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DISEASES OF IMMUNITY Raymond L. Konger, M.D. Associate Professor [email protected] Robbins Pathologic Basis of Disease, 8th Ed. Chapter 6 OBJECTIVES Lecture 1: • Review basic principles of cellular and humoral immunity • Immune tolerance • Four types of hypersensitivity reactions • Transplant / Graft rejection Lecture 2: • Systemic autoimmune diseases • Immunodeficiency disorders • Amyloidosis FIGURE 6-1 The principal classes of lymphocytes and their functions in adaptive immunity. CD4+ Th Development Naive ThP Ag:MHC II APC Uncommitted Th0 IL-2 IL-12/ IFN-g IL-4 Th1 IFN-g IL-2, TNF-a Th2 IL-4, IL-5 TGF-b TGF-b IL-23 IL-6 FoxP3 (-/-) = AI disease CD4+/CD25+ Th17 Treg IL-17, IL-22, PMN / Monocyte Chemokines TGF-b IL-10 OBJECTIVES Lecture 1: • Review basic principles of cellular and humoral immunity • Immune tolerance • Four types of hypersensitivity reactions • Transplant / Graft rejection Lecture 2: • Systemic autoimmune diseases • Immunodeficiency disorders • Amyloidosis Central T-cell Tolerance Central tolerance: Clonal deletion of self-reactive T cells in thymus. First: Positive selection for T-cells recognizing MHC molecules (cells lacking recognition are deleted). Second: Negative selection for cells with high affinity interaction with self antigens (cells deleted). Some T-cells that recognize self Ag are converted to Treg cells. AIRE (Autoimmune regulator): Transcriptional regulator induces “peripheral Ag” expression in thymic cells (Mutated in autoimmune polyendocrinopathy) Initiation of Adaptive Immune Response by Professional APCs: Dendritic Cells Activated APC: High CD80/86 ( ) + Ag presentation MHCI &II ( ) Pathogen Immature APC: CD80/86 (B7.1/7.2) Low Activated APC: Migrates to LN for Presentation of Ag to CD4 & CD8 cells Migration and homing (e.g to High Endothelial Venules) Requires Specific Chemokines (e.g. CCL19/21) & Adhesion Receptors (e.g. ICAM-1) Ag:MHCI & II processing CD80/86 CD80/86 interaction with CD28 (T-Cells) Is Critical T-cell peripheral tolerance: CD80/86 (B7.1/7.2) costimulation Activation vs. Tolerance Dependent on maturation state of APC cells. Immature APC cells: Low MHC Class I & II and CD80/86 (B7.1/7.2) co-stimulatory molecules Mature APC cells: Increased MHC & CD80/86 T-cells also express inhibitory B7 receptor, CTLA-4 ((-/-) mice assoc. with AI disease) Polymorphisms assoc. with human AI disease FoxP3(-/-) CD-28 CTLA-4 Treg IL-10 TGF-b APC maturation: Viral syndromes often precede AI onset Immune privilege: eyes, testes, fetal trophoblast Other T-cell : APC co-receptors Anti-PD-1 or anti-CTLA-4: Tumor Immunotherapy B-cell Tolerance Central (BM): • Immature B-cells exposed to high levels of circulating self antigens undergo receptor editing (BCR rearrangements in hypervariable region that do not recognize self). • If not successful, undergo apoptosis B-cell Activation: Peripheral Tolerance 1. B-cell Antigen Recognition and BCR Clustering (Mature B-cell) or TI-Antigens (e.g., LPS) 2. T-cell antigen Recognition and CD40 Co-stimulation (Naïve B-cell) Ag MHC-II / TCR Ag B-cell C3b CD21 B-cell Ag CD40 CD40L CD4+ T-cell EBV B-cell C3b Ab production MHC-II upregulation IFN-g IL-4, IL-2 B-cell class switch & Proliferation & Affinity Maturation T-cell independent antigens: (e.g. Pokeweed mitogen & Carbohydrate antigens) Induce low affinity IgM and no memory cells OBJECTIVES Lecture 1: • Review basic principles of cellular and humoral immunity • Immune tolerance • Four types of hypersensitivity reactions • Transplant / Graft rejection Lecture 2: • Autoimmune diseases • Immunodeficiency disorders • Amyloidosis Comparisons of Type I-IV Hypersensitivity Reactions Type I: IgE mediated “allergic” response Primary Mediators (preformed granules) Histamine (Antihistamines): Chemotactic factors: (LTB4, Eosinophil chemotactic factor) Secondary Mediators (Lipid mediators) Cysteinal Leukotrienes (C4, D4), PGD2, PAF CysLT1 receptor antagonists: zafirlukast (Accolate), montelukast (Singulair). 5-LO inhibitors: Zileuton (Zyflow) Secondary Mediators (Cytokines) TNF IL-4, IL-5 Early response: Wheel and flare / bronchospasm (LKT C4/D4, PAF) and mucous hypersecretion: vasodilation (histamine, PAF); vascular permeability (histamine, PAF, LKT C4/D4). Late-phase response: Recruitment of eosinophils, basophils, neutrophils, CD4+ (TH2). Tissue remodeling. Extreme Early Response: Anaphylaxis Fatal acute laryngeal edema during an anaphylactic reaction to penicillin. Asthma: Tissue Remodeling Mucus Plug Basement membrane thickening Inflammation with eosinophils Also: CD4+/Th2 NK-T cells Type 2 Hypersensitivity: AntibodyMediated Reactions In all cases: Immune reaction against Ab/complement bound to cell or tissue Type II: Cytotoxic Antibody Mediated Complement + Ab C5-9 C3b Target Cell Fc Receptor Macrophage Membrane Attack Complex Osmotic Lysis C3b Opsonized Cell C3b Receptor Phagocytosis Ab binding to Ag on cell results in complement fixation and opsonization, resulting in lysis or phagocytosis (e.g. transfusion reaction, AI hemolytic anemia, AI thrombocytopenia) Type II: Antibody Dependent Cellular Cytotoxicity Ab binding to cells activates effector cells: NK cells & also Monocytes, PMNs, Eosinophils, that lyse Ab-coated cells via cytotoxic mechanisms (e.g. granzyme/perforin) (No phagocytosis). Eos use this mechanism to destroy parasites. Type II: Antireceptor antibodies Antibody has natural ligand activity (Graves Disease) Antibody has natural ligand blocking activity (Myasthenia gravis) Diseases associated with Type II antibody-mediated reactions: Goodpasture’s Syndrome -- Type IV collagen Bullous pemphigoid -- skin basement membrane Pernicious anemia -- intrinsic factor Acute rheumatic fever -- antibodies against streptococcus cross react with heart Erythroblastosis fetalis -- Rh D antigen Transfusion reactions -- ABO and minor antigens Aschoff Bodies: Hallmark of Rheumatic Fever Granulomatous lesions that follow necrosis/degenerative phase and precedes fibrosis (Found in only a small subset of patients) Anitschkow cell Aschoff Giant Cell Lymphocyte FB Type III: Immune Complex Phase 1: Formation of immune complexes in the circulation Phase 2: Deposition of the immune complexes in various tissues (vasculitis, glomerulonephrits, or arthritis) Phase 3: An inflammatory reaction provoked by activation of PMNs and macrophages by Fc or C3b receptors. Immune Complex Vasculitis: Fibrinoid necrosis & infiltrates Type III Prototype: Acute post-streptococcal glomerulonephritis The reaction in the tissue is characterized by necrosis, with deposits of “fibrinoid” and an infiltrate of PMNs. glomerulus Key difference from Type II Reaction: Reaction is to immune complex deposition (bystander effect) rather than to Ab bound to specific Ag on Tissue/cell. Direct IF: Detects Ab/Immune Complex Directly in biopsy Patient’s tissue Granular pattern: Type III IC Acute post-streptococcal GN / SLE Smooth pattern: Type II Ab Goodpasture Syndrome Anti-Glomerular BM (collagen IV) Type 4 Hypersensitivity: Cell mediated hypersensitivity No Antibodies CD4+ Th1/Th17: Delayed type hypersensitivity (Granuloma, tuberculin reaction) Activated macrophages / histiocytes CD8+ CTL: Direct cell cytotoxity (graft rejection & virus infection): Perforin/granzyme & FAS/FASL T cell–mediated (type IV) hypersensitivity reactions Unlike other hypersentivity reactions, this reaction takes days CD4+ TH1 cells (and sometimes CD8+ T cells, not shown) respond to tissue antigens by secreting cytokines that stimulate inflammation and activate phagocytes, leading to tissue injury. CD4+ TH17 cells contribute to inflammation by recruiting neutrophils (and, to a lesser extent, monocytes). Anti-CD4 Ab + Classic Tuberculin Reaction (PPD): Reddening and induration peaking at 24-72 hrs. Perivascular infiltration of T cells (CD4+) and mononuclear phagocytes “perivascular cuffing” T cell–mediated (type IV) hypersensitivity reactions CD8+ cytotoxic T lymphocytes (CTLs) directly kill tissue cells. The Good: Likely important in clearing of virally infected cells / intracellular pathogens & tumor immune surveillance. The Bad: Important in mediating graft rejection and some autoimmune diseases Chronic Type IV reaction: Granuloma Chronic Type IV reactions to persistant or nondegradable Ags (TB and foreign bodies (e.g. sutures) lead to granulomatous inflammation. OBJECTIVES Lecture 1: • Review basic principles of cellular and humoral immunity • Immune tolerance • Four types of hypersensitivity reactions • Transplant / Graft rejection Lecture 2: • Systemic autoimmune diseases • Immunodeficiency disorders • Amyloidosis REJECTION PROCESSES Hyperacute: Preformed antidonor antibody (ABO incompatibility). RARE Characterized by Ab: Complement in endothelium Gross: Pale/cyanotic non-functioning organ Histology: Rapid thrombotic vasculitis w/ PMN perivascular infiltrates/ischemic necrosis Acute & Chronic Rejection Acute Humoral Rejection: Type II Antibody Mediated (Acute rejection vasculitis) Can range from Necrotizing vasculitis (more acute-Ab mediated activation of phagocytes) to less acute: Intimal thickening with inflammatory cells, foamy macrophages and smooth muscle proliferation Need B-cell depleting therapy: (e.g. Rituximab (Rituxan®), humanized monoclonal anti-CD20, a B lymphocytespecific antigen). Acute Cellular Rejection Acute tubulointerstitial mononuclear infiltrate T-cells Chronic Rejection Obliterative intimal fibrosis “Graft ateriosclerosis” Graft arteriosclerosis. The vascular lumen is replaced by an accumulation of smooth muscle cells and connective tissue (fibrosis) in the vessel intima. Chronic Rejection: Interstitial fibrosis and tubular atrophy Normal Graft vs. Host Disease Bone Marrow Transplants Transplanted T-cells recognize recipient as “foreign” and mount rejection response. High mortality rate: sepsis Bone marrow Trasplants: High dose steroids & T-cell Depletion (anti-T cell antibodies) Immunosuppressed: Irradiated Blood Products containing Leukocytes Besides the icterus (yellow color, jaundice) in this skin there is a fine scaling rash in this patient following bone marrow transplantation with a 5 out of 6 antigen match. This is an example of graft versus host disease in which donor lymphocytes attack host tissues. Apoptosis and lymphocytic infiltrates in epidermal/dermal junction GVHD Cholestasis (brown bile) & lymphocytic infiltrate OBJECTIVES Lecture 1: • Review basic principles of cellular and humoral immunity • Immune tolerance • Four types of hypersensitivity reactions • Transplant / Graft rejection Lecture 2: • Systemic autoimmune diseases • Immunodeficiency disorders • Amyloidosis Mechanisms of Autoimmune Diseases: Genetics (DR3/4, B27) & Environment play a role A. Failure of peripheral tolerance. B. Molecular mimicry -- cross reacting antibody (Rheumatic fever) C. Breakdown of immune privilege (sperm and ocular antigens) D. “Epitope spreading”: Immune response against initial “self” Ag induces cell damage or alteration of macromolecules that reveals additional epitopic sites that can be recognized – thus epitope spreading: 1. Release of “hidden” intracellular Ags or Ags protected by large protein/lipid complexes, or released by proteolysis of tertiary protein folding. 2. Enzymatic modification in response to infection/inflammatory response (e.g. Citrullinated proteins in RA) that alters normal structure. Immune Mediated Inflammatory Diseases 1. Antibody or Immune Complex Mediated Organ-specific (Covered in organ-specific chapters) Autoimmune hemolytic anemias Myasthenia gravis Graves disease Goodpasture syndrome Systemic autoimmune diseases Systemic lupus erythematosus (SLE) 2. Primarily T-cell mediated diseases (Autoantibodies present) Organ-specific Type I diabetes Multiple sclerosis Systemic autoimmune diseases Rheumatoid arthritis Systemic sclerosis (Scleroderma) Sjogren syndrome Immune Mediated Inflammatory Diseases (Not covered – Not AI disease) 3. Chronic inflammatory disease / overly robust immune responses Inflammatory bowel diseases Crohn’s disease Ulcerative colitis Psoriasis IBD/Psoriasis: Anti-TNFa therapy (i.e. remicade) useful Also useful for Rheumatoid Arthritis Ab vs T-cell mediated AI disease not absolute As expected, B-cell depletion therapy (anti-CD20; i.e. rituximab) is useful in treating Ab-mediated diseases (i.e., SLE) However, B-cell depletion therapy has also been shown to be useful in treating T-cell dependent AI disease (i.e. Rheumatoid arthritis, Sjogrens Syndrome). Thus, autoantibodies may play an important role in these diseases. Systemic AI Diseases Systemic Lupus Erythematosis Scleroderma: Systemic Sclerosis Sjogren’s Syndrome Mixed Connective Tissue Disease (MCTD) SYSTEMIC LUPUS ERYTHEMATOSUS 1. Systemic inflammatory disease mediated by immune complex deposition in vascularized tissues. Chronic, remitting and relapsing, febrile illness. 2. Characteristic antinuclear antibodies: Positive ANA test: dsDNA, RNA, ribonuleoprotein, histone proteins. +ANA = HI SENSITIVITY 3. Anti-dsDNA or Smith (Sm) Ag is virtually diagnostic of SLE. + Anti-dsDNA or Sm = HI SPECIFICITY 4. Numerous Autoantibodies (over 120 described), tests for syphilis and HIV may be false positive. Systemic Lupus Erythematosus Visceral lesions are caused by DNA-anti-DNA complex deposits. High titer anti-dsDNA = nephritis (titers used to monitor therapy & disease progression) Anti-SS-A (Ro)/B (La): Maternal - fetal transfer = present in 90% of mothers with neonatal lupus (heart block) Anti-SS-A/B and neonatal lupus also seen with Sicca (Sjogrens) Syndrome Lupus Anticoagulant: Antiphospholipid Syndrome (PROTHROMBOTIC STATE) LUPUS NEPHRITIS: (Classification) Class Notes I. Minimal Mesangial Normal Glomeruli - Light microscopy (LM). Immune complex (IC) deposits seen only by electron microscopy & immunofluorescence II. Mesangial Proliferative Matrix expansion with mesangial hypercellularity by LM. III. Focal Proliferative Glomerulonephritis in < 50% of glomeruli (May involve all or portions of each glomerulus). Crescents & fibrinoid necrosis may be present. IV. Diffuse Proliferative As in class III, but involvement of ≥ 50% of glomeruli. Advanced and often rapidly progressive to ESRD V.Membranous Thickened glomerular basement membrane without a hypercellular glomerulus (non-proliferative). High rate of nephrotic syndrome (protein loss & edema). Tends to be more indolent VI. Advanced Sclerotic ≥ 90% of glomeruli sclerosed. No evidence of active glomerular disease. End-stage renal disease DNA:anti-DNA Deposition in Lupus Glomerulonephritis 1&2. Subepithelial deposition w/humps (1) & spikes (2) 3. Subendothelial deposition 4. Mesangial deposition 5. Basement membrane I. Minimal Mesangial: Mesangial immune complex (IC) deposits by electron microscopy (EM) or direct immunofluorescence (DIF), not light microscopy (LM) II. Mesangial: Granular mesangial IC deposits by LM III. Focal Proliferative (FP): Mesangial/subendothelial IC deposits IV. Diffuse proliferative (DP): Extensive Mesangial/subendothelial/subepithelial IC deposits by LM (wire loops may be seen). If subepithelial extensive = combined class IV & V. V. Membranous (ME): Subepithelial +/- Mesangial & subendothelial. Wire loops may be seen. Proliferative GN Proliferative GN: Lots of cells (not normal) Remember the other type III glomerular disease: Post-streptococcal GN IgG Direct IF “granular” Normal Glomerulus Proliferative GN Glomerulus with segmental endocapillary proliferation SLE: Glomerulonephritis with “wire loop” thickening of the glomerular capillary basement membrane (Extensive subendothelial IC deposits). Wire loop Normocellular GN Membranous GN: Silver stain best for detecting subepithelial deposition: Silver stains BM, but not IC deposits. Interdigitating spikes (arrow) represent BM staining as the BM wraps around IC deposits. Over time, BM will completely cover the deposits with domes and markedly thickened, irregular BM. Glomerular Sclerosis: Entire Bowman’s capsule space is scarred over Disorders Related to SLE (anti-dsDNA rare) • Discoid Lupus - affects skin only-erythematous, scaly plaques, alopecia. Causes scarring (characteristic dermoepidermal Ig). Systemic symptoms uncommon. • Subacute Cutaneous Lupus – tends to be more widespread, superficial and non-scarring. Most have mild systemic symptoms. Anti-SS-A/B Abs & HLA-DR3 genotype common. • Drug-induced lupus -- drug causes positive ANA, but symptoms are mild and remit with drug withdrawal (anti-histone Ab’s). Rash in neonatal lupus: Subacute cutaneous lupus Cutaneous Lupus Inflammation necrosis Edema Avoid UV light! Note + stained nuclei in epidermis (ANAs) Junctional IgG (Direct IF) (aka: Lupus Band Test) Systemic AI Diseases Systemic Lupus Erythematosis Scleroderma: Systemic Sclerosis Sjogren’s Syndrome Mixed Connective Tissue Disease (MCTD) Scleroderma or “Progressive” Systemic Sclerosis Systemic inflammatory disease marked by progressive interstitial and perivascular fibrosis of skin and viscera. Intimal proliferation (100% of digital arteries): Proliferation of intimal cells, endothelial cells, and smooth muscle cells with perivascular fibrosis. Perivascular lymphocytic cuffing (CD4+ T-cells) is seen. Fibrosis leads to: Peripheral vascular disease Renal hypertension / failure Pulmonary HTN/fibrosis Dysmotility syndromes (esophageal/gut) CD4+ T-cell activation (unknown Ag trigger) with production of repair or fibrogenic cytokines (e.g. TGFb). Alternatively, abnormal FB responses may be involved: FB hyper-responsiveness to fibrogenic cytokines or abnormal FB collagen production. Skin: Increased dermal collagen. Chronic inflammatory cells are sparse with systemic sclerosis, unlike SLE. At high magnification, the dermis is expanded by dense collagenous fibrosis. Subtypes of systemic sclerosis 1. Diffuse systemic sclerosis Skin Gastrointestinal tract Renal (about 30%): Renal arterial intimal fibrosis leading to malignant hypertension and renal infarcts. Interstitial lung disease (30%–40%): Most common cause of death Pulmonary hypertension - may be primary arterial hypertension (small percentage) or secondary to interstitial lung disease Myositis Cardiac Autoantibodies in diffuse disease: Scl 70 antibodies (10-20%)—increased risk of interstitial pulmonary fibrosis RNA polymerases I, III—increased risk of renal disease, probably cardiac disease Subtypes of systemic sclerosis 2. Limited systemic sclerosis Skin involvement of fingers, later hands, face, and feet Raynaud phenomenon Visceral disease less common and occurs late Gastrointestinal involvement Primary pulmonary hypertension (25%–50%) Interstitial pulmonary fibrosis (10%) Anticentromere antibodies (20-30%)—indicates increased risk for pulmonary hypertension & CREST CREST syndrome common: Calcinosis cutis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangietasia Microvascular intimal fibrosis and subepithelial/submucosal fibrosis Trichrome stain submucosal fibrosis Submucosal collagen deposition. Such fibrosis can occur anywhere in the gastrointestinal tract, but is most common in the lower esophagus, leading to the esophageal dysmotility with systemic sclerosis. Intimal fibrosis mucosa Renal disease suggests diffuse scleroderma in this patient with hyperplastic arteriolosclerosis and malignant hypertension (blood pressure 300/150 mm Hg). Systemic Sclerosis: Pulmonary Alveolitis Inflammatory "alveolitis" of scleroderma lung. Note the irregular thickening of alveolar walls by inflammatory cells (arrows), sometimes making lymphoid aggregates (LA). ◄ Pulmonary Interstitial Fibrosis: Alveolar walls are distended by collagen (arrows), fibroblasts, and some chronic inflammation (blue cells here). Pulmonary HTN: Primarily vascular fibrosis ► Pulmonary artery in a scleroderma patient with pulmonary hypertension. ◄ Normal Pulmonary Artery Systemic AI Diseases Systemic Lupus Erythematosis Scleroderma: Systemic Sclerosis Sjogren’s Syndrome Mixed Connective Tissue Disease (MCTD) Sjogren’s (Sicca) Syndrome: Symptoms: keratoconjunctivitis & siccaxerostomia Laboratory: anti-SS-A / anti-SS-B Physical Exam: Mikulicz syndrome: lacrimal and salivary gland enlargement Can also have babies with neonatal lupus Salivary Gland: Sjogren’s Syndrome Interstitial fibrosis Mononuclear infiltrate Glandular atrophy -Extraglandular involvement (approx 30%): Pleuritis & pulmonary interstitial fibrosis, synovitis, tubulointerstitial nephritis, skin, peripheral neuropathy. -Approx 40 x increased rate of B-cell marginal zone lymphomas Systemic AI Diseases Systemic Lupus Erythematosis Scleroderma: Systemic Sclerosis Sjogren’s Syndrome Mixed Connective Tissue Disease (MCTD) Mixed Connective Tissue Disease A mixture of SLE, RA, scleroderma, and polymyositis. Anti-snRNP U1 ribonucleoprotein (U1-RNP) Polymyositis: Inflammatory Myopathy (Covered in Ch 27) Disease ANA SLE dsDNA SS-B histone Sjogrens Scleroderma Specific Association High titers = Nephritis Neg. Assoc. w/ nephritis Drug-induced Lupus SS-A/B: Neonatal lupus SS-A/SS-B Congenital Heart Block/rash ScI-70 centromere Diffuse disease CREST / Prim. Bil. Cirrhosis Note: If anti-dsDNA or -Sm Ag is present, regardless of other antibodies present = most likely SLE OBJECTIVES Lecture 1: • Review basic principles of cellular and humoral immunity • Immune tolerance • Four types of hypersensitivity reactions • Transplant / Graft rejection Lecture 2: • Systemic autoimmune diseases • Immunodeficiency disorders • Amyloidosis PRIMARY IMMUNODEFICIENCY SYNDROMES (very rare to relatively common genetic disorders) Defect of humoral immunity: • X-linked agammaglobulinemia of Bruton (tyrosine kinase deficiency) • Common variable immunodeficiency • Isolated IgA deficiency (related to CVI) • X-linked Hyper IgM Defect of Cell mediated immunity: • DiGeorge’s syndrome (thymic hypoplasia) • SCID Types of Infection Associated with Immunodeficiencies Pathogen Type T-Cell Defect B-Cell Defect Bacteria Bacterial Sepsis ● Pyogenic bacteria Streptococci Staphylococci Haemophilus Viruses ● Cytomegalovirus ● Epstein-Barr Virus ● Severe Varicella ● Chronic Infections with respiratory & enteroviruses Enteroviral encephalitis Fungi & Parasites ● Candida ● Pneumocystis Severe intestinal giardiasis Special Features ● Aggressive disease with opportunistic pathogens ● Failure to clear infecions ● Recurrent sinopulmonary infections ● Sepsis ● Chronic meningitis Granulocyte Defect Staphylococci Pseudomonas ● Candida ● Nocardia ● Aspergillus Complement Defect ● Neisserial infections ● Other pyogenic bacteria infections X-linked Agammaglobulinemia of Bruton (tyrosine kinase deficiency (Btk)) Defect in B-cell maturation and light chain rearrangement (cytoplasmic heavy chain is produced, but no light chain) Onset after maternal IgG titer drops. Recurring sinopulmonary infections (almost always Haemophilus influenzae, Streptococcus pneumoniae, or Staphylococcus aureus). Prone to meningoencephalitis with enteroviruses (No live polio vaccine) and persistant Giardia protozoan infections also seen. High frequency of Autoimmune Disease Common Variable Immunodeficiency Relatively common (Sporadic & Inherited forms). Males = Females Hypogammaglobulinemia (variable loss of Ig classes (can be only IgG). Symptoms usually less severe than those observed in Bruton’s agammaglobulinemia. Defects detected in a small subset of inherited form of CVI: • BAFF cytokine receptor mutation (B-cell survival & differentiation). • ICOS: Protein homologous to CD28 and involved in T-cell activation and B-cell interaction. Relatives have high frequency of selective IgA deficiency High frequency of AI disease and lymphoma Isolated IgA Deficiency: Most common primary immunodeficiency disease (1:600 of European descent). Familial and acquired (e.g. post-viral syndrome) Like CVI, defect in B-cell maturation to IgA-producing cells (e.g. BAFF cytokine mutation also seen in CVI). Associated with mucosal infections (sinopulmonary, GI, UTI) and high rates of atopy (i.e. allergic bronchitis) and autoimmune disease. Anaphylactic reaction during transfusions (whole blood, plasma containing IgA). Common Board question. Hyper IgM Syndrome Defect of B-cell class switching and maturation: Pyogenic infections / pneumonia from intracellular pathogen: Pneumocystis jiroveci 70%: X-linked loss of CD40 ligand (CD154) on T-cells Remaining: Autosomal recessive – Mutations encoding CD40 or the enzyme activationinduced deaminase (Enzyme required for class switching) T-cell antigen Recognition and CD40 Co-stimulation B-cell Ag Th-cell CD40 CD40L IFNg IL-4 DiGeorge Syndrome: Thymic Hypoplasia Chromosomal deletion syndrome (22q11 deletion syndrome (Ch 5): Aplasia or hypoplasia of 3rd and 4th pharyngeal pouch (Thymus and parathyroid) during embryogenesis. Other associated abnormalities of aorta, congenital heart disease and facial anomalies Failure of T-cell maturation (absent thymus) and hypocalcemic seizures/tetany (absent parathyroid) (usually cause for diagnosis in newborns) Both Cellular & Humoral Severe Combined Immunodeficiency (SCID) “bubble baby”. Severe bacterial, viral, fungal infections. Thymus small and devoid of lymphocytes. X-linked (most common) Genetic loss of common gc-chain for cytokine receptors (IL-2, IL-4, IL-7 etc). IL-7: Lymphoid progenitor proliferation Autosomal Recessive Adenosine Deaminase (ADA) JAK3 (gc chain signaling) IL-7a receptor MHC class II deficiency (“bare lymphocyte syndrome”) ACQUIRED SECONDARY IMMUNODEFICIENCY SYNDROMES (very common conditions) • AIDS • Cancer (e.g. myeloma) • Cancer treatment: (Bone marrow transplant) radiation, chemotherapy • Aging: Most common immunodeficiency syndrome. Decreased T-cell proliferative responses, blunted cytokine response (IL-2), decreased circulating naive T-cells (ThP). B and T-cell anergy OBJECTIVES Lecture 1: • Review basic principles of cellular and humoral immunity • Immune tolerance • Four types of hypersensitivity reactions • Transplant / Graft rejection Lecture 2: • Systemic autoimmune diseases • Immunodeficiency disorders • Amyloidosis AMYLOIDOSIS One of the extracellular “hyaline” accumulations Amyloid deposition results from deposition of distinct proteins (e.g. lambda light chains, b-amyloid protein) which aggregate as b-pleated sheets secondary to altered protein secondary or tertiary structure and are resistant to proteolytic degradation. Congo Red Birefringence SYSTEMIC PRIMARY AMYLOIDOSIS: Amyloid (AL) Ig light chain fragments “Bence Jones protein”, synthesized in copious excess by simply dysfunctional, or overtly malignant (multiple myeloma) monoclonal plasma cells. SECONDARY REACTIVE SYSTEMIC (AA): Amyloid (AA) from serum amyloid associated (SAA) protein synthesized by liver in response to inflammatory cytokines (e.g. IL-1). Associated with chronic inflammatory diseases (e.g. Rheum. Arthritis)(Heroin “skin poppers”)(Also Heriditary Familial Mediterranean Fever). SECONDARY HEMODIALYSIS-ASSOCIATED (Ab2m): Amyloid from b2 microglobulin (component of MHC class I receptor) HEREDITARY AMYLOIDOSIS: Transthyretin (ATTR): Neuropathic disease with pre-albumin (transthyretin) amyloid SYSTEMIC DISEASE Kidney: Nephrotic syndrome-End stage kidney disease - Congo-Red birefringence in glomeruli. Spleen (Splenomegaly): Splenic follicle deposition (Sago)/Sinus deposition (lardaceous) Liver (hepatomegaly) Heart: CHF, conduction defects, restrictive cardiomyopathy Adrenals, thyroid, pituitary, GI tract Localized Amyloidosis Alzheimers: Amyloid beta (Aβ) plaques from Amyloid precursor protein (APP). Senile systemic amyloidosis: Systemic deposition of transthyretin (ATTR)-biggest issue is restrictive cardiomyopathy and conduction abnormalities. Inherited: Mutant transthyretin (ATTR amyloid) (4% African-Americans carriers) – Cardiac mainly Endocrine amyloid (tumors, IDDM): Polypeptide protein (e.g. calcitonin) or unique proteins that produce microscopic lesions Congo red stain of kidney biopsy. Plane-polarized birefringence amyloid Cardiac Amyloidosis Cardiac muscle Amyloid Free Lambda LC Direct IF: AL Amyloid Liver Amyloid Congo Red Tongue: Macroglossia The End