Immunopathology: Type II and Type III Reactions

4. Type II Reaction – some examples • Complement dependent reactions • Transfusion reactions • Erythroblastosis fetalis • Autoimmune hemolytic anemia • ADCC • Killing of parasites and tumor cells • Transplant rejection • Cellular dysfunction • Myasthenia gravis • Grave’s disease • Antibodies against Extracellular antigens • Good Pasture’s syndrome –autoantibodies bind to Glomerular & Alveolar BM proteins • Pemphigus Vulgaris – autoantibodies against intercellular proteins (desmosomes)

5. Immunopathology Type III Hypersensitivity • Type III reactions involve immune complexes of antibody and antigen. • The antibodies are of IgM or IgG type, but the antigen is usually a soluble antigen. • Reactions due to large amounts of persistent immune complexes in tissues and organs • Larger complexes are removed by the mononuclear phagocyte system. Most pathogenic complex of small or intermediate size circulate longer and bind less avidly to MPS • Major target – Blood vessels (vasculitis)

6. Systemic immune complex disease • First phase – formation of antigen-antibody complexes in the circulation after the introduction of antigen (about 5 days after the introduction) • Second phase – deposition of complexes • Third phase – the development of inflammatory reaction (About 10 days) • -Due to activation of complement vaculitis is the hallmark feature • - During acute phase of the disease consumption of complement causes a decrease in serum levels

7. Type III Hypersensitivity • Immune complex mediated disease can be • Generalized (serum sickness – injection of exogenous serum ) • Localized (Arthus reaction)

10. Type III reaction -Examples • Acute – post streptococcal glomerulonephritis • Chronic - SLE

11. Normal Renal Biopsy

12. Immunopathology Type III reaction - Glomerulonephritis

13. Post Streptococcal Glomerulonephritis, E.M • Sub-epithelial “Humps” • Neutrophil with granules in cytoplasm

14. Local immune complex (Arthus reaction) disease • Localized area of tissue necrosis resulting from immune complex vasculitis • Develops when antigen is intracutaneously introduced into an individual having circulating antibodies against that antigen. • In contrast to anaphylactic reaction which starts immediately, arthus reaction develops over a period of hours and peaks 4-10 hrs after injection • Erythema and edema due to Fibrinoid necrosis of vessels with vasculitis are important morphological features

16. Fig 5-11 IC Vasculitis

17. ImmunopathologyType IV reaction(Cell Mediated) • The Type IV, or delayed-type hypersensitivity reaction (DTH), does not require antibody. • Involves CD 4 + and CD 8+ lymphocytes • Example : TB granuloma Contact Dermatitis

19. Type IV Hypersensitivity (Granulomatous Inflammation)

20. granuloma

21. Tuberculin test • PPD • Intradermal injection • Erythema (redness) and hardening (induration) after 2-3 days indicates previous exposure • Fully developed lesions have perivascular cuffing of CD4+ lymphocytes

22. Contact Dermatitis • Induced by nickel, cosmetics, poison-ivy • Small molecules penetrate skin • Conjugate to self proteins • Sensitization • Second contact - Ags presented to sensitized TH1cells • Cytokines secreted lead to inflammation • Inflammation is severe to cause vesicle formation (Eczematous dermatitis)

23. Type IV Reaction – T Cell Mediated Toxicity • CTLs kill via perforins, very similar to the way complement kills cells with the MAC. • Also produces granzymes which causes apoptosis • -increases Fasligand which causes apoptosis by binding to Fas of target cells • Play an important role in. • Resistance against viral infections. • Transplant rejection.

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27. Transplant Rejection

28. Transplant rejection • Mechanisms involved in transplant rejection • T cell mediated – delayed type hypersensitivity • Direct pathway via recipient CD4+ and CD8+ recognition of MHC Class I & II antigens on donor APCs (interdigitating dentritic cells) • Indirect pathway whereby processing of antigen by the recipient’s APCs is required • Antibody mediated

29. Renal Transplant rejection • Hyperacute: due to preformed antibodies, usually in multiparous women - rare because of antibody screening (Arthus reaction-Type III) • Acute • Vascular rejection (type II) • Cellular (tubulo-interstitial) rejection (type IV) – Good response to treatment • Chronic

30. Renal transplant rejection-Hyperacute Rejection • Caused by preformed antibodies in the recipient • Occurs within minutes • Grossly kidney purple and swollen • Widespread acute arteritis and arteriolitis • Thrombosis of vessels • Ischemic necrosis • Results in loss of graft

31. Hyperacute Rejection • Microthrombi • PMN’s

32. Acute Rejection • Occurs as early as 10-14 days. • Decreased renal function. May have fever and tenderness of the graft. • Tubulointerstitial (cellular) or vascular(humoral) rejection

33. Acute Vascular Rejection • Humorally mediated • Vascular inflammation • Necrotizing vasculitis (rejection vasculitis) • Intimal thickening • Responds less well to therapy

34. Acute Rejection - Vascular (Micro)

35. Acute Tubulointerstitial (Cellular) Rejection • Cell mediated • Lymphocytic infiltrate of the interstitium and tubulitis (T cells of both types – CD4 & CD8) • Responds well to therapy

36. . Acute tubulointerstitial rejection Mononuclear interstitial infiltrate

37. Chronic Rejection • After fourth month • Vascular changes • Intimal fibrosis • Progressive luminal narrowing • Interstitial fibrosis and tubular atrophy • Ischemic glomerulosclerosis • No effective therapy

38. Chronic rejection

39. Immunopathologymanagement • Host vs. graft reactions • With kidney transplants, a close match of MHC I and II antigens is sought (less important with heart and liver transplants, where size of the donor organ is paramount) • Transplant rejection is treated with immunosuppressive drugs such as cyclosporine (inhibits IL-2 formation) or anti-thymocyte globulin (anti-CD3)

40. Bone Marrow Transplant • Hematopoietic malignancies • Aplastic anemia • Immunodeficiency states • Certain non-hematopoietic malignancies

41. Complications of Allogeneic BM Transplants • Graft versus host disease • Immunologically competent cells from donor • Affects liver, skin, gut (jaundice, rash, diarrhea) • Acute or chronic • GVH can be prevented by depleting donor T cells before grafting • Graft versus leukemia effect may be beneficial (CML-Donor T cells are deliberately introduced) • Rejection of allogeneic (donor) marrow cells- Host T cells and NK cells

42. GVH disease • Acute • Within days to weeks • Skin, liver & intestine are affected • Generalized rash with desquamation • CMV infection – sometimes fatal • Chronic • May follow acute or may begin insidiously • Changes may resemble scleroderma

43. Immunopathology Chronic GVH

44. Immunodeficiency diseases • Primary immunodeficiency-genetic • Secondary immunodeficiency – Infections - Immunosuppression - Malnutrition

45. Primary Immunodeficiency • Inherited, genetically determined • Many X-linked • Males more at risk • Affects • HMI • CMI • Complement • Phagocytes

46. Primary Immunodeficiencies • Most manifest in infancy between 6 months & 2 years • Noted because of the susceptibility of the affected children to recurrent infections

47. B-cell Deficiencies • Disease • Recurrent pyogenic bacterial infections • Staphylococci, Streptococci, pneumococci • Normal immunity to viral, fungal infections

48. Immunopathology Primary Immunodeficiencies • Deficiencies of antibody-producing cells (B cells) • Congenital (Bruton) X-linked hypogammaglobulinemia • Common variable immune deficiency(1:50,000 to 1:200,000) • X linked hyper IgM syndrome • Selective IgA deficiency (common – 1:700)

49. X-linked Agammaglobulinemia • Failure of B cell precursors to differentiate to mature B cells due to deficiency of Bruton’s tyrosine kinase (btk) • Complete Ig molecules are not produced • Free heavy chains are seen in the cytoplasm • Occurs almost entirely in males • Becomes apparent at 6 months of age • Respiratory infections by Strep. Pneumoniae, staph and hemophilus;Viral infections & protozoal infections are also common • 35% develop infectious arthritis(Mycoplasma) • B cells and plasma cells are depleted • Prophylactic immunoglobulin therapy

50. Common Variable Immunodeficiency (CVID) • Common Variable Hypogammaglobulinemia –all immunoglobulin chains • Group of disorders –Sporadic and inherited • Cause (etiology) generally unknown – unidentified gene in HLA locus • Affects older patients 20s-30s • Both gender affected • Recurrent bacterial and giardia infections • B-cell cannot differentiate into Ab producing cells • 50 fold increased risk for gastric cancer