLE

Type II Hypersensitivity
Mediated by IgG (or less
commonly IgM) antibodies
binding to host cells,
inducing complement
activation, injurious tissue
inflammation/injury or host
cell opsonization and
removal

Antibodies are directed

against

Hapten-modified self
antigens that create a novel
(non-self) epitope. Hapten
= small molecule that
attaches covalently to host
protein creating a novel
foreign epitope Ab
response

Allelic variations of self

antigens - in mother-baby
(e.g.,Rh disease) or
transplant situations

Self antigens in
autoimmune diseases

Note: macrophage in pic should be DC

DISEASE

CAUSE/COMPLICATIONS

Hypoglycemia

Type II Hypersensitivity

Tx?

EXAMPLE

Insulin receptor agonist

Chronic
Urticaria

Type II Hypersensitivity
Receptor-bound IgE or IgE
agonist

Type III
Hypersensitivit
y

Antigen must induce

antibodies and then persist
long enough to form
abundant antigen:antibody
complexes at ~1:1 ratio
Common antigens: foreign
serum proteins (e.g.,
immunoglobulins) = serum
sickness; also caused by
some drugs and some
bacterial pathogens

Persistent itchy rash

DISEASE

Delayed
contact
hypersensitivit
y

CAUSE/COMPLICATIONS

Tx?

Type IV Hypersensitivity

Treatment
removal of
inciting
agent,
topical
corticosteroi
ds

Poison ivy/oak,
Plants, metals, etc.
Delayed hypersensitivity
tuberculosis the TB skin
test index of past
infection and of Th1 T cell
immunity
Contact hypersensitivity
e.g., poison oak, metals
anti-hapten-self-protein
Th1 and CD8 T cell
immunity

InsulinDependent
Diabetes
Mellitus

see slide
(note: predisposition does
not equal predestination)
T cell (type IV)- and T celldependent IgG antibody
(type II) -mediated
[common forms of
endocrine autoimmunity]
autoimmunity to insulin
and other proteins specific
to pancreatic insulinproducing cells (b cells)
Autoimmunity islet
inflammation destroys b
cells over months to years
loss of insulin
production diabetes
Disease onset most
common in childhood,
incidence increasing

Diet, insulin

EXAMPLE

DISEASE

Sympathetic
Opthalmia

CAUSE/COMPLICATIONS

Autoimmunity
: Bystander
Activation

Rheumatic
Fever (post
strep A
infection)

Common
autoimmune
disorders postinfectious

Tx?

EXAMPLE

ignorance to self-cells is lost

exposure induces autoimmunity

infection
MHC II expression on wrong
tissue type

molecular mimicry

A child develops pharyngitis due to group

A streptococcus, but this goes undetected
and untreated. Three weeks later, she
develops fever, shortness of breath and
migratory joint pains. On examination you
hear a loud systolic cardiac murmur.

DISEASE

Human
Papilloma
Virus 16

CAUSE/COMPLICATIONS

Tx?

cervical cancer

Preexposure
Vaccine

(HPV)

Cat-Scratch

Fever

rod shaped gram neg. bact

Bartonella

Eaton-Lambert
Syndrome
(inverse
myasthenia
gravis)
actin defect (rod-like
Nemaline
structures)
myotonia

CharcotMarie-Tooth

Hereditary Motor and

Sensory Neuropathy
(HMSN), Hereditary
Sensorimotor Neuropathy
(HSMN), or Peroneal
Muscular Atrophy, is a
heterogeneous inherited
disorder of nerves
(neuropathy) that is
characterized by loss of
muscle tissue and touch
sensation, predominantly in
the feet and legs but also in
the hands and arms in the
advanced stages of disease.
The disorder is caused by
the absence of proteins that
are essential for normal
function of the nerves due
to errors in the genes
coding these molecules. The
absence of these chemical

EXAMPLE

DISEASE

CAUSE/COMPLICATIONS

Tx?

EXAMPLE

substances gives rise to

dysfunction either in the
axon or the myelin sheath
of the nerve cell. Most of
the mutations identified
result in disrupted myelin
production, however a
small proportion of
mutations occur in gene
MFN2, which doesn't seem
to have anything to do with
myelin. Instead MFN2
controls behaviour of
mitochondria. Recent
research showed that the
mutated MFN2 causes
mitochondria to form large
clusters. In nerve cells these
large clusters of
mitochondria failed to
travel down the axon
towards the synapses. It is
suggested these
mitochondria clots make
the synapses fail, resulting
in CMT disease

Biochem:

Presently incurable, this

37 in 100,000 affected.

Metabolic
Myopathies:
Tarui Disease
McArdles (see
above entry,
M glycogen
phosphorylase
def.)

M type PFK deficiency

Difficulty w/exercise, muscle weakness,

pain, & cramping. During vigorous exercise
they show no elevation of blood lactic acid
and they excrete high levels of myoglobin
in urine due to muscle damage.

DISEASE

Beriberi

CAUSE/COMPLICATIONS

Thiamine (vit. B1) deficiency

needed for TPP (bridging
step glycolysis to TCA)

Tx?

EXAMPLE
High rice diets, low protein

Co2 transfer rxns

may be mild or severe,

PDH deficiency

subunit poisoning (E1, E2,

E3) OR regulatory
phosphatase mutation

ALL have lactic acidosis, spectrum of

neurological problems

DISEASE

Niacin (of
NAD/NADP)
deficiency =
Pellagra

CAUSE/COMPLICATIONS

Tx?

EXAMPLE

dermatitis, diarrhea,
irritability, sleeplessness, &
confusion.
Limited ability to make
tryptophanniacin with B6

Niacin=vit. B3

But not enough for needs

RiboFlavin
The F in FAD
Vit. B2

Niacin is one of five

vitamins associated with a
pandemic deficiency
disease: these are niacin
(pellagra), vitamin C
(scurvy), thiamin (beriberi),
vitamin D (rickets), and
vitamin A (no common
name, but one of the most
common symptomatic
deficiencies worldwide).
made by intestinal bacteria
Patients with anorexia
nervosa
Individuals who avoid dairy
products (such as people
with lactose intolerance)
since dairy products are a
good source of riboflavin
Patients with malabsorptive
syndromes such as celiac
sprue, malignancies, and
short bowel syndrome
Rare inborn errors of
metabolism in which there
is a defect in riboflavin
synthesis [28]
Long-term use of
phenobarbital and other
barbiturates, which may
lead to oxidation of
riboflavin and impair its

The corn in this picture must be treated

with lime (KOH or CaOH used for making
tortillas=nixtamalization) to release niacin
in a bio-available form.

DISEASE

CAUSE/COMPLICATIONS
function [29]

Dinitrophenol
poisoning

Cyanide,
carbon
monoxide,
rotenone

uncouples proton gradient

in mitochondria
diet pill
can overheat & die

block electron transport

chain

glutathione doesnt work

well as an antioxidant,
because you need NADPH
to keep it going.

Poisoning

G6PD
Deficiency

These individuals have an

inefficient PPP, therefore
less NADPH

Tx?

EXAMPLE

DISEASE

CAUSE/COMPLICATIONS

Tx?

EXAMPLE

mtDNA defect
Leber's
Hereditary
Optic
Neuropathy
(LHON)

Missense mutation of the

mtDNA for complex 1

Neurogenic
muscle
weakness,
Ataxia and
Retinitis
Pigmentosa
(NARP)

Missensse mutation for

mtDNA for ATP synthase

Myoclonic
Epilepsy and
Ragged-Red
Fiber Disease
(MERRF)

Mutation in protein
biosynthesis tRNA lys

http://en.wikipedia.org/wiki/Mitochondri
al_disease

DISEASE
Mitochondrial
Encephalomyop
athy, Lactic
Acidosis and
Strokelike
Symptoms
(MELAS)

CAUSE/COMPLICATIONS
Mutation in tRNA leucine

Leigh Syndrome

Devastating
encephalopathy arises
from mutation resulting
in cytochrome oxidase
deficiency

(nDNA)

CoQ deficiency
(nDNA)

Fructose
intolerance
aldolase B
deficency

Tx?

Also nDNA mutation

resulting in inability to
synthesize CoQ from
tyrosine.

Administer
CoQ

Because fructokinase
step is not regulated, f1
phosphate accumulates

Dont give
parenteral
fructose

Problem with aldolase B

Depletion of ATP, causing
liver and kidney damage

EXAMPLE

DISEASE
Galactosemia

CAUSE/COMPLICATIONS
Most common mutation
galactose-1-PUDPgalactose (transferase)

Tx?
Treated
with
lactosedeficient
diet

EXAMPLE

High
fructose in
the urine

Normal individuals

Autosomal recessive
(~1:50,000 births)
reasonably frequent human
disease several alleles in uridyl
transferase, these are
the most common. There are some
mutations in the epimerase
both lead to the build up of
galactose in the blood
TREAT early by avoiding lactose

Essential
Fructosuria

Fructokinase deficiency

Hers Disease

Deficiency of liver
glycogen phosphorylase

Why are the symptoms so mild?

Still able to do gluconeogenesis

Symptoms
Glycogen,
hepatomegaly
Mild hypoglycemia
Good prognosis
hepatomegaly
Von Gierkes
Disease

Deficiency of G6P
phosphatase

Type I Glycogen
Storage Disease

Symptoms
cant release glycogen
from the liver

Frequent
feedings,
continuous
nocturnal
feeding to
avoid
fasting

Why are the symptoms so severe?

DISEASE

CAUSE/COMPLICATIONS
severe hypoglycemia
lactic acidosis
glycogen accumulation,
hepatomegaly

Biotin (vit. B7)

deficiency

Coenzyme of
carboxylation reactions.
pyruvate carboxylase
acetyl CoA carboxylase
No RDA, adequate
intake, 50 g/1000 kcal.

Pyridoxal
Phosphate (PLP)
Vitamin B6
deficiency

Tx?
Fasting
hypoglyce
mia life
threatening

EXAMPLE

Deficiency:
raw egg diet (avidin, Kd = 10-15 M).
dermatitis, hair loss
muscle pain
http://www.illumistream.com/index.php?
vitamins_and_minerals

PLP needed for:

Anemia

-transamination rxns

Irritability

-decarboxylation rxns

Nervousness

-glycogen phosphorylase

Convulsions (infants)

-heme synthesis

Dermatitis

-synthesis of niacin to
tryptophan

May be caused by Isoniazid (hydrazine)

anti-tuberculosis treatments

-conversion of SerGly

DISEASE

CAUSE/COMPLICATIONS

Tx?

EXAMPLE

Maple Syrup
Urine disease

Deficiency in oxidative
de-carboxylation step of
branched amino acid
catabolism [leucine,
valine, isoleucine]

Treat with
protein
restricted
diet

Screening in some Mennonite

communities

Maple syrup scent and

appearance to the urine

Low
protein for
life

Hypotonia, apnea,
feeding difficulty
hypoglycemia, seizures,
retardation and death

Congenital
Hyperammonia

-Carbamoyl phosphate
synthetase deficiency

Vomiting hepatomegaly, lethargy,

retardation, protein intolerance

-Ornithine
transcarbamylase
deficiency

AMMONIA TOXICITY

-Citrullinimia

Chronic
metabolic
acidosis

Glutamine goes to
kidneys instead of to liver

Symptoms of acidosis

DISEASE

NADH shift

CAUSE/COMPLICATIONS
NADH shift can cause a
blocking of glucose
production in liver
This can cause problems
with gout patients
drinking alcohol or
patients taking insulin to
tightly regulate blood
sugar

Tx?

EXAMPLE
Alcohol dehydrogenase & acetaldehyde
dehydrongenase BOTH convert NAD+ to
NADH, thus pushing LDH toward lactic
acid.
Oxaloacetate gets pushed to malate (also
depletes reactants for gluconeogenesis)

Alcohol combined with

lack of
nutrition=hypoglycemia
Methanol &
ethylene glycol
poisoning

Convert to aldehydes=
poison

MCAD
mutations

Fasting hypoglycemia, Boxidation is inefficient,

cant burn fat to run
gluconeogenesis during
periods of fasting

(less
common=VLCA
D, LCAD, SCAD)

Fasting hypoglycemia dangerous

Medium chain acylCoA

dehydrogenase mutated
Rel. Common 1/15,000
Adrenoleukodys
trophy (ALD)

Enzyme catalyzing
activation of very long
chain fatty acids is
deficient

In juvenile form, results in cerebral

demyelination, blindness, spastic
tetraplegia, & death

DISEASE
Kwashiorkor

CAUSE/COMPLICATIONS
Malnutrition associated
with inadequate protein

Tx?

EXAMPLE

Ascites, dermatitis,
depigmentation
Often when weaned off
bm

Maramus

Severe calorie deficiency

Chachexia

Weight loss, muscle

atrophy, loss of appetite
in a person not fasting

Diabetic Coma

Three types:
1. ketoacidosis
2. insulin shock
(hypoglycemia)

Generally caused by an underlying disease

DISEASE

CAUSE/COMPLICATIONS
3. hyperosmolar
nonketotic coma

Tx?

EXAMPLE

Table 1
Inherited Diseases of Glycogen Metabolism
Type Enzyme
0
Glycogen synthase

Organ Affected
Liver

G6P phosphatase
(Von Gierkes
disease)
Lysosomal glucosidase
(Pompes disease)

Liver

III

Debranching enzyme
(Coris disease)

Liver, muscle

IV

Branching enzyme

Liver, spleen

Glycogen
phosphorylase
(McArdless disease)
Glycogen
phosphorylase
(Hers disease)
Phosphofructokinase
(Taruis disease)
Phosphorylase kinase

Muscle

II

VI

VII
VIII

RARE:

Generalized

Liver

Muscle, RBC

Symptoms
Hypoglycemia, hyperketonemia,
failure to thrive, early death
Enlarged liver and kidney, failure to
grow, fasting hypoglycemia, acidosis,
lipemia
Infantile form: early-onset progressive
hypotonia, cardiac failure, death
before two years, glycogen deposits in
lysosomes
Fasting hypoglycemia, enlarged liver,
myopathic features, glycogen
deposits with short outer branches.
Enlarged liver, glycogen deposits
without branches, foreign body
reaction, often fatal.
Exercise-induced muscular pain,
cramps, progressive weakness,
sometimes with myoglobinuria.
Enlarged liver, mild hypoglycemia,
good prognosis.
As in V

Liver & muscle Enlarged liver

(autosomal
recessive)

Table 1
Inherited Diseases of Glycogen Metabolism
Type Enzyme
0
Glycogen synthase
I

II

G6P phosphatase
(Von Gierkes
disease)
Lysosomal glucosidase
(Pompes disease)

III

Debranching enzyme
(Coris disease)

IV

Branching enzyme

Glycogen
phosphorylase
(McArdless disease)
Glycogen
phosphorylase
(Hers disease)
Phosphofructokinase
(Taruis disease)
Phosphorylase kinase

VI

VII
VIII

Organ Affected Symptoms

Liver
Hypoglycemia, hyperketonemia,
failure to thrive, early death
Liver
Enlarged liver and kidney, failure to
grow, fasting hypoglycemia, acidosis,
lipemia
Generalized
Infantile form: early-onset progressive
hypotonia, cardiac failure, death
before two years, glycogen deposits in
lysosomes
Liver, muscle
Fasting hypoglycemia, enlarged liver,
myopathic features, glycogen
deposits with short outer branches.
Liver, spleen
Enlarged liver, glycogen deposits
without branches, foreign body
reaction, often fatal.
Muscle
Exercise-induced muscular pain,
cramps, progressive weakness,
sometimes with myoglobinuria.
Liver
Enlarged liver, mild hypoglycemia,
good prognosis.
Muscle, RBC

As in V

Liver & muscle Enlarged liver

(autosomal
recessive)