Autoimmunity

1. Autoimmunity Dr. Prakash Nagarkatti Associate Dean for Basic Science 733-3180 pnagark@gw.med.sc.edu

2. Autoimmunity • Immune response to self antigens. • Tolerance to self Ags is maintained by central and peripheral mechanisms. • Dysregulation in these mechanisms will trigger autoimmune disease. • A family of 80 chronic and disabling diseases • Affects about 15-23 million people in the USA.

3. Effector mechanisms of autoimmune damage • Specific components: • Antibodies (majority) • T cells • Nonspecific components: • Complement • Phagocytes (PMN and macrophages) • NK and other cells

4. Tissues and organs involved • Organ-specific diseases • Damage is confined to the organ against which the immune response is mounted • Non-organ-specific diseases • Immune response against antigens which are not associated with the organ involved

5. Tissues and organs involved

6. Role of genetic factors in autoimmunity

7. Myasthenia gravis B A Schwann cell ACh at nerve endings ACh Y post synaptic membrane Auto Abs Y Y Y Y Y Y ACh receptors ACh receptor Muscle fiber No sodium influx No muscle Contraction C ACh Internalized vesicles with ACh receptors

8. Myasthenia gravis (A) In normal individuals, acetyl choline(ACh) is produced at motor nerve terminals. When released, it interacts with ACh receptors on post synaptic membrane of the muscle, ultimately activating contractile machinery. In Myasthenia gravis (B and C), Auto Abs are produced against ACh receptors which can activate complement and cause damage to post synaptic membrane(B) or the ACh receptors are internalized and destroyed (C). The net result is that there is loss of ACh receptors.

9. Myasthenia Gravis • Neuromuscular disorder. • Caused by autoAbs against acetylcholine receptors. • Weakness and fatigue of voluntary muscles. • Difficulty in swallowing, breathing, can lead to death.

10. Diabetes • An estimated 20.8 million people in the United States—7.0 percent of the population have diabetes. • Mainly two types: Type 1 and type 2. • Insulin-dependent (Type 1) Accounts for 5-10% of diagnosed cases. • Type 1 starts in childhood or young adult but can occur at any age. • In type 1, CD4+ and CD8+T cells destroy pancreatic beta cells. AutoAbs specific for islet cell proteins are detected and have diagnostic value but may not play a role in pathogenesis.

11. Diabetes • In type 2 diabetes, Several mechanisms have been proposed: • Increased non-esterified fatty acids, inflammatory cytokines (TNF, IL-6), and mitochondrial dysfunction for insulin resistance, and glucotoxicity, lipotoxicity, and amyloid formation for β-cell dysfunction. • Anti-insulin receptor Abs (see next slide)

12. Insulin-resistant Diabetes Adipocyte Insulin receptor various intracellular processes Insulin in blood Pancreaticcells Adipocyte Insulin receptor Insulin Pancreaticcells Y Y Y Y Y Y Y Y Auto Ab against insulin receptors

13. Sjogren’s syndrome Immune cells attack and destroy the glands that produce tears and saliva. Infiltration of lymphoid cells in a lesion The secretory duct from a patient with Sjogren’s syndrome Immunofluorescent detection of Anti-duct mitochondrial antibody in a patient with Sjogren’s syndrome

14. Pemphigus and pemphigoid Chronic autoimmune skin disease, leading to skin blisters and antibodies against the type XVII collagen component of hemidesmosomes Immunofluorescent detection of anti-skin basement membrane antibody in pemphigoid Immunofluorescent detection of anti-desmosome antibody in pemphigus

15. Systemic Lupus Erythematosus (SLE) • Auto Abs are produced mainly against nucleic acids(dsDNA). • Ag-Ab complexes are deposited in kidneys and vascular tissue. • Trigger Type III hypersensitivity. • Severe damage to kidneys, vascular tissue.

16. Type III Hypersensitivity--->Lupus platelets Neutrophil Blood Vessel Wall Y Y Ag Ag Y Y Ab Ab activate C activate C enzyme release mediators Y Basophil Immune complexes are deposited Increased vascular permeability

17. Rheumatoid Arthritis • Auto Abs against Fc portion of IgG often called rheumatoid factor. • Abs against collagen. • Immune complexes deposited in joints. • Complement activation leads to inflammation---Type III hypersensitivity.

18. Experimental Allergic Encephalomyelitis(EAE) Nervous tissue of rat +Freunds Adjuvant Hind leg paralysis and death This disease can also be induced by injecting myelin basic protein----a major Ag present on myelinated nerve fibers. Mimics human Multiple Sclerosis(MS).

19. nucleated cell body Myelin sheath Axon(conducting zone) Neuron(communication cells of brain, spinal cord, and nerves)

20. Experimental Allergic Encephalomyelitis(EAE) (Multiple Sclerosis) Th Th cells get activated Inject Myelin Basic Protein (MBP) in an adjuvant MBP is processed by dendritic cells and presented to Th cells Th T h cells cross blood-brain barrier Th Th cells produce cytokines that attract macrophages triggering inflammation, which destroys myelin sheath Macrophage Th Myelin Sheath Axon hind leg paralysis

21. Multiple sclerosis • One of the few autoimmune diseases caused by T cells. Abs are produced but their role is controversial. • Mediated by Th17 cells.

22. Role of IL-17 in autoimmunity • Unique T cells that produce IL-17 have been discovered that are distinect from Th1 and Th2 subsets. • Such cells are called Th17 cells. • Th1 cells differentiate in the presence of IL-12. • Th2 cells use IL-4. • Th17 cells differentiate in the presence of TGF-beta and IL-6. • Mice deficient in IL-17 do not develop EAE.

23. Spontaneous Infertility • Exposure of immune system to a self Ag absent during ontogeny. • Production of Abs to spermatozoa • Immunity to spermatozoa after vasectomy. sperm

24. Vasectomy APC T T cell and Abs to sperm

25. Abs against spermatozoa can lead to agglutination and loss of motility • I can’t swim!!

26. Infertility: • Can result from Abs to spermatozoa. • Abs can be seen in both male and females. • Treatment with immunosuppressive drugs leads to fertility.

27. Autoimmune Thyroid Disease • Immune response against thyroid tissue and hormone receptors can lead to a wide range of thyroid diseases, including tissue destruction, increased or decreased metabolic activity, and thyroid cell division.

28. Hashimoto’s thyroiditis • Ab response against Thyroid Ags. • Decreased production of thyroid hormones. • Pituitary gland attempts to stimulate thyroid to produce more thyroid hormones, thus causing thyroid gland to enlarge (goiter).

29. Grave’s disease:(Hyperthyroidism) • Abs to receptors for thyroid stimulating hormone(TSH). • These Abs mimic TSH and over stimulate production of thyroid hormones. • Increased heart rate, weight loss, agitated, nervous. • Such IgG can cross placenta.

30. Pernicious Anemia Ab against intrinsic factor

31. What causes Autoimmunity? • Defect in clonal deletion(-ve selection). • Exposure to Ag absent during ontogeny. • Ex:Following Vasectomy. • Decreased regulatory T cell function. • Increased Th17 function.

32. Autoimmunity: • Infections---Molecular mimicry: • Adenovirus type 2 mimics myelin basic protein. • Cell wall M protein of Streptococci mimics myosin of heart causing rheumatic fever. • M.tuberculosis can cause arthritis.

33. What causes Autoimmunity?Defect in Fas and Fas ligand Fas(CD95) Activation of T cells Fas ligand Apoptosis (cell-death)

34. ALPS • Mutations in Fas or Fas ligand genes in humans leads to development of Autoimmune lymphoproliferative syndrome (ALPS). • Patients with ALPS have chronic, nonmalignant lymphadenopathy and splenomegaly of childhood onset and an increased risk of B-cell lymphomas, autoimmune complications, increased numbers of normally rare α/βTCR+ CD3+CD4-CD8- or "double negative T cells"

35. Treatment of Autoimmunity • Immunosuppressive drugs • Corticosteroids, Azathioprine • Cyclosporin A • Anti-inflammatory • Oral administration of myelin purified from cow brains--to treat MS. • Transfer of regulatory T cells.

36. Immunotherapy of autoimmune disease Use of Regulatory T cells Isolate lymphocytes from blood lymphocytes +IL-2 Purify regulatory T cells (Foxp3+)

37. Treatment of MS Th APC MBP V17 & 5 Th + C Ab against V  17& 5 • In MS, most T cells that respond to MBP use V17 and V  5, TCR. Thus Abs against such T cells are being tested.

38. Treatment of Autoimmunity • Use of beta-interferon to treat MS blocks HLA expression. • Use of Abs against TNF--->suppresses arthritis pain for 5-10 weeks. • Use of Abs against adhesion molecules---> VLA-4, ICAM-1, etc. • Use of Abs against CD4 Th.

39. MS treated with Abs against CD4 MRI

40. Summary of Autoimmunity • Cause: Multiple—genetic, environmental, nutrition, infections, etc • Breakdown in self-tolerance. • Organ specific or Systemic. • Majority are caused by autoAb production • Treatment: Immunosuppressive drugs, Abs against TCR, cytokines, adhesion molecules, etc.

41. The End