Immunopathology

1. Immunopathology Dr. Amitabha Basu MD

2. OUR TOPIC • TRANSPLANT REJECTION • Graft Vs Host disease • AUTOIMMUNE DISEASES

3. TRANSPLANT REJECTION and MHC matching Type of graft. Mechanism of rejection. Graft survival. Complication of immunosuppression. Management. Graft Vs Host reaction.

4. Type of Grafts • Allograft: An organ or tissue transplanted from one individual to another of the same species, i.e. human to human. • Auto graft: Tissue that is taken from one site and grafted to another site on the same person; "skin from his thigh replaced the burned skin on his arms“ • Xenograft: A xenograft is a transplantation of tissue from a donor of one species to a recipient of another species • Fetal tissue grafts: Less chance of reaction.

5. Mechanism of allograft rejection • T cell mediated reaction • Involve Cytotoxic T cell ( CD8+) • Type IV hypersensitivity reaction • Antibody mediated reaction (mainly ADCC).

6. When you give a graft….. • The organ contain • Tissues of the organ • Some lymphocytes of the donor • Some macrophage (APC) of the donor

7. In the direct pathway, • Donor class I and class II antigens on APC of the graft are recognized by CD8+ cytotoxic T cells and CD4+ helper T cells of host. • CD4+ cells→ cytokines→ tissue damage by a local delayed hypersensitivity reaction. • CD8+ T cells→ kill graft cells

8. In the indirect pathway • Activate macrophage= tissue damage. • Form antigen antibody complex and produce vasculitis= tissue damage.

9. Types of rejection reaction • Hyper acute rejection • Acute rejection: • Chronic rejection

10. Hyperacute rejection • Hyperacute rejection occurs when preformed antidonor antibodies are present in the circulation of the recipient. • Morphology: shrunken liver, necrotic swollen tubular epithelial cell, may show pyknotic nuclei. • Scanty bloody urine.

11. Transplant reaction

13. Kidney change

14. Management • Drug cyclosporine (block nuclear factor of activated T cells- thus inhibit the gene for IL-2). • Monoclonal anti-T-cell antibodies (e.g., monoclonal anti-CD3 and antibodies against the IL-2 receptor α chain).

15. Methods of Increasing Graft Survival • HLA ( both Class I and class II antigen) matching in transplants. • Immunosuppressive therapy.

16. Survival of grafts: HLA matching in transplants • HLA matching ( of donor and recipient cells) for both class I and class II antigens improves survival: MHC MHC Good = Donor R MHC MHC = Bad

17. Immunosuppressive therapy As a method of graft survival What are the risks?

18. Complications of Global Immunosuppression Opportunistic infections: Pneumocystis Carinii Sliver stain. Cytomegalovirus (CMV) pseudohyphae : Candida

19. Candida (C. albicans ) infection Location: skin, mouth, gastrointestinal tract, and vagina . Risk : DM and immuno compromised patient. Presentation:(thrush-oral). Gray-white, dirty-looking pseudomembranes composed of matted organisms and inflammatory debris ,

20. Others • Risk for developing EBV-induced lymphomas, • Human papillomavirus-induced squamous cell carcinomas, and • Kaposi sarcoma

21. Transplantation of Hematopoietic Cells • Develop Graft vs host reaction. • GVH disease occurs in any situation in which immunologically competent cells are transplanted into immunologically crippled recipients. • Example: bone marrow, whole blood.

22. Mechanism • Results from the donor lymphocytes attacking the recipient tissues that has offending HLA antigens. Lymphocyte of donor [CD8+ cells] Host tissue

23. Types • Acute – days to week • Donor cells infiltrate host’s epithelia, liver, bile duct , Gut, lymphnode and dysfunction them. • Infection – CMV • Clinical: Jaundice, skin rash, bloody diarrhea, hepatomegaly heavy infiltration of lymphocytes in the host tissue.

24. d/d of acute type of GVH • Transfusion reaction (TR) • in contract to GVH, TR occur immediately after transfusing a mismatched blood. • ( if you donate A+ blood to a person with B+ blood group etc)

25. Types • Chronic – skin atrophy and cholestatic jaundice.

26. C/F=GVH disease : Jaundice and Rash,

27. Time for Autoimmunity

28. Topic • Immune tolerance • Termination of tolerance • Definition: AUTOIMMUNITY • Mechanisms proposed for development of autoimmunity • Mediators • Autoantibody • Diseases

29. Immune tolerance • A state of unresponsiveness to a specific antigen or group of antigens to which a person is normally responsive. • Self tolerance: Immune tolerance against self- antigen.

31. Termination of tolerance • X-irradiation • Immunization with cross reactive antigens. • Autoimmune diseases.

32. AUTOIMMUNITY  • Autoimmunity can be defined as breakdown of mechanisms responsible for self tolerance.

33. Mechanisms proposed for development of autoimmunity include: 2 • Failure of “activation induced death” of self reactive T cell. Self reactive T cell So these T cells kills the cell of our body in spite they contain self antigen.

34. Mechanisms proposed for development of autoimmunity include: • Molecular mimicry ; Some cells of our body share similar antigen like that of microbes, when antibodies produced to kill these microbes , they destroy cells of the body also. Host cell bacteria

35. Termination of tolerance : examples (nice to know)

36. Mediators • Cytokines. • Compliments.

37. Cytokines • Interleukins • TNF-alpha • Interferons

38. Few examples • IL-1, TNF-α, type 1 interferons & IL-6: innate immunity • IL-2 : Growth factor for T-cells • IL-12 and IFN-γ: involved in both innate and adaptive immunity • IL-10 and TGF-β: down-regulate immune responses

39. Cytokines induce their effects in three ways: • Autocrine effect: IL-2 produced by antigen-stimulated T cells stimulates the growth of the same cells • Paracrine effect: IL-7 produced by bone marrow or thymic stromal cells promotes the maturation of B-cell progenitors in the marrow or T-cell precursors in the thymus, respectively • Endocrine effect: IL-1 and TNF- produce the systemic acute-phase response during inflammation. • Acute Inflammatory effect: IL1 and IL8.

40. Autoantibody • Definition : Antibody against “self antigen”. • Mainly against various component of Nuclei. • These are celled : Antinuclear Antibodies (ANA).

41. ANA DETECTION • By estimation of serum titer • By staining pattern the tissue.

42. Disease ANA Staining pattern

43. SLE Diffuse and Rim

44. Systemic Lupus Erythematosus (SLE) • *Skin rash - Malar or discoid • Sensitivity to light (photo dermatitis) • Serositis/synovitis - inflammation of serosal surfaces along with effusions

45. Typical skin lesion in SLE An immunofluorescence micrograph stained for IgG reveals deposits of immunoglobulin along the dermal-epidermal junction.

46. SLE • Glomerulonephritis – Lupus nephritis = Nephrotic syndrome . • *Cytopenias - anemia, leucopenia, thrombocytopenia. • Heart: Libman-Sachs Endocarditis • Thrombosis - Antiphospholipid syndrome (APS) can occur in patients with SLE. • Splenomegaly: periarteriolar fibrosis ("onion skinning") .

47. SLE • *Arthritis, fever, weight loss. • Vasculitis – with fibrinoid necrosis.

48. Lupus nephritis : Wire loop lesion. Deposit of C1q occur.

49. Chronic Discoid Lupus Erythematosus • Less severe. • Skin plaques showing varying degrees of edema, erythema, scaliness. • Diagnosis: positive ANA test, but dsDNA are rarely present.

50. Drug induced lupus • Hydralazine, procainamide, INH, and D-penicillamine. • Diagnoses: • Positive antihistone antibodies. • Negative (mostly( dsDNA).