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Immunopathology
Ahmad Shihada Silmi
Hematologist & Immunologist
IUG
Section A
Hypersensitivity
Gell and Coombs Classification of Hypersensitivities
Types of Hypersensitivity
Adapted from: Kuby Immunology, Sixth Edition
Type I Hypersensitivity
Classic allergy
• Mediated by IgE attached to Mast cells.
• The symptoms resulting from allergic
responses are known as anaphylaxis.
– Includes: Hay fever, asthma, eczema, bee stings,
food allergies.
Allergens
• Allergens are nonparasite antigens that can
stimulate a type I hypersensitivity response
• Allergens bind to IgE and trigger
degranulation of chemical mediators.
Allergens
Proteins
Foreign serum
Vaccines
Plant pollens
Drugs
Penicillin
Sulfonamides
Local anesthetics
Foods
Nuts
Eggs
Insect products
Bee venom
Dust mites
Mold Spores
Animal hair and dander
Characteristics of allergens
• Small 15-40,000 MW proteins.
• Specific protein components
• Often enzymes.
• Low dose of allergen
• Mucosal exposure.
• Most allergens promote a Th2 immune
response.
Allergens
Example: Der P1
• Der P1 is an enzyme
allergen
• from the fecal pellets of
the dust mite.
Der P1 Allergen
Allergen is easily aerosolized and inhaled. Der P1 breaks down
components of tight junctions which helps it to cross mucosa.
Atopy
• Atopy is the term for the genetic trait to have
a predisposition for localized anaphylaxis.
• Atopic individuals have higher levels of IgE
and eosinophils.
Genetic Predisposition
Type I hypersensitivity
• Candidate polymorphic genes include:
–
–
–
–
–
IL-4 Receptor.
IL-4 cytokine (promoter region).
FcεRI. High affinity IgE receptor.
Class II MHC (present peptides promoting Th2 response).
Inflammation genes.
Mechanisms of allergic response
Sensitization
• Repeated exposure to allergens initiates
immune response that generates IgE isotype.
• Th2 cells required to provide the IL-4
required to get isotype switching to IgE.
Mechanisms of allergic response
Sensitization
Th2/B cell interaction
Drive B cell Activation and IgE secretion
Mechanisms of allergic response
Sensitization
• The IgE can attach to
Mast cells by Fc receptor,
which increases the life
span of the IgE.
• Half-life of IgE in serum
is days whereas
attached to FcεR it is
increased to months.
Mechanisms of allergic response
Fc ε receptors (FcεR)
FcεR1
• High affinity IgE receptor found on
• mast
cells/basophils/activated eosinophils.
• Allergen binding to IgE attached to FcεR1
triggers release of granules from cell.
Mechanisms of allergic response
Effector Stage of Hypersensitivity
Secondary exposure to allergen
• Mast cells are primed with IgE on surface.
• Allergen binds IgE and cross-links to activate
signal with tyrosine phosphorylation, Ca++
influx, degranulation and release of mediators.
Type I hypersensitivity. IgE produced in response to initial allergen exposure binds to
Fc receptors on mast cells and basophils. Rechallenge with the same allergen leads to
release of histamine and other mediators, which produce various symptoms of
localized atopic reaction or generalized anaphylaxis.
Type I: Effects of Degranulation
Mediators of Type I Hypersensitivity
Immediate effects
• Histamine
• Constriction of smooth muscles.
• Bronchiole constriction = wheezing.
• Constriction of intestine = cramps-diarrhea.
• Vasodilation with increased fluid into tissues
causing increased swelling or fluid in mucosa.
• Activates enzymes for tissue breakdown.
• Leukotrienes
• Prostaglandins
Immediate vs. late effects
Mediators of Type I Hypersensitivity
Primary Mediators
Pre-formed mediators in granules
• Histamine
• Cytokines TNF-α, IL-1, IL-6.
• Chemoattractants for Neutrophils and
Eosinophils.
• Enzymes
• tryptase, chymase, cathepsin.
• Changes in connective tissue matrix, tissue
breakdown.
Type I Hypersensitivity
Secondary mediators
formed after activation
• Leukotrienes
• Prostaglandins
• Th2 cytokines- IL-4, IL-5, IL-13, GM-CSF
Continuation of sensitization cycle
• Mast cells control the immediate response.
• Eosinophils and neutrophils drive late or
chronic response.
• More IgE production further driven by
activated Mast cells, basophils,
eosinophils.
Continuation of sensitization cycle
Eosinophils
• Eosinophils play key role in late phase reaction.
• Eosinophils make:
• enzymes,
• cytokines (IL-3, IL-5, GM-CSF),
• Lipid mediators (LTC4, LTD4, PAF)
• Eosinophils can provide CD40L and IL-4
for B cell activation.
Localized anaphylaxis
• Target organ responds to direct contact with
allergen.
• Digestive tract contact results in vomiting,
cramping, diarrhea.
• Skin sensitivity usually reddened inflamed
area resulting in itching.
• Airway sensitivity results in sneezing and
rhinitis OR wheezing and asthma.
Systemic anaphylaxis
•
•
Systemic vasodilation and smooth muscle
contraction leading to severe bronchiole
constriction, edema, and shock.
Similar to systemic inflammation.
Treatment for Type I
Pharmacotherapy
•
Drugs
–
–
–
–
Non-steroidal anti-inflammatories
Antihistamines block histamine receptors.
Steroids
Theophylline OR epinephrine -prolongs or
increases cAMP levels in mast cells which
inhibits degranulation.
Treatment for Type I
Immunotherapy
•
•
Desensitization (hyposensitization) also
known as allergy shots.
Repeated injections of allergen to reduce
the IgE on Mast cells and produce IgG.
Treatment for Type I
Effect of allergy shots
Allergen Specific Antibodies
Hypersensitivity
Type II: Antibody-Mediated Cytotoxic
Hypersensitivity
• Players
– Cell-surface antigens
– Antibodies  IgM, IgG
• Inappropriate response
– Normally: eliminate foreign cells
– But: autoimmunity, or when foreign cells
should be tolerated
Type II: Mechanism
Antigen on cell surface

Antibody bind to antigens

1. Activate complements  membrane attach complex
2. Antibody-dependent cell-mediated cytotoxicity (ADCC)
 cytotoxic cells with Fc receptors bind to Fc region of
antibodies on cell
3. Opsonization  phagocytosis
Type II: Example - Autoimmunity
• Goodpasture’s Syndrome
• Antigen = α3 chain of basement membrane collagen
– Found in kidneys and lungs
• Auto-antibodies binds to α3 on own cells  crosslink Fc
receptors on cytotoxic cells  activates monocytes,
neutrophils, tissue basophils  chemokines  rescuit
more neutrophils  self tissue destruction
Type II: Example - Autoimmunity
From: Dokkyo Medical University http://www.dokkyomed.ac.jp/dep-k/cli-path/a-super/vasculitis/vashtml/vas-63.html
Type II: Example – Foreign Antigen
• Transfusion reaction  ABO blood-group
incompatibility
From: http://www.collectmedicalantiques.com/images/bloodletting/4_transfusion.jpg
TYPE II Hypersensitivity
Antibody mediated cytotoxicity
Blood Transfusion reactions
Innocuous antigens on red blood cells
EXAMPLE: ABO blood group antigens
ABO Blood Groups
• Antibody against RBC antigen binds and
mediates killing of RBCs via C’or ADCC causes
systemic inflammation.
TYPE II
Antibody mediated cytotoxicity
Drug reactions
• Drug binds to RBC surface and antibody
against drug binds and causes lysis of
RBCs.
• Immune system sees antibody bound to
"foreign antigen" on cell. ADCC
Drug-induced Thrombocytopenic
Purpura
TYPE II
Hemolytic disease of newborn
Rh factor incompatibility
• IgG Abs to Rh an innocuous RBC antigen
– Rh+ baby born to Rh- mother first time fine.
2nd time can have abs to Rh from 1st
pregnancy.
– Ab crosses placenta and baby kills its own
RBCs.
– Treat mother with Ab to Rh antigen right after
birth and mother never makes its own
immune response.
TYPE II
Rh factor incompatibility
Hypersensitivity
Type III: Immune Complex-Mediated
Hypersensitivity
Adapted from: Kuby Immunology, Sixth Edition
Type III: Immune Complex-Mediated
Hypersensitivity
• Players
– Soluble antigens
– Antibodies  IgG
– Complements
Inappropriate response
– Normally: antibody-antigen immune complex
helps antigen phagocytosis + clearance
– But: when large amount of complexes present
 tissue damage
Type III: Localized Reaction
Also called “Arthus reaction”
Previously sensitized host

Antigen exposure to specific site (ex. Inhalation, injection, etc.)

Immunoglobuin-antigen complex (IgG)

1. Complement activation (C3a/C5a anaphlytoxins, chemotactic
agents, membrane attack complex)
2. Bind Fc receptor on leukocytes (lytic enzyme secretion,
phagocytosis)
Type III: Localized Reaction
• Similar to type I hypersensitivity except for
– IgG, complement activation, inflammation, phagocytosis
TYPE III
Antigen antibody immune complexes
IgG mediated
Immune Complex Disease
• Large amount of antigen and antibodies
form complexes in blood.
• If not eliminated can deposit in capillaries
or joints and trigger inflammation.
Type III (Immune Complex) Reactions
• IgG antibodies and antigens form complexes that
lodge in basement membranes.
Type III Hypersensitivity
Autoimmunity
TYPE III
Immune Complexes
• PMNs and macrophages bind to immune
complexes via FcR and phagocytize the
complexes.
BUT
• If unable to phagocytize the immune
complexes can cause inflammation via C’
activation  C3a C4a, C5a and "frustrated
phagocytes".
TYPE III
Immune Complex Disease
"Frustrated Phagocytes”
• If neutrophils and macrophages are unable to
phagocytize the immune complexes these cells
will degranulate in the area of immune complex
deposition and trigger inflammation.
• Unable to eat -------try to digest outside cell.
Type III: Localized - Example
From: Rocking J Farm http://www.rockinjfarm.com/images/hay.jpg
• Extrinsic allergic alveolitis: “Farmer’s Lung”
• Spores of thermophilic actinomycetes in dry and dusty
moldy hay  inhale large amount  initial exposure
leads to circulating IgG  repeated exposures produce
IgG-antigen complex in lungs  pneumonitis + alveolitis
Type III: Generalized Reaction
Systemic exposure to antigen (ex. Blood stream)

Large amount of antigen load compared to amount of IgG

Small IgG-antigen complexes

Difficult to clear

Circulate and become deposited all over body

Tissue damage (same effector mechanism as localized reaction)
Type III: Generalized – Foreign Antigen
• Serum sickness
• Intravenous injection of
antitoxins/antivenins (ex.
developed from immunizing a
horse)  7-10 days  B cell
priming + class-switch to IgG
against foreign serum proteins 
IgG-antigen complexes circulating
in blood
– Joints  arthritis
– Skin  rash
– Kidneys  glomerulonephritis
From: Encyclopaedia Britannica http://student.britannica.com/comptons/art56794/A-scientist-collects-venom-from-a-snake
Serum Sickness
TYPE III
Immune Complex Disease
Localized disease
• Deposited in joints causing local
inflammation = arthritis.
• Deposited in kidneys = glomerulonephritis.
Type III: Generalized – Self Antigen
• Autoimmunity: systemic lupus erythematosis
• Environmental trigger (ex. UV)  cell death  impaired
apoptic cell clearance  nuclear proteins + DNA
exposed in circulation  auto-antibodies against nuclear
components  B cell priming + class-switch to IgG 
circulating self IgG-self antigen immune complexes
Hypersensitivity
Delayed type hypersensitivity
Th1 cells and macrophages
• DTH response is from:
– Th1 cells release cytokines to activate
macrophages causing inflammation and
tissue damage.
– Continued macrophage activation can cause
chronic inflammation resulting in tissue
lesions, scarring, and granuloma formation.
• Delayed is relative because DTH response
arise 24-72 hours after exposure rather
than within minutes.
Type IV: Delayed-Type Hypersenstivity
• Major players
– T helper 1
– Macrophages
• Inappropriate response
– Normally: necessary immune protection against
intracellular pathogens
– But: prolonged response leads to extensive tissue
destruction
Stages of Type IV DTH
Sensitization stage
• Memory Th1 cells against DTH antigens are
generated by dendritic cells during the
sensitization stage.
• These Th1 cells can activate macrophages
and trigger inflammatory response.
Type IV: Sensitization Phase
First exposure to antigen

Antigen-presenting cell (dendritic cells, macrophages)

MHC II presentation

Naïve CD4+ T cells

Activated, antigen-specific T helper 1 cells
• Time frame = 1-2 weeks
• Primary response established
Stages of Type IV DTH
Effector stage
• Secondary contact yields what we call DTH
• Th1 memory cells are activated and produce
cytokines.
– IFN-γ, TNF-α, and TNF-β which cause tissue
destruction, inflammation
– IL-2 that activates T cells and CTLs
– Chemokines- for macrophage recruitment.
– IL-3, GM-CSF for increased monocyte/macrophage
Stages of Type IV DTH
Effector stage
Secondary exposure to antigen
• Inflamed area becomes red and fluid filled can
form lesion.
– From tissue damage there is activation of clotting
cascades and tissue repair.
• Continued exposure to antigen can cause chronic
inflammation and result in granuloma formation.
Type IV: Effector Phase
Second exposure

Memory T helper 1 activated

Effector T helper 1

Inflammatory cytokines (ex. IFN)
Chemokines for phagocyte recruitment

More activated macrophages to exposure site
• At exposure site
– Mostly non-specific inflammatory cells(ex. Macrophages)
– Few antigen-specific cells (ex. T cells)
Type IV: Effector Phase
Problematic consequence
(ex. Mycobacterium tuberculosis)
bacteria cannot be cleared

Granuloma formation

Continuous macrophage + T helper 1
activation

High lytic enzyme secretion

Tissue damage
Granuloma Formation from DTH
Mediated by Chronic Inflammation
Type IV DTH
Contact dermatitis
• The response to poison oak is a classic
Type IV.
– Small molecules act as haptens and complex
with skin proteins to be taken up by APCs and
presented to Th1 cells to get sensitization.
– During secondary exposure Th1 memory cells
become activated to cause DTH.
Contact dermatitis
Type IV: Examples
• Contact dermatitis
– Small molecules (ex. Nickel)  bind to skin protein 
able to be presented and recognized by T cells
From: Mayo Clinic http://www.mayoclinic.com/health/nickel-allergy/DS00826/DSECTION=causes
Type IV (Cell-Mediated) Reactions
• Delayed-type
hypersensitivities
due to TD cells
• Cytokines attract
macrophages and
initiate tissue
damage
Type IV: Examples
• Mantoux Test (Mycobacterium tuberculosis)
– Tuberculin (purified protein derivative)  intradermal
injection  48-72 hours  swelling
– Swelling = previous exposure/sensitization
– No swelling = no previous exposure/sensitization
From: Centers for Disease Control and Prevention – Public Health Image Library
Type IV DTH
Drug reactions can be any Type
of Hypersensitivity
Section B
Autoimmunity
What is Autoimmunity?
• Autoimmunity is an immune response to
self antigens that results in disease.
• The immune response to self is a result of
a breakdown in immune tolerance.
Immune Tolerance
• Tolerance of self is a hallmark of adaptive
immune response.
• B cell tolerance vs. T cell tolerance.
B cell Tolerance
No T cell help
• Autoreactive B cells that enter lymph node should fail to get
costimulation from T cells and therefore never enter primary
follicles.
Maintenance of T cell tolerance
• Clonal deletion
– negative selection in the thymus, deletion in
the periphery.
• Sequestration of antigens
– Inside nucleus
– Inaccessible to immune system (brain, eye,
testes)
• Immunological ignorance
– self antigens at low density on APCs
– or T cells do not cross barrier.
Maintenance of T cell tolerance
• Anergy
– Lack of co-stimulation or second signal to T
cells results in anergy.
• Suppression
– T-cell cytokine mediated suppression.
– Regulatory T cells. CD4+CD25+ CTLA4+ T
cells that produce suppressive cytokines.
Inducing Autoimmunity OR
Breaking of self-tolerance
Injury (inflammation)
or
Infection
"Viral Trigger" is term for virus infection
leading to autoimmune response.
Inducing Autoimmunity
Breaking of self-tolerance
• Release of sequestered antigens: Tissue
damage by infection may allow access of T
cells and B cells to sequestered antigens.
• Antigenic (molecular) mimicry is when
similarity between foreign antigen and self
protein results in cross-reactivity.
Antigenic Mimicry
Breaking of self-tolerance
• Inappropriate expression of Class II MHC.
– Abnormal expression of class II molecules can
lead to presentation of self antigens that were
not presented in thymus or periphery.
– "non-APC" becomes APC with inflammation.
Classification of
autoimmune diseases
Autoantibody or
T cell mediated
autoimmune diseases
Antibodies to RBC antigens
Autoantibodies to surface receptors
Graves' disease =hyperthyroid
Stimulating autoantibodies bind thyrotropin receptor for thyroid stimulating hormone.
Myasthenia Gravis
Blocking Autoantibodies
Antibodies to acetyl choline receptors block muscle activation
and trigger Inflammation that causes the destruction of the
nerve/muscle junctions resulting in paralysis.
Autoantibodies to surface receptors
Blocking autoantibodies
• Hashimoto's thyroiditis =hypothyroid
– Blocking autoantibodies inhibit thyroid
function.
Goodpasture's Syndrome
• Autoantibodies to type IV collagen and
noncollagenous basement membrane
• Antibodies bind in lung and kidney causing
inflammation and destruction.
Rheumatoid Arthritis
Immune Complex Disease
• Autoantibodies to ubiquitous antigens
– IgM against IgG is called "rheumatoid factor"
– IgG against glucose-6-phosphate isomerase.
• Primary disease manifestation
– immune complexes get deposited in joints
and trigger inflammatory response.
– Complement and FcγRs play large role.
Systemic lupus erythematosus (SLE)
Immune complex disease
• Chronic IgG production to intracellular
proteins.
• Disease symptoms are widespread and
varied.
– kidney damage, lung disease, skin, eye, etc.
Systemic lupus erythematosus (SLE)
• Autoantibodies against nucleoprotein
particles:
– Nucleosome
– Spliceosome
– Ribonucleoprotein complexes
• Th response to one epitope can drive auto
Abs.
Systemic lupus erythematosus (SLE)
Lupus
• One T helper
epitope can provide
help to multiple
antibody epitopes
in the same particle
Potential disease cycle for SLE
• Immune complexes form 
– get deposited in joints, small blood vessels 
C' activation, activation of phagocytes 
– Inflammation/damage causes more release
of intracellular antigens and then
– MORE immune complexes can form
T cell Mediated Autoimmune Diseases
Multiple sclerosis (MS)
• T cell responses to myelin basic protein
(MBP).
• The destruction of the myelin sheath
results in neurological symptoms
Multiple sclerosis (MS)
• The cause remains unknown, but
autoimmunity possibly triggered during an
inflammatory response to a viral infection
is implicated.
• MBP has high sequence homology with
measles protein and Hepatitis B virus
protein.
Antigenic mimicry?
Insulin-dependent (type I)
diabetes mellitus (IDDM)
Type I diabetes
• Selective destruction of insulin-producing
β cells in the islets of Langerhans of the
pancreas.
• Autoantibodies and self-reactive T cells
have been found in human patients with
IDDM.
Type I diabetes
Specific killing of insulin producing β
islet cells
Diabetes
• CD8+ CTLs are thought to be responsible
for the actual killing of the islet cells.
• Autoantibodies are present in IDDM.
– However, animal models of IDDM have shown
that these autoantibodies alone cannot cause
IDDM.
Susceptibility Factors
MHC
• Relative Risk--- ratio of having a specific
MHC allele increases risk for that disease.
– e.g. Ankylosing spondylitis, an inflammatory
disease of the vertebral joints, the RR with
HLA-B27 is 87.
MHC
Risk for Diabetes (IDDM)
• The relative risk associated with having the
DR3/DR4 combination is 25:1
Susceptibility Factors
Gender
• Increased risk associated with gender.
– e.g. Female to male ratio for
•
•
•
•
SLE 10:1
MS 5:1
Hashimoto's thyroiditis 4:1
But IDDM is 1:1 and AS is 0.3:1.
Susceptibility Factors
Immune regulation genes
• Increased risk associated with changes in
expression of immune regulation genes.
• Decreased expression of Fas, FasL, assoc
with SLE.
• Decreased amount of Complement
proteins (C1, C2, C4) has been assoc with
SLE.
Susceptibility
Environmental factors
• Smoking has been associated with
Goodpasture's syndrome.
– Potentially the damage to lung basement
membrane helps trigger autoimmune
response.
• Pollution, occupational exposure, etc.
Treatment of Autoimmune Diseases
• Pharmacotherapy
– Anti-inflammatories--steroids or NSAIDS.
– Other specific drugs for symptoms e.g. insulin
• Possible Immunotherapies
– Block co-stimulation
– Peptide vaccines. Inject peptides to block
MHC and prevent self peptides from binding.
– Oral Tolerance. MBP ingested to induce
tolerance.
Section C
Immunodeficiencies
Host Defense Mechanisms
• Skin and mucosal barriers
• Humoral immunity (B cells, plasma cells,
Ab)
• Cell-mediated immunity (T cells)
• Phagocytosis
• Complement
Suspecting Immunodeficiency
• Look for infections that are:
–
–
–
–
–
–
Frequent
Recurrent/chronic
Unusual organisms
Organisms that respond poorly to therapy
Growth retardation
Family history
Suspecting Immunodeficiency
• Humoral (antibody) deficiency associated with:
– Recurrent infections with encapsulated bacteria
– Chronic sinupulmonary infections
• Cell-mediated deficiency characterized by:
– Recurrent infections with
•
•
•
Viruses
Fungi
Opportunistic organisms (PCP)
– Diarrhea, wasting, growth retardation
• Combined immunodeficiency
Humoral Immunodeficiency (B
cells)
Humoral Immunodeficiency
(B cells)
•
Transient hypogammaglobulinemia of infancy
–
–
–
–
•
Slow to develop normal levels of antibody
Asymptomatic, minor infections
Low levels of IgG, IgA (IgM usually normal)
Resolves by 3-6 yo
IgA deficiency
–
–
–
–
–
–
Most common humoral antibody deficiency
50-80% asymptomatic
Recurrent sinopulmonary infections most frequent
manifestation
May have severe malabsorption (chronic diarrhea)
Isolated low IgA level
Increased risk of autoimmune disorders
Bruton’s X-linked Agammaglobulinemia
• No B cells
• Child clinically well for first 6 months of life
• Recurrent upper/lower respiratory tract
infections with encapsulated bacteria
(S. pneumo, H.flu)
– Bronchiectasis  chronic cough/increased sputum
•
•
•
•
Sepsis, meningitis, skin infections
Paucity of lymphoid tissue (tonsils, adenoids)
Markedly decreased IgG, IgA, IgM
Treatment: IVIG, antibiotic therapy
Common Variable
Immunodeficiency
• B lymphs don’t differentiate into plasma
cells
• Recurrent sinopulmonary infections
• Low IgG, IgA, IgM
• Treatment: IVIG
• Associated with autoimmune disease,
lymphoma
Cellular Immunodeficiency
(T cell)
DiGeorge Syndrome
• No T cells secondary to thymic hypoplasia
• “CATCH 22”
• Overwhelming infections with viruses,
fungi, bacteria
• Treatment: correct hypocalcemia, cardiac
defects, fetal thymus transplant
Combined Immunodeficiency
SCID
• Defects in stem cell maturation
• Adenosine deaminase deficiency (toxic insult to
T and B cells)
• Manifestations seen in first 3 months of life
– Recurrent, severe bacterial, viral, fungal, and
protozoan infections (usually respiratory infections)
– Failure to thrive, diarrhea, dermatitis, candidiasis
• Most have lymphopenia, decreased IgG, IgA,
and IgM
– Diagnosis made by analysis of T, B, and NK cell
subsets
• Treatment: isolation, treat underlying infections,
bone marrow transplant
Wiskott-Aldrich Syndrome
• X-linked recessive
• Symptoms in infancy
– Recurrent, severe infections
– Eczema
– Thrombocytopenia (petechiae)
• Low levels of IgM
• Increased risk for hematologic
malignancy
• Treatment: manage bleeding/infections,
BMT
Ataxia Telangiectasia
• Autosomal recessive deficiency in DNA
repair affecting T and B cells
• Progressive ataxia, telangiectasia,
variable immunodeficiency (recurrent
sinopulmonary infections common)
• Increased risk of malignancy (leukemia,
lymphoma)
Hyper IgE (Job) syndrome
• Autosomal recessive
• Symptoms/signs
– Coarse facial features/skeletal abnormalities
– Recurrent staph infections
•
•
Impetigo (resistant)
Pneumonia with pneumatocele formation
– 3 E’s: Elevated IgE, Eosinophilia, Eczema
Hyper IgM Syndrome
• T cell abnormality preventing IgM  IgG
• X-linked recessive (males 6 mo-1 year)
• Frequent sinopulmonary infections,
diarrhea, opportunistic infections (PCP)
• Low levels of IgG/IgA, high levels of IgM
• Treatment: Ig replacement
HIV
• Retrovirus infecting CD4 + cells
– Vertical transmission, breastmilk, sex
• Wide range of clinical manifestations
– Failure to thrive, fevers, night sweats,
malaise, recurrent thrush, recurrent bacterial
infections
• Decreased CD4 count, may have
elevated Ig
Acquired Immunodeficiency Syndrome (AIDS)
Structure of HIV-1
gp120
gp41
Envelope
env
Protease
Reverse
Trascriptase
Integrase
pol
Matrix (p17)
gag
Genome
Capsid (p24)
Serological Profile
Kuby, 2007
Immunological Abnormalities
• Infection and destruction of dendritic cells,
macrophages and Th cells
• Late decrease in Th cell numbers (200/mm3
blood)
Phagocytic Disorders
Chronic Granulamatous Disease
(CGD)
• Defective NADPH oxidase
• 75% X-linked recessive, 25% autosomal
recessive
• Severe, recurrent staph aureus infections of
lymph nodes, and skin (granulomas, heal
slowly), pneumonitis, osteo,
hepatosplenomegaly
• Dx: Nitroblue tetrazolium (NBT) test
• Treatment: antimicrobial prophylaxis, IFNgamma, BMT
Leukocyte adhesion deficiency
(LAD)
• Deficient chemotaxis
• Recurrent soft tissue, skin, respiratory
infections, impaired wound healing
(typically no pus, minimal inflammation)
• Delayed umbilical separation
• Increased WBC count
• Treatment: BMT
Complement System Disorders
• Defects of early components (C1-C4)
associated with infections with encapsulated
bacteria
– Present similarly to humoral immune deficiencies
• Defects of late components (C5-C9) associated
with Neisseria infections
• Also associated with autoimmune-like
conditions
• CH50 functional assay assesses entire
complement cascade
– Also may use individual components
• Treatment: treat infectious and autoimmune
sequelae
Summary
• Primary immunodeficiencies are inherited
• They can affect hematopoietic stem cells,
lymphoid or myeloid cells.
• Secondary immunodeficiencies are due to
infections, aging, cancer or chemical exposure
• HIV affects immune system by eliminating CD4+ T
cells