Etiopathogenesis of Rheumatic Diseases Dr Raj

ETIOPATHOGENESIS OF RHEUMATIC DISEASES Inflammatory reactions in musculoskeletal tissues Immunological mechanisms of inflammation Role of autoimmunity Immunogenetic factors Rheumatic diseases: Inflammation & Damage to Joints / Tissues - Mediated by the immune system - Exact etiology unknown - Multifactorial in origin (Environmental & Genetic) Infection or other challenges Pathology in genetically susceptible persons - Persistent or exaggerated immune response Tissue inflammation or abnormal function BASIC CONCEPTS IN IMMUNOLOGY - 1  Innate and acquired immunity  Humoral vs Cell-mediated immunity  Cells involved in inflammation : T cells, B cells, NK, monocyte-macrophage, eosinophils, basophils, mast cells  T cells: CD4+ & CD8+  B cells   Antibodies  T cells   Cytokines - T helper & T cytotoxic  Monocytes/macrophages – phagocytosis, APC BASIC CONCEPTS IN IMMUNOLOGY - 2 APC + Ag + T cells T cell activation Activated T helper cells Th1 Th2 CMI HI How do we know that immune system is involved?  Other AID in same individual or family  HLA alleles associated with certain AID  Infiltrating lymphocytes showing limited Ig, TCR  Sometimes abnormal expression of MHC Class II in affected organ  Good response to immunosuppressive agents Rheumatic Diseases: Inflammation & damage to joints and/or tissues – - Multifactorial in origin (Environmental, Genetic) 1. Which self antigens? 2. Triggering stimulus 3. Genetic susceptibility 4. Other influences e.g. hormonal 1. Which self antigens? What are the self-antigens involved? Disease Ankylosing spond. R. A. SLE Scleroderma Sjogrens syndrome Self-antigen Vertebrae Immune response Immune complexes Connective T cells, Immune tissue, IgG complexes DNA, nuclear ags Auto-abs, Imm complexes Nuclei, heart, Autoantibodies lungs Salivary gland, Auto-antibodies liver 2. What are the triggering stimuli? I. Microbial Infection in Rheumatological Disorders Direct invasion of joints or tissues Septic arthritis, osteomyelitis, pyomyositis – bacteria, HIV Microbes   Chronic inflammation 1. Persistence due to defective immune clearance (Lyme arthritis) 2. Multiplication of organisms (EBV in salivary glands in Sjogren’s) 3. Persistence of breakdown products (LPS in reactive arthritis) Sustained immune response in joint WITHOUT viable organisms Microbial Infection in Rheumatological Disorders Possible Mechanisms 1. Molecular Mimicry: antigenic similarity between microbes and self antigens  damaging immune response to self tissues e.g. acute rheumatic fever, AS?, RA? So, “proper” immune response against microbes leads to “improper” cross-reaction against self antigens. 2. Polyclonal B Cell Activation: non-specific activation of B cells  production of antibodies of diverse specificities, which may include some anti-self antibodies etc EBV, LPS. So, “by chance” inclusion of antibodies against self Microbial Infection in Rheumatological Disorders Possible Mechanisms 3. Superantigens: bind to both TCR and MHC and activate T cells non-specifically, e.g. Staph toxins Non-specific activation of large number of T cells; some of these T cells could be “autoreactive” 4. Retroviruses: incorporate viral DNA into host genome and affect cell function, e.g. HIV, HTLV These viruses infect cells and can cause various diverse rheumatological manifestations Microbial Infection in Rheumatological Disorders Possible Mechanisms 5. Immune Response to Breakdown Products: Reactive arthritis due to enteric or urethral infection etc 6. Microbial Immune Complex Deposition: Hepatitis A and B, infective endocarditis etc 3. Genetic factors in autoimmunity II. Genetic Factors in Rheumatological Disorders MHC or HLA  2 classes of MHC / HLA – Class 1 and Class 2  Class 1 on all cells, Class 2 on APC  Extremely polymorphic, large number of alleles  Therefore, individuals are unique and different  Many rheumatic diseases linked to HLA genes  Severity, Subtypes, Ab prod. - HLA-associated II. Genetic Factors in Rheumatological Disorders MHC (HLA) Associations Disease HLA Effect(s) association HLA-DR2, DR3 Disease susceptibility HLA-DR4 Susceptibility, severity HLA-B27 Disease susceptibility SLE R.A. A.S. II. Genetic Factors in Rheumatological Disorders MHC or HLA Associations Disease Ankylosing spondylitis Rheumatoid arthritis SLE MHC Gene HLA-B27 HLA-DR4 HLA-DR2 HLA-DR3 Relative Risk 87 6 4 6 4. Other influences III. Other Factors in Rheumatological Disorders Gender: Higher prevalence in women, except A.S. Due to hormones? Estrogen? Environmental Factors: Stress: Physical, emotional Diet: Malnutrition, vitamin, mineral deficiency Drugs: Hydralazine  lupus Bleomycin  scleroderma L-tryptophan  eosinophilia-myalgia Interaction of Factors in Rheumatological Disorders  Many people have susceptibility genes, but only a few develop disease  Therefore, etiology = multifactorial  Other factors = Age, trauma, tobacco, alcohol, sex of individual, hormones, stress, infections  Lupus in susceptible females manifests at puberty or when stress increases, or when certain infections occur How is Autoimmunity induced? 1. Release of sequestered antigens 2. Molecular mimicry 3. Inappropriate expression of Class II MHC 4. Polyclonal B-cell activation BASIC CONCEPTS IN AUTOIMMUNITY 1 2 3 4 Immunological Abnormalities Role of Autoimmunity Immunological Abnormalities Role of Autoimmunity Synovial inflammation in RA, SLE, AS due to IR Autoimmunity – Autoabs & Autoreactive T cells Autoantibodies – tissue inflammation ADCC Complement-mediated injury Mediators by mast cells Deposition of immune complexes Immunological Abnormalities Autoantibodies in CTD Usually non-organ specific (against variety of cells) Against cells (lymphocytes, erythrocytes, platelets) Against molecules (phospholipid, Ig) - In RA, IgM anti-IgG Fc portion (Rheumatoid Factor) - But RF seen in only 75% of chronic RA, not all cases - Serum RF levels do not always correlate with severity - Because autoreactive T cells also involved Against nuclear components (DNA, nucleolus, histones) Autoantibodies – tissue inflammation and disease by ADCC Complement-mediated injury Release of mediators by mast cells Deposition of immune complexes 4 Rheumatoid Arthritis • Common AID • Chronic inflammation of the joints + hematologic, cardiovascular and respiratory systems also affected • Common autoantibody = anti-IgG (Rheumatoid Factor) • Usually IgM anti-IgG (Fc) antibody • Anti-IgG + IgG complexes • Deposited in joints • Stimulation of complement cascade Stimulation of Type III hypersensitivity Chronic inflammation of the joints Immunopathogenesis of R.A. Both Ab and Th1 cells mediate damage in R.A. Th1 and Th2 cells Th1 cells - Cell-mediated inflammatory reactions, - Interact with mononuclear cells & help them eliminate intracellular pathogens - CMI Th2 cells – Strong humoral and allergic reactions, - Interact with B cells and cause B cell activation, division and differentiation - HI Immunopathogenesis of R.A. Both Ab and Th1 cells mediate damage in R.A. • T cells drive autoantibody production • Autoantibodies form Ag-Ab complexes Inflammation • Th1 cells inflammatory cytokines Induce cytokine production Inflammation • Thus, some tissue damage is due to immune complexes, and some of the tissue damage is due to T-cell activated cytokine production Synovial cavity filled with synovial fluid Infiltrating leukocytes Cartilage Deposited immune complexes Synovial membrane Cytokines Proinflammatory Act to make disease worse IL-1, TNFa, IL-6 Anti-inflammatory Reduce inflammation and promote healing IL-10, IL-4, TGF Inflammatory reactions in R.A. Activated Th1 cells and immune complexes Pro-inflammatory cytokines (TNFa, IL-1, IL-6) Activation of macrophages and fibroblasts Corrosion of cartilage and bone T B Ab Ag-Ab complexes Cytokines Ag-Ab complexes Complement Synovial lining cells Joint space Pannus Acute inflammation IL-1, IL-6, TNF Cartilage Breakdown, Bone Erosion Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis & Rheumatism. 36(12):1681-90, 1993 Dec. Elliott MJ. Maini RN. Feldmann M. Long-Fox A. Charles P. Katsikis P. Brennan FM. Walker J. Bijl H. Ghrayeb J. et al. Treatment with anti-TNF alpha……… resulted in significant clinical and laboratory improvements. These preliminary results ……. suggest that it may be a useful new therapeutic target in this disease. Autoimmunity in Sjogren’s Syndrome Targets of autoimmune attack are Exocrine glands e.g. tear glands, salivary glands Lack of production of lubricating fluids in eyes, mouth, joints, mucosal surfaces Autoimmunity in SLE Complement-fixing auto-antibodies to DNA, histones + Autoantigens Immune complexes Deposition in Kidney, skin, joints, choroid plexus Type III Hypersensitivity Reactions ETIOPATHOGENESIS OF RHEUMATIC DISEASES Inflammatory reactions in musculoskeletal tissues Immunological mechanisms of inflammation Role of autoimmunity Immunogenetic factors