Autoimmunity

1. Done by:Bilal M. K. Marwa Thanks for the notes of: Abdullah Al Harby Bander AlSubai3y Sarah AlHuwaidy from the lecture of: Dr. Adel AlMogren Autoimmunity

2. OVERVIEW

3. How does our Immune system differentiate self from non-self antigens? • In innate Immunity, • Relies upon a set of genetically encoded receptors • In adaptive Immunity • A system evolved to discriminate between self and non-self signals. This is developed during fetal life • This system is not so efficient, so there must be a system that identifies self-reactive cells (lymphocytes that attack our own body) and kill them, • If the body fails to inactivate self-reactive cells, this will lead to autoimmunity.

4. After the immune system recognizes the self antigen.. • Tolerence:is when the immune system doesn’t respond to a particular antigen. • In normal cases, the immune system is tolerant to self antigns. • Cells which are not self-tolerant are self-reactive • To ensure self-tolerance, the self-reactive B- and T- lymphocytes should be deleted or inactivated. • This deletion or inactivation may be in early development (central tolerance) • Or may be applied to the lymphocytes in the periphery (peripheral tolerance).

7. Central tolerance • Occurs during early differentiation of B cells in bone marrow and T cells in the thymus(in primary lymphoid organs) • The cell (T or B) that binds to self antigens is deleted by apoptosis. • The elimination of self-reactive • In the thymus, the elimination of self-reactive T cells involves contact with APC presenting self-peptides.

8. Central Tolerance

9. Peripheral tolerance • Some of the T and B cells are still self-reactive and they are either inactivated (by clonal anergy) or deleted (by apoptosis) in peripheral tissues. (Absence of Co-stimulation) Inactive T-cell  deletion or clonalanergy

10. ClonalAnergy • Anergy: a state of nonresponsiveness in lymphocytes after there receptors bind to antigens or APC.

11. ClonalAnergy in T lymmphocytes • In normal cases, for an APC (antigen presenting cell) to present an antigen to the T cell, it should express also another signal (B7 molecule) on its surface, that binds to CD-28 receptor on the surface of the T-cell. • This is called co-stimulation. • So, the T-cell is activated by 2 signals • The MHC molecule (with the antigen) • Co-stimulation signal - Unless the T-cell gets both these signals, it will not induce an immune response

12. ClonalAnergy in T-lymphocytes • If the co-stimulatory signal is absent, the T-cell undergoes anergy. • The self-reactive cells bind to antigens on the MHC-I and MHC-II cells (body cells) without co-stimulation. (not good ) • For that, they undergo anergy, and are inactivated forever.

13. ClonalAnergy in B-lymphocytes • If a B-cell is self-reactive, and recognizes a self-antigen without the additional necessary T-cell signals, the B-cell becomes anergic • The CD4 T-cells encouters the anergic B-cell and sends a “death message”, that is Fas (on B-cell)binds to Fas-L (on T-cell) to induce apoptosis. This makes sure that anergic B-cells are killed.

14. Autoimmune diseases related to hypersensitivity reactions (II, III and IV) Organ specific autoimmune diseases Proposed mechanisms of Autoimmune diseases AUTOIMMUNE DISEASES

15. Autoimmune Disease • Autoimmune diseases (AI): diseases involving an immunological response to normal tissue. • Concept: • a mutation happens to some receptors on leukocytes. • These receptors are specific for a foreign antigen but when they get mutated, they form a new class of receptors that are specific to self antigens

16. E • Autoimmune diseases can be either systemic or organ-specific.

17. Pathology of Autoimmune Diseases • Most of the autoimmune diseases attributed to autoantibodies (self-reacting antibodies) • Other autoimmune diseases have an autoreactive (self-reactive) T cell component. • Disease processes and tissue damage are due to Type II, Type III and Type IV hypersensitivity reactions.

18. Autoimmunity due to Type II Hypersensitivity • Antibody attacks and deposit at a fixed antigen from the body, e.g. in extracellular matrix • This attracts and activates complement system, which atracts neutrophils and cause inflammation and tissue injury

19. Autoimmunity due to Type II Hypersensitivity

20. Autoimmunity due to Type II Hypersensitivity

21. Autoimmune Diseases due toType III Hypersensitivity • A soluble antigen swimming in the circulation is caught by a complex of anitbodies that form insoluble antigen-antibody complexes that circulate in blood, and then they deposit in tissues, activating complement system and causing inflammation.

22. Autoimmune Diseases due toType III Hypersensitivity

23. Autoimmune Diseases due toType III Hypersensitivity

24. Autoimmune Diseases due toType IV Hypersensitivity Mediated through cells (no antibodies involved)

25. Autoimmune Diseases due toType IV Hypersensitivity

26. Organ-specific Autoimmune diseases

27. Grave’s Disease • Organ-specific AI disease • Autoantibodies bind to the receptor of thyroid stimulating hormones (TSH), causing overstimulation of the receptor and so overstimulation of the thyroid gland. • These autoantibodies are called long-acting thyroid stimulating hormones

28. Myasthenia Gravis • Organ-specific AI disease • Caused by autoantibodies that block to nicotonic receptors at neuromuscular junction, and so prevents Ach from combining to the receptor. No action potential and no muscle contraction is produced. • The patient’s muscles will be flaccid and weak • Note that unlike grave’s disease, where the antibodies mimic the action and activate the receptor, here in myasthenia gravis, the autoantiobiesblock the action of the receptor

29. Myasthenia Gravis Motor end-plates of muscles

30. Systemic autoimmunde diseases 1) Systemic Lupus Erythromatosis (SLE) • An autoimmune disease affecting connective tissue all over the body. • Variety of symptoms (according to american college of rheumatology, if a patient has 4 of these 11 symptoms, he has SLE: • Molar rash, discoid rash, photophobia, serositis, hematologial disorders, renal disorder, neurological disorder, oral ulcer, • For more information, go to wikipedia (SLE).

31. 2) Multiple Sclerosis • Autoreactive T cells attack the myelin sheath of nerve fibers, causing slower nerve signals that hardly reaches its target. • Affects CNS mainly, but can affect peripheral nerves, and that’s why it is a systemic AI disease Individuals with the DR2&DR3 variant of MHC genes are most susceptible to the disease.

32. note DR, DP and DQ are genes involved with MHC-II DA, DB and DC are genes involved with MHC-I Individuals with the DR2&DR3 variant of MHC genes are most susceptible to multiple sclerosis

33. 3) Rheumatoid arthritis (RA) • Affects peripheral joints. • May cause destruction of both cartilage and bone. • Affects mainly individuals carrying the DR4 gene

34. How do Autoimmune diseases happen? • There are three proposed mechanisms that may explain how autoimmune diseases occur: • Sequestered (hidden) antigens • Molecular mimicry • Inappropriate expression of class II MHC

36. 1) Sequestered Antigens • Early in life, immature T-cells are exposed to self-antigens in primary lymphoid organs to induce self-tolerance. • Some antigens, called sequestered antigens, do not appear in the thymus during this process, and so the T-cells do not recognize them. • If the T-lymphocyte encouters these antigens, they will attack them considering them as foreign antigens.

37. 1) Sequestered Antigens

38. 1) Sequestered Antigens • Examples: • Myelin basic protien (MBP) in Multiple Sclerosis • Sperm-associated antigens in some individuals following vasectomy • Lens and corneal proteins of the eye following infection or trauma • Heart muscle antigens following myocardial infarction

39. 2) Cross-reacting antigens (Molecular Mimicry ) • Occurs when a virus or a bacterium posses antigenic determinants that are very similar or identical to normal host cell components • Molecular mimicry may be the initiating step in a variety of autoimmune diseases. • E.g. Rheumatoid fever occurs after streptococcal infection

40. More examples !!

41. 3) Inappropriate expression of class II MHC molecules • Some normal body proteins (highly specific proteins) are formed later in life, after the development of T-cells in primary lymphoid organs, and so are not presented to T-cells during their development. And so no clonal deletion or self-tolerance is developed against them. • In normal cases, the T-cell doesn’t attack them because they do not express MHC-II, and because they are not circulating in the blood (they are fixed).

42. 3) Inappropriate expression of class II MHC molecules • If abnormally they express MHC-II (in addition to their MHC-I and the highly specific proteins), the T-cells will attack them. • This is caused by over-production of IFN-γ (due to a viral infection or so), which will increase the expression of MHC-II in different cells. • If the tissue containing the highly specific proteins gets injured and circulates in the blood, it will be considered as foreign antigen  attacked by T-cell.

43. Type I Diabetes: Pancreatic β cells express abnormally high levels of MHC I and MHC II MHC II – APC only! This may hypersensitize TH cells to β cell peptides. Normal Pancreas Pancreas with Insulitis

44. Polyclonal B Cell Activation • Some viruses and bacteria can induce nonspecific polyclonal B cell activation, including: • Certain gram negative bacteria • Herpes simplex virus. • Cytomegalovirus • Epstein Barr Virus • Human immunodeficiency virus (HIV) • They induce the proliferation of numerous clones of B cells to secrete IgM even without needing CD4 T cell help. • Polyclonal activation leads to the activation of self-reactive B cells and autoantibody production. • Patients with mononucleosis (caused by EBV) and AIDS (HIV) have a variety of autoantibodies.

45. Autoimmunity can be caused by immunological, genetic, viral, drug-induced, and hormonal factors. • There are 4 immunological mechanisms of autoimmunity. • All mechanisms cause abnormal B or T cell activation. • Most instances of autoimmune diseases occur with multiple mechanisms, which makes treatment difficult.

46. Read & Understand page 470-471 Why are women more susceptible than men to autoimmunity?

47. Problem 1 A 60-year-old woman, presents with atrial fibrillation (abnormal hearth rhythm). The patient says that for the last several months she was experienced intermittent palpitation, has lost approximately ten pounds, and has mild heat intolerance and frequent bowel movements. Physical examination revealed an anxious female with slight exophthalmos (protrusion of the eyeball) and hand resting tremor (involuntary shaking). The patient also mentioned that her mother also had similar symptoms many years ago and died because there was no treatment. Q: What immunologic processes might be involved in her problems?

48. Problem 2 1.What is the association between infection, autoimmunity and hypersensitivity ? 2.Mention 2 infections which may lead to development of autoimmunity and the underlying hypersensitivity causing the pathological tissue damage ? 3.Mention 2 autoimmune diseases in which tissue damage is caused by more than one hypersensitivity reaction ?