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Immunopathology. Ahmad Shihada Silmi Hematologist & Immunologist IUG. Section A. Hypersensitivity. Gell and Coombs Classification of Hypersensitivities. Adapted from: Kuby Immunology, Sixth Edition. Types of Hypersensitivity. Type I Hypersensitivity Classic allergy. - PowerPoint PPT Presentation
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Immunopathology Ahmad Shihada Silmi Hematologist & Immunologist IUG
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Page 1: Immunopathology

Immunopathology

Ahmad Shihada Silmi

Hematologist & Immunologist

IUG

Page 2: Immunopathology
Page 3: Immunopathology

Section A

Hypersensitivity

Page 4: Immunopathology
Page 5: Immunopathology

Gell and Coombs Classification of Hypersensitivities

Page 6: Immunopathology

Types of Hypersensitivity

Adapted from: Kuby Immunology, Sixth Edition

Page 7: Immunopathology

Type I HypersensitivityClassic 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.

Page 8: Immunopathology

Allergens

• Allergens are nonparasite antigens that can stimulate a type I hypersensitivity response

• Allergens bind to IgE and trigger degranulation of chemical mediators.

Page 9: Immunopathology

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

Page 10: Immunopathology

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.

Page 11: Immunopathology

Example: Der P1• Der P1 is an enzyme

allergen• from the fecal pellets of

the dust mite.

Allergens

Page 12: Immunopathology

Der P1 Allergen

Allergen is easily aerosolized and inhaled. Der P1 breaks down components of tight junctions which helps it to cross mucosa.

Page 13: Immunopathology

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.

Page 14: Immunopathology

Genetic PredispositionType 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.

Page 15: Immunopathology

Mechanisms of allergic response

Sensitization

• Repeated exposure to allergens initiates immune response that generates IgE isotype.

• Th2 cells required to provide the IL-4required to get isotype switching to IgE.

Page 16: Immunopathology

Mechanisms of allergic response

Sensitization

Th2/B cell interaction

Drive B cell Activation and IgE secretion

Page 17: Immunopathology

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 whereasattached to FcεR it is increased to months.

Page 18: Immunopathology

Mechanisms of allergic response

Fc ε receptors (FcεR)

• High affinity IgE receptor found on• mast cells/basophils/activated eosinophils.

• Allergen binding to IgE attached to FcεR1triggers release of granules from cell.

FcεR1

Page 19: Immunopathology

Mechanisms of allergic responseEffector Stage of Hypersensitivity

• Mast cells are primed with IgE on surface.

• Allergen binds IgE and cross-links to activatesignal with tyrosine phosphorylation, Ca++influx, degranulation and release of mediators.

Secondary exposure to allergen

Page 20: Immunopathology

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.

Page 21: Immunopathology

Type I: Effects of Degranulation

Page 22: Immunopathology

Mediators of Type I HypersensitivityImmediate 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

Page 23: Immunopathology

Immediate vs. late effects

Page 24: Immunopathology

Pre-formed mediators in granules

Mediators of Type I HypersensitivityPrimary Mediators

• Histamine• Cytokines TNF-α, IL-1, IL-6.• Chemoattractants for Neutrophils andEosinophils. • Enzymes

• tryptase, chymase, cathepsin.• Changes in connective tissue matrix, tissue breakdown.

Page 25: Immunopathology

Type I Hypersensitivity Secondary mediators

formed after activation

• Leukotrienes• Prostaglandins• Th2 cytokines- IL-4, IL-5, IL-13, GM-CSF

Page 26: Immunopathology

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.

Page 27: Immunopathology

Continuation of sensitization cycleEosinophils

• 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-4for B cell activation.

Page 28: Immunopathology

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.

Page 29: Immunopathology

Systemic anaphylaxis

• Systemic vasodilation and smooth muscle contraction leading to severe bronchiole constriction, edema, and shock.

• Similar to systemic inflammation.

Page 30: Immunopathology

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.

Page 31: Immunopathology

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.

Page 32: Immunopathology

Treatment for Type IEffect of allergy shots

Allergen Specific Antibodies

Page 33: Immunopathology

Hypersensitivity

Page 34: Immunopathology

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

Page 35: Immunopathology

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

Page 36: Immunopathology

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

Page 37: Immunopathology

Type II: Example - Autoimmunity

From: Dokkyo Medical University http://www.dokkyomed.ac.jp/dep-k/cli-path/a-super/vasculitis/vas-html/vas-63.html

Page 38: Immunopathology

Type II: Example – Foreign Antigen• Transfusion reaction ABO blood-group incompatibility

From: http://www.collectmedicalantiques.com/images/bloodletting/4_transfusion.jpg

Page 39: Immunopathology

TYPE II HypersensitivityAntibody mediated cytotoxicity

Blood Transfusion reactions

Innocuous antigens on red blood cellsEXAMPLE: ABO blood group antigens

Page 40: Immunopathology

ABO Blood Groups

• Antibody against RBC antigen binds and mediates killing of RBCs via C’or ADCC causes systemic inflammation.

Page 41: Immunopathology

TYPE IIAntibody 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

Page 42: Immunopathology

Drug-induced Thrombocytopenic Purpura

Page 43: Immunopathology

TYPE IIHemolytic 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.

Page 44: Immunopathology

TYPE IIRh factor incompatibility

Page 45: Immunopathology

Hypersensitivity

Page 46: Immunopathology

Type III: Immune Complex-Mediated Hypersensitivity

Adapted from: Kuby Immunology, Sixth Edition

Page 47: Immunopathology

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

Page 48: Immunopathology

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)

Page 49: Immunopathology

Type III: Localized Reaction

• Similar to type I hypersensitivity except for– IgG, complement activation, inflammation, phagocytosis

Page 50: Immunopathology

TYPE IIIAntigen 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.

Page 51: Immunopathology
Page 52: Immunopathology

• IgG antibodies and antigens form complexes that lodge in basement membranes.

Type III (Immune Complex) Reactions

Page 53: Immunopathology

Type III HypersensitivityType III HypersensitivityAutoimmunityAutoimmunity

Page 54: Immunopathology

TYPE IIIImmune 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".

Page 55: Immunopathology

TYPE IIIImmune 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.

Page 56: Immunopathology

Type III: Localized - Example

• 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

From: Rocking J Farm http://www.rockinjfarm.com/images/hay.jpg

Page 57: Immunopathology

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)

Page 58: Immunopathology

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/art-56794/A-scientist-collects-venom-from-a-snake

Page 59: Immunopathology

Serum Sickness

Page 60: Immunopathology

TYPE IIIImmune Complex Disease

Localized disease

• Deposited in joints causing local inflammation = arthritis.

• Deposited in kidneys = glomerulonephritis.

Page 61: Immunopathology

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

Page 62: Immunopathology

Hypersensitivity

Page 63: Immunopathology

Delayed type hypersensitivityTh1 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.

Page 64: Immunopathology

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

Page 65: Immunopathology

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.

Page 66: Immunopathology

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

Page 67: Immunopathology

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

Page 68: Immunopathology

Stages of Type IV DTH

Effector stageSecondary 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.

Page 69: Immunopathology

Type IV: Effector PhaseSecond 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)

Page 70: Immunopathology

Type IV: Effector PhaseProblematic consequence

)ex. Mycobacterium tuberculosis(

bacteria cannot be cleared

Granuloma formation

Continuous macrophage + T helper 1

activation

High lytic enzyme secretion

Tissue damage

Page 71: Immunopathology

Granuloma Formation from DTHMediated by Chronic Inflammation

Page 72: Immunopathology

Type IV DTHContact 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.

Page 73: Immunopathology

Contact dermatitis

Page 74: Immunopathology

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

Page 75: Immunopathology

• Delayed-type hypersensitivities due to TD cells

• Cytokines attract macrophages and initiate tissue damage

Type IV (Cell-Mediated) Reactions

Page 76: Immunopathology

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

Page 77: Immunopathology
Page 78: Immunopathology

Type IV DTH

Page 79: Immunopathology

Drug reactions can be any Typeof Hypersensitivity

Page 80: Immunopathology

Section B

Autoimmunity

Page 81: Immunopathology

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.

Page 82: Immunopathology

Immune Tolerance

• Tolerance of self is a hallmark of adaptive immune response.

• B cell tolerance vs. T cell tolerance.

Page 83: Immunopathology

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.

Page 84: Immunopathology

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.

Page 85: Immunopathology

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.

Page 86: Immunopathology

Inducing Autoimmunity ORBreaking of self-tolerance

Injury (inflammation)

or

Infection

"Viral Trigger" is term for virus infection

leading to autoimmune response.

Page 87: Immunopathology

Inducing Autoimmunity

Page 88: Immunopathology

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.

Page 89: Immunopathology

Antigenic Mimicry

Page 90: Immunopathology

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.

Page 91: Immunopathology

Classification ofautoimmune diseases

Autoantibody or

T cell mediated

autoimmune diseases

Page 92: Immunopathology

Antibodies to RBC antigens

Page 93: Immunopathology

Autoantibodies to surface receptors

Graves' disease =hyperthyroidStimulating autoantibodies bind thyrotropin receptor for thyroid stimulating hormone.

Page 94: Immunopathology

Myasthenia GravisBlocking Autoantibodies

Antibodies to acetyl choline receptors block muscle activation and trigger Inflammation that causes the destruction of the nerve/muscle junctions resulting in paralysis.

Page 95: Immunopathology

Autoantibodies to surface receptorsBlocking autoantibodies

• Hashimoto's thyroiditis =hypothyroid– Blocking autoantibodies inhibit thyroid

function.

Page 96: Immunopathology

Goodpasture's Syndrome

• Autoantibodies to type IV collagen and noncollagenous basement membrane

• Antibodies bind in lung and kidney causing inflammation and destruction.

Page 97: Immunopathology

Rheumatoid ArthritisImmune 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.

Page 98: Immunopathology

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.

Page 99: Immunopathology

Systemic lupus erythematosus (SLE)

• Autoantibodies against nucleoprotein particles:– Nucleosome– Spliceosome– Ribonucleoprotein complexes

• Th response to one epitope can drive auto Abs.

Page 100: Immunopathology

Systemic lupus erythematosus (SLE)

Lupus• One T helper

epitope can provide help to multiple antibody epitopes in the same particle

Page 101: Immunopathology

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

Page 102: Immunopathology

T cell Mediated Autoimmune DiseasesMultiple sclerosis (MS)

• T cell responses to myelin basic protein (MBP).

• The destruction of the myelin sheath results in neurological symptoms

Page 103: Immunopathology

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?

Page 104: Immunopathology

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.

Page 105: Immunopathology

Type I diabetesSpecific killing of insulin producing β

islet cells

Page 106: Immunopathology

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.

Page 107: Immunopathology

Susceptibility FactorsMHC

• 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.

Page 108: Immunopathology

MHCRisk for Diabetes (IDDM)

• The relative risk associated with having the DR3/DR4 combination is 25:1

Page 109: Immunopathology

Susceptibility FactorsGender

• 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.

Page 110: Immunopathology

Susceptibility FactorsImmune 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.

Page 111: Immunopathology

SusceptibilityEnvironmental factors

• Smoking has been associated with Goodpasture's syndrome.– Potentially the damage to lung basement

membrane helps trigger autoimmune response.

• Pollution, occupational exposure, etc.

Page 112: Immunopathology

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.

Page 113: Immunopathology

Section C

Immunodeficiencies

Page 114: Immunopathology

Host Defense Mechanisms

• Skin and mucosal barriers

• Humoral immunity (B cells, plasma cells, Ab)

• Cell-mediated immunity (T cells)

• Phagocytosis

• Complement

Page 115: Immunopathology

Suspecting Immunodeficiency

• Look for infections that are:– Frequent– Recurrent/chronic– Unusual organisms– Organisms that respond poorly to therapy– Growth retardation– Family history

Page 116: Immunopathology

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

Page 117: Immunopathology
Page 118: Immunopathology

Humoral Immunodeficiency (B cells)

Page 119: Immunopathology

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

Page 120: Immunopathology

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

Page 121: Immunopathology

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

Page 122: Immunopathology

Cellular Immunodeficiency (T cell)

Page 123: Immunopathology

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

Page 124: Immunopathology

Combined Immunodeficiency

Page 125: Immunopathology

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

Page 126: Immunopathology

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

Page 127: Immunopathology

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)

Page 128: Immunopathology

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

Page 129: Immunopathology

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

Page 130: Immunopathology

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

Page 131: Immunopathology

Acquired Immunodeficiency Syndrome (AIDS)

gp120gp41

Envelope

Capsid (p24)Genome

Structure of HIV-1

Matrix (p17)

Reverse Trascriptase

env

gag

Integrase

Protease

pol

Page 132: Immunopathology

Serological Profile

Kuby, 2007

Page 133: Immunopathology

Immunological Abnormalities

• Infection and destruction of dendritic cells, macrophages and Th cells

• Late decrease in Th cell numbers (200/mm3 blood)

Page 134: Immunopathology

Phagocytic Disorders

Page 135: Immunopathology

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, IFN-

gamma, BMT

Page 136: Immunopathology

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

Page 137: Immunopathology

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

Page 138: Immunopathology

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


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