Autoimmune Diseases

1. Autoimmune Diseases Lecture 3 Monday, January 22, 2007 Ref. Immunology Chapter 16 Basic Pathology Chapter 5 p. 125-144

2. Pernicious anemia • Due to malabsorption of Vitamin B12. • Lack of B12 prevents normal maturation of erythroblasts. • There are too few RBCs (anemia), and they are abnormally large (megaloblastic). • The malabsorption of B12 is due to lack of secretion of intrinsic factor by gastric parietal cells. • Autoimmune gastritis destroys parietal cells. Auto-antibodies are present, but T cells are required in the experimental model.

3. Poststreptococcal glomerulonephritis • An example of disease mediated by Ag:Ab complexes, similar to a type III hypersensitivity reaction. • Occurs 1-4 weeks after a streptococcal infection of the pharynx or skin. • Usually in children. • Granular deposits in the glomerulus. • Prognosis in children is quite good with recovery in about 95% of cases.

4. Spontaneous infertility • Normally, the inner portions of the seminiferous tubules are immunoprivileged sites. • Exposure of sperm to the immune system can result in autoantibody production.

5. Systemic autoimmune diseases • Involve multiple systems • often multiple autoantibodies and/or T cells to self antigens • Lesions are usually located in connective tissue and blood vessels of affected organs. • Sometime referred to as collagen vascular diseases or connective tissue diseases. • The self antigen is not connective tissue

6. Systemic autoimmune diseases • Systemic lupus erythematosus (SLE) • Ankylosing spondylitis • Multiple sclerosis • Rheumatoid arthritis • Scleroderma • Sjogren’s syndrome

7. Systemic lupus erythematosus (SLE) • Many organs may be involved and clinical signs include glomerulonephritis, fever, polyarthritis, polymyositis, weakness, thrombocytopenia, anemia, and vasculitis. • Antinuclear antibodies are common. Patients may have autoantibodies to many tissue antigens. • More common in women than in men. • Women : Men ratio is 10:1 • Part of the damage is due to circulating immune complexes.

8. Ankylosing spondylitis • Spondylitis is inflammation of the vertebrae. • Clinical signs are pain and stiffness. • Strong association of disease with MHC allele B27. • Relative risk for a person with HLA B-27 is 90.

9. Multiple sclerosis • Mediated by auto-reactive T cells. • Lesions are demyelination and occur in brain and spinal cord. • Clinical signs are intermittent, remitting and relapsing, and generally progressive eventually leading to paralysis and loss of vision. • Cause is unknown--many false alarms such as measles or owning dogs (distemper virus), etc. • A viral infection may trigger or predispose to MS. • Environment and genetics are important (higher incidence above the 37th parallel and higher concordance in monozygotic twins).

10. Rheumatoid arthritis • Damage appears to be due mainly to self-reactive T cells. • Most frequently begins in women aged 20-40. • F:M is 3-5:1 • Susceptibility is associated with HLA alleles • Rheumatoid factors are autoantibodies (usually IgM) against the Fc region of IgG, but are probably not critical to the cause of disease. • Inflammatory reaction leads to destruction of joints.

11. Scleroderma • Chronic hardening and shrinking of the connective tissue in any part of the body • Often affects skin, heart, esophagus, kidney, lung.

12. Sjogren’s syndrome • Named for a Swedish ophthalmologist. • Occurs in middle-aged or older women. • Signs include keratoconjunctivitis, pharyngitis sicca, enlargement of the parotid glands, chronic polyarthritis, and xerostomia (dry mouth).

13. Animal models • Autoimmunity develops spontaneously in some • NOD mice develop type 1 diabetes mellitus • (NZB x NZW) F1 mice develop an SLE-like disease • Autoimmunity can be induced experimentally • Immunization with AChR produces experimental autoimmune myasthenia gravis. • Immunization with myelin basic protein or proteolipid protein causes a multiple sclerosis-like disease (EAE) • Both types of models have been useful in studying autoimmunity.

14. Knowledge gained from studies in animal models • Mechanisms • Production of anti-AChR antibodies in rabbit lead to discovery of cause of myasthenia gravis. • In EAE, T cells were shown to mediate the disease. MBP-specific T cells transferred disease to naïve animals. • Treatment • Strategies for intervening in autoimmune disease such as depleting T cells, using monoclonal antibodies, and induction of tolerance have been tested in models.

15. Experimental autoimmune encephalomyelitis in rats KI 16-11

16. Proposed mechanisms for induction of autoimmunity • Release of sequestered antigen • Lens proteins in the eye are normally sequestered. Injury to eye may lead to formation of auto-antibodies • Molecular mimicry (see table16-3) • Inappropriate expression of Class II MHC • Polyclonal B-cell activation • Failure to develop peripheral tolerance. • These mechanisms are not mutually exclusive, and it is likely that more than one event triggers autoimmunity.

17. Proposed mechanisms for induction of autoimmunity KI 16-12

18. Sequence homology between pathogens and human proteinsTable 16-3

19. Evidence for inappropriate antigen presentation • Beta cells in diabetic patients express class II MHC • IFN-g increases the expression of class II MHC • Transgenic mice that over-express IFN -g in the islets, develop type 1 diabetes.

20. Experimental model of type 1 diabetes mellitus.KI 16-13a

21. Islets of Langerhans: Left = normal; Right = experimental model of Type 1 diabetes mellitus KI 16-13b

22. Development of peripheral tolerance • Lack of costimulation leads to anergy. • absence of B7 on most cells • Binding of CTLA-4 to B7 inhibits T cell activation • After activation of T cell, CTLA-4 expression is induced. • Mice lacking CTLA-4 develop massive lymphoproliferation and autoimmune disease. • Treg cells inhibit T-cells in an antigen-specific manner • Direct contact is required.

23. Regulatory T cells • A unique subset of CD4+ T cells • Have a T-cell receptor specific for self antigen. • Also express high levels of CD25 (IL-2Ra chain) • Express cytokines • IL-4 • IL-10 • TGFb • Develop from thymocytes with intermediate affinity for self antigen. • Kronenberg and Rudensky, 2005, Nature 435:598

24. Treg cells are generated in the thymus. They are a subset of CD4+,CD25+ cells. KI 16-14

25. Activation-induced cell death • Activation-induced cell death is essential for both central and peripheral tolerance. • Fas-Fas ligand interaction is important in activation-induced cell death. • Mice lacking Fas (lpr/lpr) and mice lacking FasL (gld/gld) develop autoimmune disease early in life. • In a rare human disease (autoimmune lympho-proliferative syndrome), patients have mutations of Fas and severe autoimmune disease.

26. Treatment of autoimmunity • Immunosuppression • Corticosteroids, cyclophosphamide, etc. increase risk of infection and cancer • Cyclosporin A or FK506-only inhibits activated T cells • Vaccination against disease-causing T cells • Worked in EAE, requires custom immunogen • Monoclonal antibodies • Against CD4, IL-2 R, MHC, TCR, peptides, etc. • Induction of tolerance • Some effectiveness of oral tolerance to MBP in mice.

27. Sites for experimental monoclonal antibodies that block autoimmune disease Imm 20-10

28. Anti-CD4 treatment improved survival in a mouse model of lupus KI 16-14

29. Antibody specific for a Vb allele decreased clinical signs in experimental autoimmune encephalomyelitis KI 16-15