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AUTOIMMUNITY AND AUTOIMMUNE DISEASE

DEPARTMENT OF IMMUNOLOGY INSTITUTE FOR IMMUNOBIOLOGY. AUTOIMMUNITY AND AUTOIMMUNE DISEASE. Bo Gao, Ph.D. Email: gb1112@163.com Tel: 54237379. 2010-07-02. Contents:. Introduction. Organ-Specific Autoimmune Diseases. Systemic Autoimmune Diseases. Mechanisms of Induction. Treatment.

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AUTOIMMUNITY AND AUTOIMMUNE DISEASE

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  1. DEPARTMENT OF IMMUNOLOGY INSTITUTE FOR IMMUNOBIOLOGY AUTOIMMUNITY AND AUTOIMMUNE DISEASE Bo Gao, Ph.D. Email: gb1112@163.com Tel: 54237379 2010-07-02

  2. Contents: • Introduction • Organ-Specific Autoimmune Diseases • Systemic Autoimmune Diseases • Mechanisms of Induction • Treatment

  3. Introduction

  4. Autoimmunity Origins • Horror autotoxicus: Literally, the horror of self-toxicity. A term coined by the German immunologist Paul Ehrlich (1854-1915) to describe the body's innate aversion to immunological self-destruction. Paul Ehrlich , Nobel Prize in 1908 for demonstrating production of antibody

  5. Clone selection hypothesis • Self-reactive lymphocyte were deleted during development Frank Burnet 1900--1990 Nobel Prize 1960

  6. Definition of autoimmune disease • Disease caused by failure of self-tolerance and subsequent immune responses against self antigens are called autoimmune diseases.

  7. 5 % to 7% adult affected. • Two third women. • More than 40 human diseases autoimmune in origin.

  8. Organ-Specific Autoimmune Diseases • Insulin-dependent diabetes mellitus • Multiple sclerosis • Myasthenia gravis • Graves’s disease • Hashimoto’ disease • Goodpasture’s syndrome ……

  9. Systemic Autoimmune Diseases

  10. Systemic Autoimmune Diseases • Systemic lupus Erythematosus (SLE) • Rheumatoid arthritis (RA) • Sjögren’s syndrome • Scleroderma • Dermatomyositis • Mixed connective tissue disease(MCTD) …….

  11. Induction Theories for Autoimmune Disorders

  12. 1. Ag released from hidden location (by injury or infection) Intraocular antigens Post-traumatic uveitis Sperm Orchitis after vasectomy

  13. 2. Molecular mimicry (Cross-reactions)

  14. Molecular mimicry • Definition: Determinants of infectious agent mimic a host antigen and trigger self-reactive T-cell clones to attack host tissues. • Examples: • Rheumatic fever due to group A streptococcus • SLE due to Epstein-Barr virus cross reactive with nuclear Sm antigen • Lyme artrhritis due to Borrelia burgdorferi reactive with LFA-1 (lymphocyte function antigen-1)

  15. Rheumatic fever is a classic example of molecular mimicry

  16. 3. Inappropriate expression of class II MHC • “Wrong” cells induced to express MHC Class II antigen (and act as APCs) – IDDM, Hashimoto’s • Additional signals, such as IFN-gamma IL-1 and TNF

  17. 4.Epitope spreading • Definition: Initialresponse to oneself determinant (one peptide) could expand to involve additional determinants on the same molecule as well as additional self-proteins.

  18. It explains how a response to one cryptic epitope can mature into a full-blown autoimmune response .

  19. 5. Polyclonal B cell activation by CMV, EBV, • and some G-negative bacteria • - T-cell-independent • - Large amounts of IgM produced

  20. 6.Role of Infection in Autoimmunity

  21. 7. Gene factors in autoimmunity • Multiple sclerosis – particular alleles of HLA-DR (DRB1*1501, DRB5*0101) • Systemic lupus – lack of C1q and C4 • Genetically determined low expression of given self-antigen in the thymus • Mutation (usually deletion) of autoimmune regulator-1 gene (AIRE-1)

  22. Association between HLA and susceptibility to autoimmune disease

  23. 8.Estrogens and Autoimmunity

  24. 9.Other factors favoring autoimmunity • Lymphocytes abnormalities • Cytokine Imbalance (↑IL-2 in SLE) • Disturbances of apoptosis ( Deficiencies in Fas, complement, CTLA-4) • Toxins, Drugs, Chemicals (including food), UV, Stress

  25. THERAPY OF AUTOIMMUNE DISEASES

  26. Reduce symptoms • Immunosuppression Corticosteroids, azathioprine, cyclophosamide • Removal of thymus • Plasmapheresis Short-term relief (Grave’s disease, RA, SLE)

  27. Reduce inflammation • TNF-alpha blockers (RA, Crohn’s dis., psoriasis) e.g., Enbrel, Remicade, Humira • IL-1 receptor antagonist (RA) • Ab’s against IL6R and IL-15R • Statins, shown to lower CRP (RA, MS)

  28. Block MHC with similar peptide or antibody • Anti-CD4 • Blockage of IL-12 activity

  29. T cell vaccines (against activated Ag-specific T cells) • Monoclonal antibodies against a variety of target antigens • Oral induction of tolerance (MS) • So far, efforts have been more successful in mice than humans

  30. Thank you !

  31. Insulin-dependent diabetes mellitus (IDDM) • Disease in which the body does not produce enough insulin. • It is a “ T cell” Disease. • T cells attack and destroy pancreatic beta cells.

  32. Insulin-dependent diabetes mellitus (IDDM)

  33. Insulin-dependent diabetes mellitus (IDDM)

  34. Multiple Sclerosis • Myelin sheath of nerves targeted • CNS attacked by inflammatory lesions • Starts in 20-40 yr. old people • Characterized by weakness, paralysis and ocular symptoms MS patients can have autoantibodies and/or self reactive T cells which are responsible for the demyelination

  35. Myasthenia Gravis • Disease marked by progressive weakness and loss of muscle control • Classified as a “B cell” Disease • Autoantibodies against nicotinicacetylcholine receptors • Eventually destroys it

  36. Myasthenia Gravis

  37. Graves’s disease Autoantibody mimics TSH, leads to constant thyroid stimulation

  38. Hashimoto’s thyroiditis • Th1 cells and autoantibodies specific for thyroid Ag’s  infiltration of thyroid by L, M, and PC’s  hypothyroidism • Chronic inflammation and enlargement

  39. Normal thyroid gland

  40. Hashimoto’s thyroiditis

  41. Hashimoto’s thyroiditis (From Robbins Basic Pathology ,2003）

  42. Goodpasture’s syndrome • Antibodies to membrane antigens in kidney and alveoli in lungs • Specificity – part of type IV collagen • Complement activation, cell damage, inflammation

  43. The anti-basement membrane antibody in Goodpasture’s syndrome forms an even layer on the glomerular basement membrane.

  44. Systemic Lupus Erythematosus (SLE) • Typical patient: young woman with butterfly rash • Symptoms unpredictable (relapsing/remitting) • Multisystem (skin, kidneys, joints, heart)

  45. Systemic Lupus Erythematosus (SLE) Etiology • Autoantibodies! • Antinuclear Ab present in all patients with SLE... but found in other autoimmune diseases too

  46. Systemic Lupus Erythematosus (SLE) What’s so bad about having these autoantibodies? • They cause tissue injury! • Form immune complexes • Cause destruction, phagocytosis of cells • Multisystem effects: • Kidney (renal failure) • Skin (“butterfly rash”) • CNS (focal neurologic deficits) • Joints (arthritis) • Heart (pericarditis, endocarditis)

  47. Systemic Lupus Erythematosus (SLE) prognosis • Variable! Some have few symptoms, rare patients die within months. • Most patients: relapses/remissions over many years. • Acute flare-ups controlled with steroids • 80% 10-year survival • Most common cause of death: renal failure

  48. Systemic Lupus Erythematosus (SLE) Lupus nephritis. There are two focal necrotizing lesions at 11 and 2 o’clock. (H&E stain.) (Dr. Helmut Rennke) Slide 7.24

  49. Systemic Lupus Erythematosus (SLE) Lupus nephritis, diffuse proliferative type. Note the marked increase in cellularity throughout the glomerulus. (H&E stain.) (Dr. Helmut Rennke) Slide 7.25

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