1. AUTOIMMUNE DISEASES 324 PHT Dr. Sarah I. Bukhari PhD in Clinical Microbiology Department of Pharmaceutics Office: 06 - 3 rd floor sbukhari@ksu.edu.sa

2. Objective:  Contribution of genes in the autoimmune disease  Give an example of autoimmune diseases  Transplantations  Types  Prevent rejection

3. Which genes are involved in the immune diseases?  Contribution of genes in the immune disease considering the fact that the autoimmune disease are multigenic based on the genetic studies = genes contribute to susceptibility to the disease.  This different form some disease such as cystic fibrosis which is caused by mutation in single gene  the most significant susceptibility (SS) gene for nearly all immune disease is MHC

4. Which genes are involved in the immune diseases? Non MHC genes MHC genes

5. Major histocompatibility complex  The major histocompatibility complex (MHC): collection of genes that encode molecules of genetically diverse glycoproteins that are found on the plasma membranes of mammalian nucleated cells (histocompatibility antigens.)  in humans the MHC is also called the human leuckocyte antigen (HLA) system

6. Major histocompatibility complex

9. HLA How could HLAs be identified & compared????? HLA typing  Certain HLAs are related to an increased susceptibility to specific diseases  transplant surgery

10. HLA typing 1-Serology Tissue typing using serology technique

11. HLA typing 2-Molecular (PCR) = polymerase chain reaction

12. HLA typing applications

13. The transfer (an organ or tissue) from one part of the body to another or from one person (the donor) to another (the recipient). Most common transplantation is blood transfusion. The heart, kidneys, liver, lungs, pancreas, intestine, and thymus. The kidneys are the most commonly transplanted organs, followed closely by the liver and then the heart. TISSUES THAT CAN BE TRANSPLANTED ARE:- Tissues include bones, tendons (both referred to as musculoskeletal grafts), cornea, skin, heart valves, and veins. The cornea and musculoskeletal grafts are the most commonly transplanted tissues. ORGANS THAT CAN BE TRANSPLANTED ARE :- Transplantation

14.  “ The force and power of individuality "  In 1954, the first kidney transplant was performed  KT, particular type of transplant has become a nearly routine medical procedure.  Other types of transplants that are now feasible include bone marrow, lungs, heart, liver, and cornea.  Transplanted organs or tissue can be taken:  recently deceased individuals  Living Donor

15. Reactions to Transplantation  Transplants recognized as non-self are rejected  attacked by T cells that directly lyse the grafted cells,  macrophages activated by T cells, and, in certain cases, by antibodies, which activate the complement system and injure blood vessels supplying the transplanted tissue  transplants that are not rejected can add many healthy years to a person’s life.

16. Reactions to Transplantation  Privileged sites and privileged tissue;  Some transplants or grafts do NOT stimulate an immune response Cornea : - rarely rejected, because antibodies usually do not circulate into that portion of the eye ( cornea lacks extensive blood vessels). - rejections do occur, especially when the cornea has developed many blood vessels from cornea infection or damage

17. Cont.... ▪ Brain : -brain lacks lymphatic vessels and because the walls of the blood vessels in the brain differ from blood vessel walls elsewhere in the body BBB which is impermeable to lymphocyte such as T- cells. -It is possible to transplant privileged tissue that does not stimulate an immune rejection. E.g. replacing a person's damaged heart valve with a valve from a pig's heart.

18. Different types of Transplants Autograft Self tissue transferred from one part of body to another Isograft (syngenic graft) Tissue transferred between genetically identical individuals Allograft Tissue transferred between genetically different members of same species – Most of our transplants Xenograft Tissue transferred between different species

19. Classification of Allograft Rejection:-  1-Graft versus host reaction (GVHR)  bone transplantation  the transplanted bone marrow contains immunocomptenet cells that mount primiarly a cell- mediated immune response against the tissue into which they have been transplanted. It could be fatal because the recipient lack the effective immunity.  This could be prevented by using umbilical cord blood instead of BM

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

21. Classification of Allograft Rejection:-  2-Host versus graft reaction (HVGR)  A.Hyperacute -Within hours B.Acute -Within weeks C.Chronic -Months to years

22. Host versus graft reaction (HVGR)  1) Hyperacute rejection:- . Occurrence time:-  Occurs within minutes to hours after host blood vessels are anastomosed to graft vessels. .Pathology :-  Thrombotic occlusion of the graft vasculature  Ischemia, denaturation, necrosis  Mechanisms:-  Preformed antibodies 1. Antibody against ABO blood type antigen 2. Antibody against VEC ( vascular endothelial cell) antigen 3. HLA antigen

23. 2) Acute Rejection:-  Occurrence time :-  Occurs within days to 2 weeks after transplantation, 80- 90% of cases occur within 1 month.  Pathology :- Acute humoral rejection:- Acute vasculitis manifested mainly by endothelial cell damage Acute cellular rejection:- Parenchymal cell necrosis along with infiltration of lymphocytes and macrophages Host versus graft reaction (HVGR)

24.  Mechanisms  Vasculitis:- IgG antibodies against alloantigens on endothelial cell CDC  Parenchymal cell damage:- Delayed hypersensitivity mediated by CD4+Th1 Killing of graft cells by CD8+Tc Host versus graft reaction (HVGR)

25.  3) Chronic or late rejection:-  Occurrence time:-  Develops months or years after acute rejection reactions have subsided  Pathology:-  Fibrosis and vascular abnormalities with loss of graft function  Mechanisms  -Not clear  -Extension and results of cell necrosis in acute rejection  -Chronic inflammation mediated by CD4+T cell/MΦ  Organ degeneration induced by non immune factors Host versus graft reaction (HVGR)

26. Stem cells Derivation of embryonic stem cells  ESCs in therapy  Adult stem cells (ASCs) Stem cells Embryonic stem cells (ESCs) ESCs are pluripotent, meanining that they are capable of generating many different types of tissue cells. # Adult stem cells (ASCs)

27.  https://www.dnalc.org/view/16991-how- embryonic-stem-cell-lines-are-made.html https://www.dnalc.org/view/16991-how- embryonic-stem-cell-lines-are-made.html

28. Prevention of graft rejection

29. Immunosuppressive agents 29 Application(s)Mode of actionAgent corticosteroids, prednisone anti-inflammatory, altering T-cell and PMN traffic organ transplant, hypersensitivity, autoimmunity rapamycin Inhibition of T cell activation by IL-2 organ transplant cyclosporine, ticrolimus sirolimus inhibition of IL-2 production by T cells Inhibit signalling thrrough IL-2 receptor organ transplant,

30. 30 application(s)mode of actionagent azathioprine, 6-MP purine metabolismorgan transplant methotrexatefolate metabolism organ transplant cyclophosphamide, melphalan alkylation of DNA, RNA and proteins autoimmune diseases, organ transplant x-irradiationLymphopenia malignancy/marrow transplantation Immunosuppressive agents

31. Thank you