ImmunoPathology II Autoimmune Diseases R. Pat Bucy, MD, PhD Professor of Pathology, Microbiology, and Medicine

Organ Specific and Non-Organ Specific Autoimmune Diseases

Breaking Tolerance Experimental Induction of anti-self responses Conjugation of self epitopes to immunogenic determinants Localization with another vigorous immune response Exposure of "Hidden" self antigens Genetic patterns of responsiveness

General Scheme Induction of Organ Specific Autoimmune Disease Induction of local immune response –Infection, Drug Rx, Trauma, etc Malfunction of immune regulation –Genetic predisposition Progressive immune response to tissue Ag –Epitope Spreading Tissue destruction and loss of function

Organ Specific Autoimmune Diseases Endocrine –Thyroiditis/Grave's Disease –Insulin Dependent Diabetes –Atrophic Gastritis/Pernicious Anemia –Idiopathic Addison's Disease –Idiopathic Hypoparathyroidism –Idiopathic Hypogonadism –Idiopathic Hypophysitis Neuromuscular system –Multiple Sclerosis –Guillian-Barre (Idiopathic Polyneuritis) –Myasthenia Gravis Joints –Rheumatoid arthritis –Relapsing Polychrondritis Gastrointestinal –Crohn's Disease –Ulcerative colitis –Primary Biliary Cirrhosis –Chronic Active Hepatitis Miscellaneous –Sjögren's Syndrome –Idiopathic myocarditis –Interstitial pneumonitis –Idiopathic Interstitial Nephritis –Lichen Planus –Bullous Skin Diseases Iatrogenic –Allo-Transplant rejection

Multiple Sclerosis Immune Destruction of CNS Myelin Histopathology - Depends on stage of lesion Viral infection as Antecedent Animal Models - EAE

Experimental autoimmune encephalomelitis (EAE)

Insulin Dependent Diabetes Mellitus Immune mediated destruction of Islet  cells Histopathology Epidemiology –Viral Antecedent –MHC linkage Animal Models –BB rat –NOD mouse –low dose streptozoticin

Islets of Langerhans Normal mouseNOD mouse with acute “insulitis”

Autoimmune Thyroiditis Lymphocytic (Hasimoto’s) Thyoiditis –Chronic inflammatory lesion that results in destruction of follicles and ultimately hypothyriodism Grave’s Disease –Antibody to TSH Receptor that stimulates receptor function and results in hyperthyroidism

Graves’ Disease

Myasthenia Gravis Muscle weakness due to autoantibody to acetylcholine receptor of neuromuscular junction Symptoms can be transferred with antibody to AchR Relationship to the Thymus

Myasthenia Gravis (Blocking auto-antibodies)

Inflammatory Bowel Disease Two clinical entities with substantial overlap Crohn's Disease (Regional Enteritis) –Transmural inflammation –Occurs throughout GI tract, terminal ileum most common –"Skip lesions" and granulomas common –Several new animal models Ulcerative Colitis –inflammation restricted to mucosa –involves contiguous areas in colon (may extend into ileum)

Rheumatoid Arthritis Chronic inflammatory disease of joint synovium Presence of Rheumatoid factor –antibody to Fc of IgG usually of IgM class –form immune complexes but rarely result in glomerulonephritis Erosive lesions of cartilage and bone result from inflammatory “pannus” Can involve other organs besides joints Occasionally associated with other autoimmune syndromes

Rheumatoid Arthritis

Rheumatoid Nodule

Plasma cells in Rheumatoid synovitis

Rheumatoid Arthritis

Rheumatoid Arthritis Synovial erosions

Systemic Lupus Erythematosis Classic “Systemic” Autoimmune Disease Mediated by immune complex injury –DNA/anti-DNA immune complexes often implicated in tissue injury Animals models - genetic predisposition to immune complex formation and nephritis Variant forms of Lupus

Lupus Nephritis A Focal Proliferative GN B Diffuse Proliferative GN C “wire loop” lesions D Subendothelial IC E “Granular” pattern of IgG

Lupus skin Lesion

“butterfly” rash

General Scheme Induction of Organ Specific Autoimmune Disease Induction of local immune response –Infection, Drug Rx, Trauma, etc Malfunction of immune regulation –Genetic predisposition Progressive immune response to tissue Ag –Epitope Spreading Tissue destruction and loss of function

Time (days) Activity anti-viral immune response Viral infection Tissue Injury (auto-antigens) auto-Ag T cells ? Potential Hypersensitivity Infection and Hypersensitivity Memory

Time (days) Activity anti-viral immune response Viral infection Tissue Injury (auto-antigens) auto-Ag T cells auto-Ag Regulatory T Infection and Hypersensitivity

Time (days) Activity anti-viral immune response Viral infection Tissue Injury (auto-antigens) auto-Ag T cells ? Potential Hypersensitivity Infection and Hypersensitivity

Time (days) Activity anti-viral immune response Viral infection Tissue Injury (auto-antigens) auto-Ag T cells Autoimmune Disease Infection and Hypersensitivity

Time (days) Activity anti-viral immune response Viral infection Tissue Injury (auto-antigens) auto-Ag T cells ? Potential Hypersensitivity Infection and Hypersensitivity

Time (days) Activity anti-viral immune response Viral infection Tissue Injury (auto-antigens) auto-Ag T cells Infection and Hypersensitivity

Time (days) Activity anti-viral immune response Viral infection Tissue Injury (auto-antigens) auto-Ag T cells Contributors to control Dynamics of infectious organism Frequencies and function of autoreactive T cells Cytokine milieu - TGF  + IL-10 versus IL-6, TNF , IFN  Amount and kinetic course of auto-Ag Infection and Hypersensitivity

Overview of ImmunoPathology Immune mechanisms that result in tissue injury Classification by mechanism vs antigen source Exogenous antigens –Infectious Agents –Environmental Agents Iatrogenic –Solid organ transplants –Bone marrow transplants Neoplastic cells Autoantigens

ImmunoPathology Lab Discussion