Immunopathology PDF

Immunopathology Henry Sánchez, MD 1  Immune System INNATE IMMUNITY ADAPTIVE IMMUNITY Microbe B lymphocytes Antibodies Epit...

Immunopathology Henry Sánchez, MD 1  Immune System INNATE IMMUNITY ADAPTIVE IMMUNITY Microbe B lymphocytes Antibodies Epithelial barriers T lymphocytes Effector T cells Phagocytes Complement NK cells 0 6 12 1 2 3 4 5 Hours Days Time after infection 2  IFNα IFNβ Cytokine Network IFNγ IL-1 IL-6 Macrophage IL-10 IL-12 IL-15 TNFα IL-1 IL-10 IL-8 IL-12 IL-1 IFNα IL-1 IFNα TNFα TNFα TNFα TNFβ IFNβ IL-6 IFNγ TNFα IL-8 IFNα IL-1 IL-1 IFNα IL-5 TNFβ IL-10 IL-8 IL-3 IFNβ IL-12 IL-4 IFNγ B-Cell IL-1 IFNα IL-15 IL-10 TNFα Neutrophil IL-6 IFNβ IL-18 IL-13 TNFβ IL-10 TNFα IL-12 TNFβ TNFα Eosinophil IL-1 IFNγ IL-1 IL-3 TNFα IFNα IL-4 TNFβ IL-2 IL-8 Basophil IFNβ T-Cell IL-4 IL-1 IL-4 IFNγ IL-3 IL-6 IL-4 IL-10 IL-2 IL-8 IL-4 IL-4 IL-13 IL-16 IL-3 IL-14 IL-4 IL-9 IL-10 IL-3 IL-17 IL-10 IL-13 IL-4 IL-6 IL-4 IL-4 IL-5 IFNα IL-10 IL-8 IL-4 IFNβ IL-5 IL-9 IFNγ Mast Cell Monocyte IL-10 IL-6 3 Hypersensitivity Reactions Immediate (Type I) Hypersensitivity (anaphylactic type) Antibody-Mediated (Type II) Hypersensitivity Immune Complex-Mediated (Type III) Hypersensitivity Cell-Mediated (Type IV) Hypersensitivity 4 5  Immediate (Type I) Hypersensitivity IgE mediated release of chemical mediators of inflammation from mast cells and basophils including: Histamine, heparin, enzymes (tryptase and beta- glucosaminidase) ECF-A and NCF - chemotaxis of eosinophils and neutrophils Synthesize SRS-A (LTC4+LTD4), prostaglandins, thromboxanes, PAF 6  Immediate (Type I) Hypersensitivity Examples: Systemic anaphylaxis - protein (antisera) and drugs (e.g., penicillin) Skin and food allergies - local reaction (atopy) 7  T cell receptor Pollen TH2 cell IL-4 Antigen IL-3, IL-5 (allergen) GM-CSF Dendritic cell IgE B cell Eotaxin INITIAL RESPONSE IgE antibody Eosinophil Mucosal IL-3 recruitment lining IL-5 Activation Release of granules IgE Fc and mediators receptor Mast cell Cross- linking Antigen Smooth muscle spasm Release of primary and secondary mediators Epithelial Edema damage LATE PHASE RESPONSE Blood vessel Leukocyte infiltration Mucus secretion 8 Antigen IgE Signals for IgE Fc receptor activation of phospholipase A2 Signals for degranulation Signals for cytokine gene activation Nucleus Degranulation Membrane phospholipids Granule contents Secreted Arachidonic PAF Histamine cytokines acid Proteases Chemotactic factors (ECF, NCF) Leukotrienes Prostaglandin B4, C4, D4 D2 Primary mediators Secondary mediators 9 Asthma 10  Asthma Mast cell 11  Antibody-Mediated (Type II) Hypersensitivity Antibodies are formed (usually, IgM or IgG) that bind to antigen on target cell surface Types: Complement dependent (e.g., autoimmune hemolytic anemias, erythroblastosis fetalis and Goodpasture syndrome) 12  Goodpasture Syndrome Endothelium Antibody Antigen 13  Antibody-Mediated (Type II) Hypersensitivity Types: Antibody-dependent cellular cytotoxicity (e.g., pernicious anemia) Antibody-mediated cellular dysfunction (e.g., Graves disease, myasthenia gravis) 14  Immune Complex- Mediated(Type III) Hypersensitivity Antigen-antibody complexes cause activation of complement initiating an acute inflammatory response leading to tissue injury 15  Immune Complex-Mediated Tissue Injury Antigen-Antibody (immune) complexes Fc receptor Complement Platelet Activation of engagement activation aggregation Hageman factor Chemotactic Anaphylatoxin Microthrombi factors generation formation NEUTROPHIL AND Release of Ischemia MONOCYTE RECRUITMENT vasoactive amines Activation of kinins Activation of VASODILATION phagocytes AND EDEMA Release of lysosomal enzymes Fibrinoid Coagulative Necrosis NECROSIS Necrosis 16  Immune Complex- Mediated(Type III) Hypersensitivity Examples: Serum sickness (e.g., horse anti-tetanus serum) System lupus erythematous (most visceral lesions) Arthus reaction (localized area of tissue necrosis due to an acute immune complex vasculitis) Certain forms of acute glomerulonephritis 17  PHASE I Antigen in Immune Complex Formation circulation B cell Endothelium Plasma cell Antigen-antibody Free antibody complex PHASE II Immune Complex Deposition Pathogenesis of Inflammatory cell Immunocomplex Induced Vasculitis Cytokines Antigen-antibody complex PHASE III Immune Complex-Mediated Inflammation Complement Neutrophil Platelet aggregation Fibrinoid necrosis Neutrophil lysosomal enzymes 18  Cell-Mediated (Type IV) Hypersensitivity Sensitized T cells exposed to specific antigens complexed to self MHC molecules Types: Delayed type hypersensitivity (MHC II) - mediated by CD4+ T cells that secrete cytokines leading to the recruitment of major effector cells (e.g., macrophages) T cell-mediated cytotoxicity (MHC I) - mediated by CD8+ T cells that directly act as the effector cells 19 A. Delayed-type hypersensitivity Inflammation Cytokines CD4+ T cell CD8+ T cell APC presenting tissue antigen Tissue injury Normal tissue B. T cell-mediated cytolysis CD8+ CTLs Cell killing and tisue injury 20 21  Cell-Mediated (Type IV) Hypersensitivity Examples: CD4+ T cells - tuberculin test, tuberculosis, etc. CD8+ T cells - viral infections, graft rejection, tumor- associated antigens, etc. 22  Antigen-presenting cell IL-12 Antigen CD4+ TH1 cell Giant cell Epithelioid cell TNF IL-2 Granuloma Formation IFN-g Monocytes Fibroblast Lymphocyte Macrophage 23 24  Th1 and Th2 T-cell Balance in Autoimmune and Allergic Diseases α β 4 CD 25 Rheumatoid Arthritis Crohn disease IL-12 Multiple Sclerosis GVHD COPD Th1 α β 4 α β CD 4 25 CD 39 CD CD 25 73 CD25 CTLA4 TGFβ CD25 Treg Naïve CD4 Th0 T-cells α β CD 4 25 Asthma IL-4 Allergy Th2 25 Autoimmune Diseases 26  Genetic Infection, inflammation susceptibility Infections, tissue inflammation Susceptibility genes Tissue Failure of Activation self-tolerance of tissue APCs Influx of self-reactive lymphocytes into tissues Self-reactive lymphocytes Activation of self-reactive lymphocytes Tissue injury: autoimmune disease 27 28  Systemic Lupus Erythematosus (SLE) Incidence of 1/2500 Female to male ratio = 10:1 Second or third decade of life Disease is more common and severe in black Americans 29  Systemic Lupus Erythematosus (SLE) Pathogenesis Failure of the regulatory mechanisms that sustain self- tolerance Antibodies are directed towards DNA, histones, non-histone proteins-RNA and nucleolar antigens (ANA [>95%], anti- dsDNA [40-60%] and anti-SM [20-30%], anti-phospholipid antibodies [40-50%] Clinical presentation Skin, joints, kidneys, heart, serous membranes, etc. 30  SLE Skin Pathology Malar rash "butterfly pattern" Maculopapular lesion - discoid lupus Urticaria Bullae Ulcerations 31 32 33  PAS Stain Immunofluorescence 34  SLE Renal Pathology Class I - No morphologic changes on LM, IF, or EM Class II - Mesangial lupus nephritis Class III - Focal glomerulonephritis Class IV - Diffuse proliferative glomerulonephritis Class V - Membranous glomerulonephritis 35 Diffuse Proliferative Glomerulonephritis 36 Deposits Endothelial cell Lumen Epithelial cell 37  SLE Cardiac Pathology Nonbacterial verrucous endocarditis (Libman-Sacks endocarditis) Myocarditis Pericarditis - acute, subacute, or chronic 38  Nonbacterial Verrucous Endocarditis (Libman-Sacks Endocarditis) Vegetations Vegetations 39  SLE Clinical course Variable and unpredictable 86% survival at 5 years Therapy - steroids and immunosuppressive drugs Death from renal failure and opportunistic infections 40 41  Sjögren Syndrome Predominantly affects females over 40 years of age 60% of cases are often associated with other collagen vascular diseases Clinical presentation Dry eyes (keratoconjunctivitis sicca) Dry mouth (xerostomia) 42 43 Parotid Gland 44  Sjögren Syndrome Pathogenesis B cell dysfunction Anti-ribonucleoproteins antibodies SS-A (Ro) SS-B (La) Complication 1 % will develop malignant lymphoma (B-cell) 45 46  Scleroderma (Progressive Systemic Sclerosis) Female to male ratio = 3:1 Third and fifth decades of life 47  Scleroderma (Progressive Systemic Sclerosis) Pathogenesis Excessive fibrosis throughout the body via fibroblast activation (IL-1, TNF-alpha, TGF-beta, PDGF) Types Diffuse scleroderma - Anti-DNA topoisomerase I antibody (Scl-70 [40-70%]) CREST syndrome - Anti-centromere antibody (90%) 48  Trigger (exogenous agent?) T cell B cell Immune system activation: Effector T cells Other leukocytes Blood vessels: Injury and narrowing Cytokines Ischemia Growth factors Fibroblasts Extracellular matrix FIBROSIS 49 Sclerodactyly 50  Systemic Sclerosis A B 51 Raynaud Phenomenon 52  Scleroderma (Progressive Systemic Sclerosis) Diffuse scleroderma Widespread involvement of skin, rapid progression and early visceral involvement CREST syndrome Calcinosis Secondary Raynaud phenomenon Esophageal motility Sclerodactyly Teleangiectasia 53 Immunodeficiency Syndromes Primary immunodeficiencies Primary B cell immunodeficiency diseases Primary T cell immunodeficiency diseases Primary B and T cell diseases Disorders of complement system Disorders of phagocytes 54 X-linked Infantile Agammaglobulinemia B cell deficiency (blood, lymphoid tissue) Immunoglobulins decreased Multiple bacterial infections Normal cellular immunity Family history (males) Early onset 55  DiGeorge Syndrome Absence of thymus Decreased T cells (blood, lymphoid tissue) Prone to fungal and viral infections Deficient, delayed type skin reactions Tetany in some cases (hypoparathyroidism) Early onset 56 Severe Combined Immunodeficiency Disease Pathogenesis Defects in lymphoid stem cells involving T cell and B cell precursors Two modes of transmission Autosomal recessive (lack of adenosine deaminase - chromosome 20q) X-linked (most common mutation involving the common gamma chain in IL receptors for IL-2, 4, 7, 9, 15 and 21) 57 Severe Combined Immunodeficiency Disease Clinical features Early onset of infection with virus, fungus, bacteria and protozoa Failure to thrive Chronic fungal infection Adverse reactions to live virus immunization Susceptible to Pneumocystis carinii infection 58 Severe Combined Immunodeficiency Disease Treatment Histocompatible bone marrow transplant Gene therapy Intramuscular gamma globulin Supportive therapy against infection 59  Wiskott-Aldrich Syndrome Clinical presentation Thrombocytopenia, eczema and a marked vulnerability to recurrent infection x-linked recessive disease Decreased serum IgM and depletion of T cell dependent paracortical areas of lymph nodes Prone to develop malignant lymphoma 60 BONE MARROW Pluripotent stem cell Primary Immunodeficiencies Myeloid stem cell Myeloid cells Lymphoid stem cell ADA deficiency Pro-B cell Pro-T cell X-linked SCID (cytokine receptor g chain) Pre-B cell Immature T cell IgM T cell heavy receptor DiGeorge syndrome X-linked chain agammaglobulinemia MHC Class II (Btk gene) deficiency CD40L IgM CD4+ T cell IgD Mature T cells Hyper-IgM syndrome Immature B cell (CD40L) CD8+ CD4+ IgA deficiency IgM IgG IgA IgE Mature B cells 61 Complement System Disorders Deficiency of factors in both the classical and alternative pathways C3 deficiency - recurrent bacterial infections and immune complex disease C5, C6, C7, and C8 deficiencies - recurrent meningococcal and gonococcal infections Deficiency of factors in classical pathway only C1q, C1r, C1s, C2, and C4 deficiency - increased immunocomplex diseases and pyogenic infections 62 Complement System Disorders Deficiency of factors in alternative pathway only Factor B and properdin - increased neisserial infections Deficiency of classical complement regulatory proteins C1-INH deficiency - hereditary angioedema Causes edema at mucosal surfaces C2 and C4 levels are low 63 Acquired Immunodeficiences Systemic diseases Diabetes mellitus Collagen vascular diseases Effects of chronic alcohol use 64 65 66 67 68 69 70  Alcohol dehydrogenase Acetaldehyde dehydrogenase Acetate 71  Acetate Glucose Acetyl-CoA Fatty Acids synthase Pyruvate dehydrogenase Citrate synthase Aconitase Pyruvate NAD NADH Citrate cis-Aconitate CO2 Oxaloacetate H 2O Aconitase Malate dehydrogenase H 2O NADH NAD Isocitrate Malate Fumarase H 2O TCA Isocitrate dehydrogenase FADH2 Oxalosuccinate Fumarate NADH NAD ATP NADH CO2 FAD GTP CO2 Isocitrate ADP + Pi Succinate NAD dehydrogenase FAD NAD dehydrogenase αα GDP α-Ketoglutarate β FADH2 NADH Succinate Succinyl-CoA α-Ketoglutarate synthetase dehydrogenase Succinyl-CoA H+ H+ H+ 72  Metabolic Consequences of Alcohol Metabolism Increase in NADH from alcohol metabolism leading to an inhibitory effect on all upstream metabolic processes that convert NAD+ to NADH Kreb cycle beta-oxidation conversion of pyruvate to acetyl coA at the end of glycolysis conversion of glycerol to DHAP in glycolysis Immunosuppressive effect on neutrophils 73 Liver: Alcoholic Cirrhosis 74 Risk factors associated with Vibrio vulnificus Liver disease including cirrhosis and hemochromatosis Chronic alcoholic use Thalassemia Cancer - if taking anti-cancer drugs or radiation treatment Lymphoma, leukemia, AIDS, Hodgkin lymphoma Diabetes mellitus Chronic renal disease Inflammatory bowel disease (or any person receiving immunosuppressive drugs) Steroid dependency 75 Acquired Immunodeficiencies Transplantation Renal Heart and/or lung Bone marrow Liver Immunosuppression secondary to drugs 76  Pathogenesis of Renal Allograft Rejection DIRECT PATHWAY INDIRECT PATHWAY Antigen-presenting cell Graft Recipient's in the graft cells antigen-presenting cell Class I Class II MHC MHC molecule molecule CD8 CD8 CD4 CD4 Graft antigen CD8 CD8 CD4 CD4 RENAL BLOOD VESSEL CD8+ CTLs CD4+ helper T cells B lymphocyte Increased vascular permeability and CD8 endothelial injury IFN-g with thrombosis Increased MHC Plasma cell CD8 CD8 CD8 CD8 Activated macrophage Antibodies Damage Endothelial injury RENAL TUBULE RENAL BLOOD VESSELS 77 Acute Vascular Rejection 78  Acute Cellular Rejection A B 79  Chronic Rejection Graft arteriosclerosis Tubular atrophy Interstitial fibrosis A B 80  AIDS Definition A CD4+ lymphocyte count less than 200 cells per microliter 81 Acquired Immunodeficiency Syndrome (AIDS) US AIDS in 1992 Reported cases = 47,095 Sex Male - 85.9% Female - 14.1% Age - 20-49 years (87.3%) Race/Ethnicity White, non-Hispanic = 47.4% Black, non-Hispanic = 33.8% Hispanic = 17.6% Other = 0.9% Region - South (33.5%), Northeast (28.7%), West (23.1%), Midwest (11.2%) 82 Mode of Transmission Sexual contact Intravenous drug use Perinatal transmission Contaminated blood products 83 Cellular Tropism of HIV CD4+ positive cells T-cell helper/inducer All macrophages Dendritic reticulum cells Follicular dendritic cells Langerhans cells Microglial cells of the brain Fixed macrophages of liver and spleen 84  Macrophage and Lymphocyte Interactions T lymphocyte Cytokines (e.g., IL-12) Activated Activated T lymphocyte macrophage Presents antigen to TNF, TNF T cells IL-1 IFN-γ Other Other inflammatory inflammatory mediators mediators Inflammation Inflammation Macrophage 85  Primary infection Dendritic of cells in blood, CD4+ cell mucosa T cell Drainage to lymph nodes, spleen Infection established in lymphoid tissue, e.g., lymph node Acute HIV syndrome, spread of infection Viremia throughout the body Immune Anti-HIV HIV-specific response antibodies CTLs Pathogenesis of HIV Partial control of viral replication Provirus Clinical latency Latent infection Low-level infection Other microbial infections; cytokines (e.g., TNF) Extensive viral replication and CD4+ cell lysis Destruction of lymphoid tissue: AIDS depletion of CD4+ T cells 86  AIDS Virus (HTLV-3) gp41 p17 matrix gp120 p24 capsid Lipid bilayer Integrase Protease RNA Reverse transcriptase 87  AIDS Virus Genome LTR vif vpu env nef Long Terminal Repeat Viral Infectivity Viral Protein U gp160 Envelope Protein Negative Effector (p24) Contains control regions Factor (p23) Promotes CD4 Cleaved in endoplasmic Promotes down- that bind host transcription Overcomes inhibitory degradation and reticulum to gp120 (SU) regulation of surface factors (NF-kB, NFAT, effect of unidentified influences virion and gp41 (TM) CD4 and MHC I Sp1, TBP) host factor, promoting release gp120 mediates CD4 expression Required for the initiation cell-free viral transmission and chemokine receptor Blocks apoptosis of transcription binding, while gp41 Enhances virion Contains RNA trans-acting mediates fusion infectivity response element (TAR) Progression to that binds Tat disease slowed significantly in absence of Nef nef gag vif vpu env LTR LTR pol vpr tat rev gag pol vpr rev tat Pr55gag Polymerase Viral Protein R (p15) Regulator of Viral Transcriptional Polyprotein processed Encodes a variety Promotes G2 Gene Expression (p19) Activator (p14) by viral protease of viral enzymes, cell cycle arrest Promotes nuclear Enhances RNA Matrix (p17) including PR (p10), Facilitates HIV export of incompletely Pol II-mediated Undergoes myristylation that RT and RNAse H infection of spliced viral RNAs elongation of helps target Gag polyprotein (p66/51), and IN (p32) macrophages integrated viral to lipid rafts, promoting virus all processed by PR DNA assembly at cell surface Capsid (p24) Binds cyclophilin A Nucleocapsid (p7) RNA binding protein p6 Interacts with VPR; core protein, participates in terminal steps of virion building 88  AIDS Virus Life Cycle gp120 Conformational gp120 CD4 change CD4 gp41 VIRUS binding bind membrane Membrane CCR-5 penetration fusion gp41 gp120 CD4 Chemokine receptor CYTOPLASM 89  AIDS Virus Life Cycle New HIV Virion binding to CD4 Fusion of HIV membrane virion and chemokine receptor with host cell membrane; entry of viral genome into cytoplasm HIV gp120/ HIV virion gp41 Cytokine Cytokine Budding and Plasma release of membrane receptor mature virion Chemokine CD4 HIV RNA receptor genome Reverse transcriptase-mediated synthesis of proviral DNA Cytokine activation of cell; transcription of HIV genome; transport of HIV core viral RNAs to cytoplasm structure Integration of provirus into host cell genome Synthesis of HIV proteins; assembly of virion core HIV DNA structure provirus HIV RNA Nucleus transcript 90  CD+4 T-cell Injury HIV CD4 Chronic T cell activation CD4 HIV-specific CTL Viral replication in Activation of uninfected Expression of HIV peptides infected CD4+ T cells CD4+ T cells on infected CD4+ T cells Death of infected cells Activation-induced Killing of infected cells (cytopathic effect of virus) cell death (apoptosis) by virus-specific CTLs 91  Stages of HIV Disease Acute phase Viral mononucleosis syndrome (lymphadenopathy) Seroconversion Chronic phase Persistent generalized lymphadenopathy Minor opportunistic infections - oral candidiasis 92  Clinical Course of HIV Disease 1200 1100 A Possible acute HIV syndrome Death Wide dissemination of virus B Anti-envelope 1000 Seeding of lymphoid organs Opportunistic 1:512 antibody 900 diseases 1:256 800 Clinical latency 1:128 Anti-p24 CD4 T cells/mm3 700 Plasma viremia titer 1:64 antibody 600 Constitutional 1:32 500 symptoms 1:16 400 300 1:8 CTLs specific 200 1:4 for HIV peptides Viral particles in plasma 100 1:2 0 0 0 3 6 9 12 1 2 3 4 5 6 7 8 9 10 11 0 3 6 9 12 2 4 6 8 10 12 14 16 Weeks Years Weeks Years 93  II 7ESTERN BLOT CONFIRMATION F -ONITORING I #$ COUNT II ()6  2.! VIRAL LOAD BY 0#2 4ABLE   )MPORTANT #$ #OUNT ,EVELS #$ #OUNT CELLSM, n .ORMAL n /RAL THRUSH +APOSI SARCOMA TUBERCULOSIS ZOSTER n 0NEUMOCYSTIS CARINII PNEUMONIA DEMENTIA  4OXOPLASMOSIS CRYPTOCOCCUS CRYPTOSPORIDIOSIS  #YTOMEGALOVIRUS -YCOBACTERIUM AVIUM COMPLEX PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY G 4REATMENT I #OMBINATION ANTIRETROVIRAL TREATMENT II 2EVERSE TRANSCRIPTASE INHIBITORS 94 Characteristic Opportunistic Infections in AIDS 95 CMV Pneumonia 96 Pneumocystis Jiroveci (Carnii) Pneumonia 97 Pneumocystis Jiroveci (Carnii) Pneumonia 98 Mycobacterium Avium-Intracellulare Complex 99 100 Invasive Candida Esophagitis 101 Herpetic Simplex Esophagitis 102 Neuropathology of HIV Disease Cryptococcal meningitis Toxoplasmosis Progressive multifocal leukoencephalopathy Malignant B-cell lymphoma (EBV+) AIDS dementia 103 Cryptococcal Meningitis 104 Cryptococcal Meningitis 105 Toxoplasmosis 106 Toxoplasmosis 107 HIV-associated Neoplasias Hairy leukoplakia Kaposi sarcoma Malignant lymphoma Non-Hodgkin Lymphoma (primarily B-cell) Hodgkin Lymphoma Parasite-derived cancer 108 Hairy Leukoplakia 109 Hairy Leukoplakia 110  Hairy Leukoplakia 111  Kaposi Sarcoma HIV KSHV Proliferation Cytokines Angiogenesis Infected Mesenchymal CD4+ cells spindle cells Endothelium RBC KAPOSI SARCOMA 112 Kaposi Sarcoma 113 Gastric AIDS-associated NonHodgkin Lymphoma 114 AIDS-associated Hodgkin Lymphoma 115 Radiographic and Pathological Features of Malignant Hymenolepis nana Muehlenbachs A et al. N Engl J Med 2015;373:1845-1852 116 Confirmation of Hymenolepis nana Infection Muehlenbachs A et al. N Engl J Med 2015;373:1845-1852 117  Summary AIDS is primarily a sexually transmitted disease Leads to polymicrobial infections, primarily involving viruses and fungi Increases the risk for AIDS-associated neoplasms 118  Amyloidosis Definition Pathologic, extracellular, amorphous, proteinaceous substance, deposited in connective tissues, and blood vessel walls throughout the body in a vary of clinical settings Primary amyloidosis Secondary amyloidosis 119  Amyloidosis Composition Fibrillary protein Amyloid P protein - serum protein (SAP) Glycosaminoglycan - heparan sulfate Green birefringence (under polarization) of amyloid when amyloid is first stained with Congo Red Chemically distinct amyloid fibril proteins Amyloid light chain (AL) Amyloid-associated (AA) 120  Amyloid protein chains Congo red molecules ¸ ˝ ˛ Fibril composed of paired filaments b-pleated sheet 121 Congo Red Polarized Light 122  Classification of Amyloidosis Systemic forms Immunocyte dyscrasias (primary amyloidosis) Reactive (secondary amyloidosis) Hemodialysis associated amyloidosis (beta2 microglobulin) Heredofamilial amyloidosis (rare) Localized forms Senile cardiac (transthyretin - prealbumin) Senile cerebral (Alzheimer's disease - A4 (beta2-protein) Endocrine (medullary carcinoma of thyroid - procalcitonin) 123  PRODUCTION OF ABNORMAL PRODUCTION OF NORMAL AMOUNTS OF PROTEIN AMOUNTS OF MUTANT PROTEIN (e.g., transthyretin) Unknown STIMULUS: Chronic Inflammation Mutation (Carcinogen?) Macrophage Monoclonal activation B-lymphocyte proliferation Interleukin 1 and 6 Plasma cells Liver cells SOLUBLE PRECURSOR: Immunoglobulin SAA Protein Transthyretin MISFOLDED Light Chains PROTEIN Limited Limited proteolysis proteolysis INSOLUBLE AL PROTEIN AA PROTEIN ATTR PROTEIN FIBRILS 124 Cardiac Amyloidosis 125 126 127 H&E Congo Red 128  Amyloidosis Clinical Course Kidney - most common organ involved Heart - restrictive/infiltrative cardiomyopathy Liver and spleen ("sago spleen" or "lardaceous spleen") Gastrointestinal tract Endocrine glands Prognosis Poor for generalized amyloidosis 129