1. Immune System Disorders Lec. 9

2. Immunodeficiency Immunodeficiency: any condition in which there is deficiency in the production of humoral and/or cell- mediated immunity. non-specificity to Ag Congenital/Genetic: varied inborn errors Acquired: - Drugs: immunosuppressive / cancer drugs -Treatments: chemotherapy, irradiation -Cancer: can be viewed as a failure of immune surveillance -Hodgkin’s disease: lymph node cancer AIDS/HIV: kills T H cells

3. Autoimmune disease: production of antibody & T H against self tissues Examples & tissue effected *Multiple sclerosis: white matter of nervous system *Graves disease: thyroid *Type I diabetes mellitus: beta cells of pancreas *Systemic Lupus Erythrematosis: (anti DNA) anti- nuclear antibodies harms kidneys, heart, lungs & skin *Rheumatoid Arthritis: destroys joints (cartilage) *Glomerulonephritis: impaired renal function (may be secondary to other autoimmune disease ) Fundamental problem: imbalance between immune activation and control autoimmune diseases

4. Pathogenesis of autoimmunity Susceptibility genes Environmental trigger (e.g. infections, tissue injury) Failure of self-tolerance Activation of self-reactive lymphocytes Immune responses against self tissues Persistence of functional self-reactive lymphocytes

5. Tolerance Definition: A type of specific unresponsiveness to an antigen induced by the exposure of specific lymphocytes to that antigen, but response to other antigens normally. : Immunologic tolerance No immune response to a specific antigen It is specific (negative) immune response Tolerogens: antigens that induce tolerance. (tolerogen vs immunogen) (Tolerance is NOT genetically programmed)

6. BASIC FACTS ABOUT TOLERANCE -To avoid excessive lymphocyte activation and tissue damage during normal protective responses against infections -Self tolerance – prevents the body to elicit an immune attack against its own tissues -Mechanisms of active tolerance prevent inflammatory reactions to many innocuous airborne and food antigens found at mucosal surfaces -Self-non-self discrimination is learned during development

7. Immunologic Tolerance and Clinic Medicine 1. To induce immunologic tolerance Prevent the rejection of organ allografts and xenografts Treat autoimmune diseases Treat allergic diseases 2. To terminate immunologic tolerance To treat tumor: To treat infection diseases

8. Mechanism of Immunologic Tolerance 1.Central tolerance: Central tolerance occurs in the central lymphoid organs as a consequence of immature self- reactive lymphocytes recognizing self-antigen. 2.Peripheral tolerance: Tolerance was induced in peripheral organs as a result of mature self-reactive lymphocytes encountering tissue specific self antigens under particular conditions.

9. The principal fate of lymphocytes that recognize self antigens in the generative organs is death (deletion), BUT: Some B cells may change their specificity (called “receptor editing”) Some CD4 T cells may differentiate into regulatory (suppressive) T lymphocytes Central and peripheral tolerance

11. Consequences of self antigen recognition in thymus Regulatory T-cells (T Reg ): release inhibitory cytokines that suppress B-cell & T-cell activity -Help to prevent autoimmune events *formerly Suppressor T (T S ) ---------------------------------------------------------------------

12. DIVISION OF TOLERANCE Central The site for T cells is the thymus The site for B cells is the bone marrow The mechanism – clonal deletion Peripheral The site – everywhere in the body Cells – both T and B Mechanisms – anergy, cell death, immune deviation

13. ARTIFICIAL INDUCTION OF TOLERANCE Tolerance can be induced artificially by the inoculation of allogeneic cells into hosts that lack immunocompetence, for example neonatal hosts or adult hosts after immunosuppressive regimens such as: *Total body irradiation *Drugs (e.g. ciclosporin) immunosuppressant drugs. *Anti-lymphocytic antibodies (anti lymphocyte globulin)

14. FUTURE APPLICATIONS OF TOLERANCE To promote tolerance to foreign tissue grafts To control the damaging immune responses in hypersensitivity states and autoimmune diseases

15. Transplantation Immunology

17. Transplantation immunology - sequence of events that occurs after an allograft or xenograft is removed from donor and then transplanted into a recipient. A major limitation to the success of transplantation is the immune response of the recipient to the donor tissue.

18. Types of Transplant Types of Transplant  Autograft is self-tissue transferred from one body site to another in the same individual.  Isograft is tissue transferred between genetically identical individuals.  Isograft is tissue transferred between genetically identical individuals (identical twin).  Allograft is tissue transferred between genetically different members of the same species.  Xenograft is tissue transferred between different species(ex. animal tissue transferred to human body).

20. Components of the Immune system involved in graft Rejection : 1) Antigen presenting cells 2) B cells and antibodies 3) T cells 4) Other cells Natural killer cells T cells that express NK cell Monocytes/Macrophages

21. Effector Mechanisms of Allograft Rejection Hyper acute Rejection Acute Rejection Chronic Rejection

22. Hyperacute Rejection *Characterized by thrombotic obstruction of the graft *Begins within minutes or hours after anastamosis *Pre-existing antibodies in the host circulation bind to donor endothelial antigens *Activates Complement Cascade *Xenograft Response:A major barrier to xenogeneic transplantation is the presence of natural antibodies that cause hyper acute rejection.

23. Hyperacute Rejection 1. Preformed Ab, 2. complement activation, 3. neutrophil margination, 4. inflammation, 5. Thrombosis formation

24. Acute Rejection Vascular and parenchymal injury mediated by T cells and antibodies that usually begin after the first week of transplantation if there is no immunosuppressant therapy Incidence is high (30%) for the first 90 days

25. Acute Rejection 1-T-cell, macrophage and Ab mediated 2-Endothelial damage 3-Inflammation

26. Chronic Rejection Occurs in most solid organ transplants – Heart – Kidney – Lung – Liver Characterized by fibrosis and vascular abnormalities with loss of graft function over a prolonged period.

27. Chronic Rejection 1-Macrophage – T cell mediated 2-Concentric medial hyperplasia

28. Tissue and Organ Transplantation Today it is possible to transplant many different organs :and tissues including Most common transplantation is blood transfusion. Bone Marrow transplantation Organs : Heart, kidneys, pancrease, lungs, liver and intestines. Tissues : include bones, corneas, skin, heart valves, veins, cartilage and other connective tissues.

29. Most Common Transplantation -Blood Transfusion- TransfuseNot transfused

30. Bone Marrow Transplantation * Used for Leukemia, Anemia and immunodeficiency, especially severe combined immunodeficiency (SCID). *About 10 9 cells per kilogram of host body weight, is injected intravenously into the recipients. *Recipient of a bone marrow transplant is immunologically suppressed before grafting. eg. Leukemia patients are often treated with cyclo- phosphamide and total body irradiation to kill all cancerous cells. Because the donor bone marrow contains immunocompetent cells, the graft may reject the host, causing graft versus host disease (GVHD).

31. Graft vs. Host Disease Caused by the reaction of grafted mature T-cells in the marrow inoculum with alloantigens of the host Acute GVHD Characterized by epithelial cell death in the skin, GI tract, and liver Chronic GVHD Characterized by atrophy and fibrosis of one or more of these same target organs as well as the lungs

32. Immunosuppressive Agents Immunosuppression can be brought about by 3 different ways :- Surgical ablation Total Lymphoid Irradiation Immunosuppressive drugs

33. Immunosuppressive Drugs Three main immunosuppressant drugs Cyclosporins act by inhibiting T-cell activation, thus preventing T-cells from attacking the transplanted organ. Azathioprines disrupt the synthesis of DNA and RNA and cell division. Corticosteroids such as prednisolone suppress the inflammation associated with transplant rejection.