Aims

1. Aims • Describe autoimmune diseases, concentrating on the role of immunity in their pathogenesis. • Readings: Robbins, Chapter 5

2. Sjögren’s Syndrome • A systemic autoimmune disease • Inflammatory destruction of _exocrine_ glands. • Several secretory gland may be affected. • salivary gland -dry mouth • lacrimal gland -dry eye Robbins’ Basic Pathology 5-26

3. Sjögren’s Syndrome • Antibodies against a cytoplasmic RNA-protein complex, SS-A (Ro) and SS-B (La). • Associated with other systemic autoimmune diseases • SLE • RA • scleroderma

4. Graves Disease • Antibody mediated • _Hyperthyroidism_induced by antibodies against TSH receptor. • Tissue-specific (thyroid gland) with systemic manifestations • exophthalmos • Associated with specific alleles of HLA-DR3. • Women 7X more likely than men. Robbins and Cotran’s Pathologic Basis of Disease 24-8

6. Graves Disease • Thyroid stimulating immunoglobulin (TSI) binds to and activates the TSH receptor. • Increased rate of thyroid hormone secretion. • TSH levels are lower than normal.

7. Graves Disease • Symptoms can be passively transferred

8. Autoimmune Hypothyroidism • TSH-binding inhibitor immunoglobulins (TBIIs) • Antibodies block TSH receptor activity rather than mimicking TSH as in Graves disease. • Antibody binding and recognition of a different epitope than that of Graves disease makes for a considerable difference in the clinical outcome.

9. Multiple Sclerosis • Primarily a T cell-mediated disease. • CD4+ and CD8 + cells • MHC class _II_ expressing cells. • Type IV hypersensitivity • Results in a progressive demyelinization of CNS leading to a loss of neuronal transmission. Adopted from WebPath

10. Multiple Sclerosis • Is defined as “ Distinct episodes of neurologic deficits separated in time and separated by space.” • Relapsing-remitting form • Myelin is destroyed, action potential is lost and neurological function is decreases. • Neurological function returns slowly as the nerves generate more Na2+ channels to compensate for loss of action potential. • Chronic progressive form • Myelin and axons are destroyed, no remissions, no return or restoration of function • Very rare acute progressive form (FYI)

11. Multiple Sclerosis • Pathogenesis due to a genetic predisposition and environmental exposure. • Linked to specific _HLA-DR2_ alleles. • Possibly linked to viral infections: • EBV • adenovirus-2 • hepatitis B • A similar disease can be induced in mice immunized with myelin basic protein and a strong adjuvant.

12. Type I Diabetes Mellitus • Mostly T cell-mediated disease. • CD8+ CTL destroy b cells of the pancreatic islets of Langerhans that produce insulin • Early • Insulitis • Lymphocyte infiltrate Similar to Robbins & Cotran’s Pathologic Basis of Disease 24-35

14. Type I Diabetes Mellitus • Genetic susceptibility • In some cases, there is a hereditary tendency for b cell degeneration. • 40% concordance in twins. • Associated with DR3 and secondarily with DR4, and relative risk is almost 100 in those carrying DR3 and DQw8 Adapted from Robbins’ Basic Pathology 17-7 7th Ed

15. Type I Diabetes Mellitus • Environment • Emigrants assume the risk of type I diabetes closer to that of their destination country than their country of origin. • Viral infections. • Coxsackie virus • Chemicals. • Cow’s milk Adopted from Robbins’ Basic Pathology 17-7 7th Ed

16. Type I Diabetes Mellitus • Organ-specific with systemic manifestations. • ~10% of patient have some other autoimmune disorder. • Anti-insulin antibodies may be generated. • Anti-islet cell antibodies (70-80-% of patients).

17. Rheumatoid Arthritis • Both antibody and T cell mediated disease. • Systemic disease. • Characterized by chronic inflammation of the synovium and other connective tissues. • The inflammation is initiated by the deposition of IC and sustained by chronic inflammatory cells.

18. Pathogenesis of Rheumatoid Arthritis • Molecular mimicry • Unknown antigen • Genetic susceptibility • Associated with HLA-DR4. • T cell activation • Rheumatoid factor production • Anti-Ig antibody (usually IgM) in a high percentage of patients. • Pannus formation Adopted from Robbins’ Basic Pathology 5-25

19. Pannus • _Fibrovascular_ tissue. • Consists of fibroblasts, macrophages, T cells and plasma cells. • Has the potential to invade surrounding tissues including the bone, cartilage, and tendon.

20. Some notes on Rheumatoid Factor and ANA • A minority of RA patients do not have elevated RF and some with RF do not have RA. • Relatively high ANA and RF may be found in some otherwise normal persons. • Certain infectious diseases induce high RF and ANA. • Titers of RF do not always correlate with severity and occurrence. • RA occurs in some agammaglobulinemic patients. • RF may be elevated in SLE and ANA in RA. • RF may be a marker but may not be a mechanism.

21. Hashimoto’s Thyroiditis • Autoimmune disease of the Thyroid gland. • Highly organ-specific. • Results in _Hypothyroidism. • Most likely T cell-mediated. • Due to presence of infiltrating mononuclear cells. • Characteristic of type IV hypersensitivity reaction. • There are autoantibodies present in these patients. • Antibodies against a cytoplasmic antigen.

22. Hashimoto’s Thyroiditis • HLA association with HLA-DR5 and DR-3 as well as HLA-B8 alleles.

23. Treatments of Autoimmune Diseases • Metabolic control therapies. • factor replacement therapy • Graves’ disease • Myasthenia gravis • organ transplant • SLE nephritis • _plamapheresis • SLE

24. Treatments of Autoimmune Diseases • Immunosuppressive therapy • inhibit inflammation • examples • NSAIDs • corticosteroids • have no effect on cause of disease

25. Recent Therapies • Bone marrow ablation and transplant • SLE and scleroderma • IFN-b.1a • MS • TNF-alpha blockade • RA

26. Oral Tolerance - Low Dose Ag Ag administered orally induces specific regulatory T-cell (Th3) Inhibits IgA isotype switch TGF-b Th3 suppresses Th1 and Th2 activation, proliferation, and cytokine production

27. Oral Tolerance - High Dose Ag • Induces Systemic T-cell tolerance • probably through clonal exhaustion

28. Oral Tolerance • Clinical trials involving oral tolerance: • Bovine myelin basic protein in MS • Type II collagen in RA • Retinal S-antigen in posterior uveitis • Insulin in type I diabetes mellitus • Oral feeding of HLA molecules to prevent graft rejection • Crohn’s and Ulcerative Colitis patients may have deficient oral tolerance mechanisms.

29. Review • Tolerance is the process by which the body ensures that immune responses are directed against foreign or altered self antigens and not normal self. • There is central and peripheral tolerance. • Autoimmune diseases result from a breakdown of tolerance. • Autoimmune diseases can be organ specific or systemic. • Autoimmune diseases can be antibody mediated, cell mediated, or both. • Autoimmune diseases can be types II, III, or IV hypersensitivity reactions. • Autoimmune diseases are treated through direct metabolic control, by immunosuppression, and by immunomodulation.

30. Next Time • Define autograft, isograft, allograft, and Xenograft. • Compare and contrast hyper acute, acute, and chronic graft rejection and graft vs. host and host vs. graft disease. • Quantitative and qualitative deficiencies in neutrophils (phagocytosis). • Readings: Abbas & Lichtman, Chapter 10

31. Objectives • Describe autoimmune diseases, concentrating on the role of immunity in their pathogenesis. • Sjogren’s syndrome, Graves disease, Autoimmune hypothyroidism, Multiple sclerosis, Type I diabetes, Rheumatois arthritis, Hashimoto’s thyroiditis • Describe the treatment options for these various autoimmune diseases.