Immunopathology Ahmad Shihada Silmi Hematologist Immunologist IUG Section

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 Ig. E 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 Ig. E 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 Th 2 immune response.

Allergens Example: Der P 1 • Der P 1 is an enzyme allergen • from the fecal pellets of the dust mite.

Der P 1 Allergen is easily aerosolized and inhaled. Der P 1 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 Ig. E and eosinophils.

Genetic Predisposition Type I hypersensitivity • Candidate polymorphic genes include: – – – IL-4 Receptor. IL-4 cytokine (promoter region). FcεRI. High affinity Ig. E receptor. Class II MHC (present peptides promoting Th 2 response). Inflammation genes.

Mechanisms of allergic response Sensitization • Repeated exposure to allergens initiates immune response that generates Ig. E isotype. • Th 2 cells required to provide the IL-4 required to get isotype switching to Ig. E.

Mechanisms of allergic response Sensitization Th 2/B cell interaction Drive B cell Activation and Ig. E secretion

Mechanisms of allergic response Sensitization • The Ig. E can attach to Mast cells by Fc receptor, which increases the life span of the Ig. E. • Half-life of Ig. E in serum is days whereas attached to FcεR it is increased to months.

Mechanisms of allergic response Fc ε receptors (FcεR) FcεR 1 • High affinity Ig. E receptor found on • mast cells/basophils/activated eosinophils. • Allergen binding to Ig. E attached to FcεR 1 triggers release of granules from cell.

Mechanisms of allergic response Effector Stage of Hypersensitivity Secondary exposure to allergen • Mast cells are primed with Ig. E on surface. • Allergen binds Ig. E and cross-links to activate signal with tyrosine phosphorylation, Ca++ influx, degranulation and release of mediators.

Type I hypersensitivity. Ig. E 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 • Th 2 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 Ig. E 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 (LTC 4, LTD 4, PAF) • Eosinophils can provide CD 40 L 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 c. AMP 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 Ig. E on Mast cells and produce Ig. G.

Treatment for Type I Effect of allergy shots Allergen Specific Antibodies

Hypersensitivity

Type II: Antibody-Mediated Cytotoxic Hypersensitivity • Players – Cell-surface antigens – Antibodies Ig. M, Ig. G • 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 = α 3 chain of basement membrane collagen – Found in kidneys and lungs • Auto-antibodies binds to α 3 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 • Ig. G Abs to Rh an innocuous RBC antigen – Rh+ baby born to Rh- mother first time fine. 2 nd time can have abs to Rh from 1 st 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 Ig. G – 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 (Ig. G) 1. Complement activation (C 3 a/C 5 a 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 – Ig. G, complement activation, inflammation, phagocytosis

TYPE III Antigen antibody immune complexes Ig. G 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 • Ig. G 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 Fc. R and phagocytize the complexes. BUT • If unable to phagocytize the immune complexes can cause inflammation via C’ activation C 3 a C 4 a, C 5 a 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 Ig. G repeated exposures produce Ig. G-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 Ig. G Small Ig. G-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 Ig. G against foreign serum proteins Ig. G-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

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 Ig. G circulating self Ig. G-self antigen immune complexes

Hypersensitivity

Delayed type hypersensitivity Th 1 cells and macrophages • DTH response is from: – Th 1 cells release cytokines to activate macrophages causing inflammation and tissue damage. – Continued macrophage activation 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 Th 1 cells against DTH antigens are generated by dendritic cells during the sensitization stage. • These Th 1 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 CD 4+ 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 • Th 1 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 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 Th 1 cells to get sensitization. – During secondary exposure Th 1 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/DS 00826/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. CD 4+CD 25+ CTLA 4+ 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 – Ig. M against Ig. G is called "rheumatoid factor" – Ig. G 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 Ig. G 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 • CD 8+ 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-B 27 is 87.

MHC Risk for Diabetes (IDDM) • The relative risk associated with having the DR 3/DR 4 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, Fas. L, assoc with SLE. • Decreased amount of Complement proteins (C 1, C 2, C 4) 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 Ig. G, Ig. A (Ig. M usually normal) Resolves by 3 -6 yo Ig. A deficiency – – – Most common humoral antibody deficiency 50 -80% asymptomatic Recurrent sinopulmonary infections most frequent manifestation May have severe malabsorption (chronic diarrhea) Isolated low Ig. A 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 Ig. G, Ig. A, Ig. M Treatment: IVIG, antibiotic therapy

Common Variable Immunodeficiency • B lymphs don’t differentiate into plasma cells • Recurrent sinopulmonary infections • Low Ig. G, Ig. A, Ig. M • Treatment: IVIG • Associated with autoimmune disease, lymphoma

Cellular Immunodeficiency (T cell)

Di. George 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 Ig. G, Ig. A, and Ig. M – 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 Ig. M • 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 Ig. E (Job) syndrome • Autosomal recessive • Symptoms/signs – Coarse facial features/skeletal abnormalities – Recurrent staph infections • • Impetigo (resistant) Pneumonia with pneumatocele formation – 3 E’s: Elevated Ig. E, Eosinophilia, Eczema

Hyper Ig. M Syndrome • T cell abnormality preventing Ig. M Ig. G • X-linked recessive (males 6 mo-1 year) • Frequent sinopulmonary infections, diarrhea, opportunistic infections (PCP) • Low levels of Ig. G/Ig. A, high levels of Ig. M • Treatment: Ig replacement

HIV • Retrovirus infecting CD 4 + cells – Vertical transmission, breastmilk, sex • Wide range of clinical manifestations – Failure to thrive, fevers, night sweats, malaise, recurrent thrush, recurrent bacterial infections • Decreased CD 4 count, may have elevated Ig

Acquired Immunodeficiency Syndrome (AIDS) Structure of HIV-1 gp 120 gp 41 Envelope env Protease Reverse Trascriptase Integrase Matrix (p 17) Genome Capsid (p 24) pol gag

Serological Profile Kuby, 2007

Immunological Abnormalities • Infection and destruction of dendritic cells, macrophages and Th cells • Late decrease in Th cell numbers (200/mm 3 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 (C 1 -C 4) associated with infections with encapsulated bacteria – Present similarly to humoral immune deficiencies • Defects of late components (C 5 -C 9) associated with Neisseria infections • Also associated with autoimmune-like conditions • CH 50 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 CD 4+ T cells