Major histocompatibility complex, transplantation and complement system

1. Major histocompatibility complex, transplantation and complement system Dr Samuel Aguazim

2. MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) • -set of GENES which encode for proteins that regulate the immune response • -class I and II: encode for cell surface proteins • -class III: encode for complement proteins • -HUMAN LEUKOCYTE ANTIGENS (HLA): MHC in humans, located on the short arm of chromosome 6

3. HLA CLASS I • -found on all the surfaces of nucleated cells and platelets • -bind endogenous peptide and present them to CD8+ cytotoxic T cells. • -has 3 types: HLA-A, HLA-B AND HLA-C • -recognize cells which have been infected by viruses, bacteria, parasites and tumors

5. HLA CLASS II • -found only on the cell surfaces of: dendritic cells, Langerhans cells, activated macrophages, B cells, thymic epithelial cells • -binds exogenous peptides and the formed complex is necessary for antigen recognition by T helper cells (CD4+ cells) • -has 3 types: HLA-DP, HLA-DQ, HLA-DR • -recognizes cell which have been infected by bacteria, parasites or injected proteins

6. HLA CLASS III • -genes which encode for complement components like C2 and C4

7. Association of HLA with disease HLA B-27: Ankylosingspondylitis Acute anterior uveitis Post gonococcal arthritis HLA DR3; Chronic active hepatitis Insulin dependent diabetes mellitus HLA DR4 Rheumatoid arthritis

8. Progression of AnkylosingSpondylitis

9. Classification of grafts • Autologous grafts (Autografts) • Grafts transplanted from one part of the body to another in the same individual • Syngeneic grafts (Isografts) • Grafts transplanted between two genetically identical individuals of the same species • Allogeneic grafts (Allografts) • Grafts transplanted between two genetically different individuals of the same species • Xenogeneic grafts (Xenografts) • Grafts transplanted between individuals of different species

11. Graft survival: a) ABO group compatibility( most important) b) absence of preformed cytotoxic antibodies against donar HLA antigens c) HLA compatibility

12. Transplant Immunology • Rejection is an immune response that mediates injury and destruction of transplanted tissue

13. Types of allograft rejection: • Hyperacute rejection • Acute rejection • Chronic rejection

14. Hyperacute Rejection • Rapid: occurs in minutes of attachment of allograft to the recipients blood supply • Mediated by preformed antibodies and complement • No treatment • Prevention

15. Hyperacute Rejection • caused by preformed Absvs graft Ags • e.g., ABO blood group incompatibility • previous transfusions / transplants → Abs- • -preformed cytotoxic antibodies in the host against foreign HLA antigens in the donor tissue

18. Acute Rejection • Most common • Occurs days to months post-transplant • Cell-mediated immune response • Treated by increasing the net state of immunosuppression

19. Acute Rejection • Primary Cellular • Massive infiltration of macrophages and lymphocytes • Decreased graft function • Clinically appears at >10 days post-tx and can occur anytime thereafter.

21. Chronic Rejection • Progressive decline in allograft function • Presents differently in each organ transplant type • Occurs months to years post-transplant • Therapy: prevent vs. delay the inevitable?

22. Graft vs Host Disease • Proliferation of T cells in donor blood reacting to MHC antigens in recipient • Recipients are immunosuppressed: • Lymphopenia, bone marrow suppression • Infants, fetus with exchange txn • Congenital immunodeficiency • Pts receiving relatives’ blood • All organs susceptible: skin, gut • 84% fatality rate (infection or hemorrhage) • Prevention: irradiated blood products

24. Complement system It consists of series of proteins synthesized by liver as acute phase reactants. • There are three main effects of complement: • (1) lysis of cells such as bacteria, allografts, and tumor cells; • (2) generation of mediators that participate in inflammation and attract neutrophils; and • (3) opsonization, ie, enhancement of phagocytosis

25. Complement Pathways

26. The multiple activities of the complement system :Lysis, opsonization, activation and clearance

27. C3a…………….anaphylotoxin • C3b ……………….opsonin • C5a…….anaphylotoxin,adhesion, chemotactic • C5b67……………chemotactic complex • C5b6789……………….MAC >>>>> MAC= Membrane Attack Complex <<<<<

28. Classic pathway • (1) Contain complément components C1. C4. C2 • (2) C1 esterase inhibitor • (a) Inactivates the protease activity of C1 • • Protease normally cleaves c2 and c4to produce C4b2b complex • (C3 convertase) The latter is C3 convertase, which cleaves C3 molecules into two fragments, • C3a and C3b. C3a, an anaphylatoxin. • (b) Inhibitor is deficient in hereditary angioedema

29. b. Alternative pathway • In the alternative pathway, many unrelated cell surface substances, eg, bacterial lipopolysaccharides (endotoxin), fungal cell walls, and viral envelopes, can initiate the process by binding C3(H 20) and factor B. • This complex is cleaved by a protease, factor D, to produce C3b,Bb. • This acts as a C3 convertase to generate more C3b.

30. d. Decay accelerating factor (DAF) • (1) Present on cell membranes • (2) Enhances degradation of C3 convenase and C5 convertase • (3) Protects the cell against MAC destruction (4) Deficient in paroxysmal nocturnal hemoglobinuria(PNH)

31. Hereditary angioedema • Autosomal dominant disorder with deficiency of C1 esterase inhibitor • Continued C1 activation decreases C2 and C4 and increases their cleavage products, which • have anaphylatoxic activity • Normal C3 • Swelling of face and oropharynx

32. C2 deficiency • Most common complement deficiency • Association with septicemia (usually Streptococcus pneumoniae) and lupus-like syndrome in children

33. C6-C9 deficiency • Increased susceptibility to disseminated Neisseriagonorrhoeae or N. meningitidis infections

34. Paroxysmal nocturnalhemoglobinuria • Acquired stem cell disease • Defect in molecule anchoring decay accelerating factor (DAF), which normally degrades C3 and C5 convertase on hematopoietic cell membranes • Complement-mediated intravascular lysis of red blood cells (hemoglobinuria), platelets, and neutrophils

35. Immune complexes bind complement, and thus complement levels are low in immune complex diseases, eg, acute glomerulonephritis and systemic lupus erythematosus. Binding (activating) complement attracts polymorphonuclear leukocytes, which release enzymes that damage tissue.

36. Patients with severe liver disease, eg, alcoholic cirrhosis or chronic hepatitis B, who have lost significant liver Function and therefore cannot synthesize sufficient complement proteins, are predisposed to infections caused by pyogenic bacteria.