Diseases of Immunity: A Two-edged Sword

1. Diseases of Immunity（免疫性疾病） 复旦大学上海医学院病理学系

2. Immune system: A Two-edged sword

3. The Common Types of the Diseases of Immunity • Transplant Rejection • Hyperactive immunity： • Diseases of Autoimmunity • Immunodeficiency: • Immunodeficiency syndrome

4. Ⅰ. Transplant Rejection • 1. Host anti-donor allograft (宿主抗移植物反应) • 2. Donor allograft anti-Host (移植物抗宿主反应)

5. The mechanism of Transplant RejectionImmuno-reaction • Cell-mediated Rejection • Antibody-mediated Rejection

6. The target of transplant rejection Major Histocompatibility Complex (MHC抗原) also referred as to Human Leukocyte Antigen (HLA抗原) Characteristics: high variety

7. Classification of Transplant Rejection • Hyperacute Rejection(超急性排异反应) Occurs within minutes to a few hours after transplantation • Acute Rejection (急性排异反应) Occurs within days, weeks, months even years. • Chronic Rejection (慢性排异反应) Occurs in months to years

8. Hyperacute rejection Antibody-mediated (type II) hypersensitivity circulating antibodies rapidly bind to endothelium of the grafted organ complement fixation and vascular thrombosis

9. Antidonor antibodies are present in the circulation of the host before transplant: • multiparous women who have anti-HLA antibodies against paternal antigens shed from a fetus. • exposure to foreign HLA from prior blood transfusions. • host who has already rejected an organ transplant.

10. Morphology • Gross: swelling, cyanotic. • Microscope: arteritis and arteriolitis vessel thrombosis ischemic necrosis.

11. Acute Rejection • The most common type of transplant rejection • Can be treated with chemotherapy • It is mainly conducted by cell-mediated rejection in the early stage. However, • antibody-mediated rejection also participate in the later stage.

12. Cell-mediated rejection: (type Ⅳ hypersensitivity ) • HLA stimulates CD4+、CD8+ T lymphocytes. The morphologic characteristic is numerous mononuclear cells invasion in the tissue.

14. antibody-mediated rejection: Also called as blood vessel type rejection. (type II hypersensitivity) • The morphologic characteristic is fibrinoid necrosis of the blood vessel wall. Immuno- fluorescence can prove there is immuno-complex precipitate in the necrosis tissue.

16. Chronic Rejection It is usually the result from acute rejection, and not respond to standard immunosuppression therapy. • Gross: shrunk kidney. • Microscope: interstitial fibrosis, loss of renal parenchyma, vascular changes (smooth muscle cell proliferation and extracellular matrix synthesis).

18. Ⅱ. Systemic Lupus Erythematosus (系统性红斑狼疮) Characteristics: • Predominantly in young women. • Mainly conducted by humoral immunity. • Variant Clinical manifestation. • Multiple organs damage. • Recurrence, with 90% and 80% 10- year survive.

19. Etiology and Pathogenesis The fundamental defect in SLE is a failure to maintain self-tolerance. 1. It is mediated by antinuclear antibodies: • Anti-double-stranded DNA • Anti-histone • Anti-Sm • Anti-ribonucleoprotein

20. 2. Genetic Factors • concordance: 25% in monozygotic twins 1% to 3% in dizygotic twins • family members have an increased risk 20% first-degree relatives reveal autoAbs • association between SLE and HLA-DQ

21. 3. Nongenetic Factors • Most patients treated with procainamide for more than 6 months develop ANAs and 20% appear SLE. • Sex hormones, especially estrogens. • Exposure to ultraviolet light.

22. Morphology • LE body: ANAs attack the damaged cell’s nuclear to produce so-called LE body. The neutrophil or macrophage the LE (LE cell) • The Basic Morphologic Changes: • Acute stage: Fibrinoid necrosis of blood vessel wall. • Chronic stage: perivascular fibrosis, producing Onion-skin lesions.

23. Fibrinoid necrosis Onion-skin lesions

24. Morphology of Common Involved Organs • Kidney:Lupus glomerolonephritis (60%) all forms of glomerulonephritis fibrinoid necrosis wire loop(白金耳) most common cause of death

25. fibrinoid necrosis Diffuse hyperplasia

26. wire loop

27. Skin: involve in a vast majority of patients erythematous eruption (butterfly pattern) (蝶形红斑) liquefactive degeneration edema (dermoepidermal junction) mononuclear infiltrates Ig and complement deposit

28. liquefactive degeneration Ig and C deposit (狼疮带)

29. Heart: Nonbacterial verrucous endocarditis, pericarditis

30. Others: more than 90% patients have joint involvement. CNS involvement is also very common. CPC: The manifestations are extremely variable because of multiple organs damaged.

31. AIDS（acquired immuno-dificiency syndrom） AIDS is a retroviral disease caused by the human immunodeficiency virus (HIV) and is characterized by profound immunosuppression: opportunistic infections secondary neoplasms neurologic manifestations.

32. The Situation of AIDS • Twenty-two million people have died of AIDS till 2000. • Three million people died of AIDS only in the year 2000 alone. • Another 3.5 million are infected with HIV. • Ninety-five percent of HIV infections are in developing countries. • In USA, the people died of AIDS more than in both Would Wars combined.

33. Epidemiology of AIDS Five groups at risk for developing AIDS: • Homosexual or bisexual males • Intravenous drug abusers • Recipients of blood and blood components • Hemophiliacs • Heterosexual contacts of members of other high-risk group

34. Three Major Transmission Routes • Sexual Transmission: accounting for more than 75% cases in the world. • Parenteral Transmission: Including three groups (1) intravenous drug abusers (2) hemophiliacs receiving factor Ⅷ or Ⅸ (3) random recipients of blood transfusion • Mother-to-Infant Transmission.

35. Etiology of AIDS • HIV 1 USA, Europe, Central Africa • HIV 2 West Africa, Asia

36. Pathogenesis of AIDS The CD4 molecule is a high-affinity receptor for HIV infection. However, binding to CD4 is not sufficient for infection. The virus should bind to CXCR4 or CCR5 to entry the cells. And then produce new virus in the CD4+ positive cell. After infected cells were killed, the virus will infect other CD4+ cells. At last, cause the loss of CD4+ cells. The cytokines production reduced so that the whole immuno-system break-down.

37. Coreceptor: CXCR4(LC), CCR5(MΦ)

39. Morphology of AIDS • Lymphoid Tissue follicles proliferating T lymphocytes(Th) decreased all kinds of lymphocytes decreased

41. Opportunity infection Pneumocystis(肺孢子虫)

42. cryptosporidium (隐孢子虫)

43. Toxoplasmosis(弓浆虫)

44. Candidiasis(白色念珠菌) Aspergillus(曲菌) Mucormysocic(毛霉菌) PAS染色 银染色

45. Cryptococcosis(隐球菌) Histoplasmosis(组织胞浆菌) 银染色 粘卡、墨、PAS染色

46. Herpes simplex virus(单纯疱疹) Cytomegalovirus(巨细胞病毒) Varicella-zoster virus (带状疱疹)

47. Secondary malignant tumors: Kaposi sarcoma Lymphoma

48. Kaposi sarcoma (卡波西肉瘤)