ImmunoPathology II Autoimmune Diseases

1. ImmunoPathology IIAutoimmune Diseases R. Pat Bucy, MD, PhD Professor of Pathology, Microbiology, and Medicine

2. Organ Specific and Non-Organ Specific Autoimmune Diseases

3. Breaking ToleranceExperimental 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

4. General SchemeInduction 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

5. 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 Organ Specific Autoimmune Diseases

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

10. Experimental autoimmune encephalomelitis (EAE)

12. Insulin Dependent Diabetes MellitusImmune mediated destruction of Islet b cells • Histopathology • Epidemiology • Viral Antecedent • MHC linkage • Animal Models • BB rat • NOD mouse • low dose streptozoticin

13. Islets of Langerhans Normal mouse NOD mouse with acute “insulitis”

14. 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

15. Graves’ Disease

20. 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

21. Myasthenia Gravis(Blocking auto-antibodies)

22. Inflammatory Bowel DiseaseTwo 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)

30. 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

32. Rheumatoid Arthritis

33. Rheumatoid Nodule

34. Plasma cells in Rheumatoid synovitis

36. Rheumatoid Arthritis

37. Rheumatoid ArthritisSynovial erosions

39. 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

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

41. Lupus skin Lesion

42. “butterfly” rash

43. General SchemeInduction 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

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

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

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

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

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

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

50. Infection and Hypersensitivity anti-viral immune response Tissue Injury (auto-antigens) • Dynamics of infectious organism • Frequencies and function of autoreactive T cells • Cytokine milieu - TGFb + IL-10 versus IL-6, TNFa, IFNg • Amount and kinetic course of auto-Ag Viral infection Contributors to control auto-Ag T cells Activity Time (days)