Autoimmunity

1. Autoimmunity

2. Autoimmunity: • Autoimmunity : The immune response which is directed against host tissue self epitopes due to loss of tolerance. • Self-Tolerance: The non-responsiveness to self epitopes due to destruction of self reactive lymphocytes, response defect, or suppress..

3. Central tolerance: Primary clonal selection of T and B lymphocytes in the thymus & bone marrow. • Peripheral tolerance: • Anergy: A state of non-responsiveness to self antigens. • Suppression: The role of T suppressor (CD4) and (CD8) cells.

4. Loss of Self-Tolerance: • Antigenic Cross-reactivity (Molecular mimicry) • Epitope spreading • Neoantigens • Loss of suppression • Sequestered and late developing antigens • Polyclonal B lymphocyte activation

5. Antigenic Cross-reactivity • Infection by certain microbes may lead to specific autoimmune diseases. • Streptococcus pyogenes infection : M protein: cross reacts with cardiac membrane and valves antigens and with some antigens of the joints (rheumatic fever). • Treponema pallidum: Rheumatoid arthritis

7. N • Epitope spreading: • Response against some infections results in tissue damage and exposes self epitopes to immune system. • E.g. Viral infection of CNS; destruction of myelin sheath that protects neuronal axons; multiple sclerosis. • Viral infection of thyroid gland; Coxsackie virus Infection; Hashimoto’s thyroiditis.

8. N • Neoantigens • Neoantigens are self antigens that have been modified by some extrinsic factor (e.g. a chemical) so that they appear foreign to the immune system. • Drugs: • Autoimmune hemolytic anemia: • Penicillin binds RBCs antigen. • α-methyl-dopa bind to Rh RBCs antigen • Thrombocytic purpura: Some drugs bind to platelets integrin.

9. One feature that distinguishes responses against neoantigens from true autoimmune responses is that responses to neoantigens should cease if the agent responsible for creation of the neoantigens is removed e.g. contact dermatitis.

10. N • Loss of suppression: • No. of suppressor T lymphocyte decline with age. Activation of auto-reactive T Cytotoxic response against • tissue • Risk for Systemic lupus erythematosus increases with age. • Ulcerative colitis.

11. N • Late developing antigens: • Sperms (late developed), formation of anti-sperms; male sterility. • Polyclonal B lymphocyte activation: • Epstein-Barr virus (EBV) infection (infectious mononucleosis): Auto-reactive antibodies formation. • Humoral-associated autoimmune diseases. • Systemic lupus erythematosus

12. Transplantation and Tissue Rejection

13. Histocompatibility genes and antigens: Minor histocompatibility complexes: • More than hundred loci. • Unknown function. • Types of inheritance : Codominance: expressed whether present as heterozygous or homozygous. • Low degree of polymorphism. • Involved in acute, and chronic tissue rejection. Depending on the difference between the donor and the recipient.

14. N Major HCs: • Only 5-10 loci on short arm of chromosome 6 • High degree of polymorphism . • Class I: A,B,C (on all nucleated cells) • Class II: DR,DQ,DP (on APC) • Type of inheritance : Codominance. • Function: Antigen presentation to T lymphocytes. • Involved in acute, hyper-acute and chronic tissue rejection.

15. MHC Class I MHC Any nucleated cell Class I MHC Class II MHC B cell Macrophage Dendritic

16. Types of Grafts: according to their anatomic location: • Orthotopic graft: Tissue grafts or organs that are placed in their normal location. • Heterotopic grafts: Tissue grafts or organs that are placed into a site other than their normal site. • Example : Skin graft transplantation, Bone marrow transplantation.

17. N Types according to donor-recipient relationship: • Autografts: from one part of an individual to another location on the same individual. • Syngeneicgrafts: transferred between identical twins. • Allogeneic graft: between two genetically variable individuals of the same species. • Xenogeneic graft: between different species.

19. Donor tissue recognition: • Direct recognition: • Only when some MHC class I and II molecules in donor and recipient tissue are identical. • Donor APCs present donor peptide and cellular debris to the TCR of recipient CD8 & CD4 T lymphocytes. • Direct cellular cytotoxicity against engrafted tissue.

20. N • Indirect recognition: • Different MHC class I and II in donor and recipient tissue. • Recipient APCs present cellular debris and MHC peptide of donor tissue to recipient T lymphocytes. • Specific recipient T CD4 response.

21. Immune response against engrafted tissue: • Little Humoral immunity . • Strong Cellular immunity against engrafted tissue.

22. Types of tissue Rejection: • Hyperacute rejection. • Acute rejection. • Chronic rejection.

23. Hyperacute rejection: • The most rapid type of rejection. • Initiated and completed within a few days. • Occurs usually before establishment of vascular connection. • Immune system attack directed against the vasculature of the graft. • It is mediated by complement, NK cells, and preexisting antibodies.

24. Acute rejection: • Occurs much sooner after transplantation than do chronic rejection. • The grafts establish vascular connection and function for short period (2 to 4 weeks) & Once started proceed rapidly. • The first signs of rejection appear rapidly asedema & inflammation, cellular infiltration, and tissue deterioration. • Typically seen when the donor and recipient differ at MHC gene.

25. Chronic rejection: • The slowest type of rejection. • The transplanted tissue establish vascular connection. • It works for weeks, months, and years. • The first signs of rejection appears slowly and gradually. • Replacement of tissue by intracellular matrix and scar tissue. • Typical when donor and recipient differ by only non-MHC gene.