1、Diseases of Immunity（免疫性疾?。?劉 穎 Office ：Rm. 214, East No.1 Building E-mail: liu_,Overview,Immune system: A Two-edged sword: responsible for defending us against the countless pathogenic microbes or tumors hypersensitive or abnormal reaction is the cause of some diseases,Hypersensitivity diseases hav

2、e been grouped into four major categories based upon their underlying causes.,The Common Types of the Diseases of Immunity,1. Transplant Rejection 2. Hyperactive immunity： Diseases of Autoimmunity systemic lupus erythematosus (SLE) 3. Immunodeficiency: Immunodeficiency syndrom acquired Immunodeficie

3、ncy syndrom (AIDS),Transplant Rejection,Host anti-donor allograft (宿主抗移植物反應(yīng)) 2. Donor allograft anti- Host (移植物抗宿主反應(yīng)) Cell mediated hypersensitivity Antibody mediated hypersensitivity,Mechanisms of Graft Rejection,Rejection of allografts is a response to Major Histocompatibility Complex (MHC抗原), als

4、o referred as to Human Leukocyte antigen （HLA抗原） Both T cells and antibodies reactive with the graft are involved in the rejection of most solid-organ allografts,T-Cell-Mediated Rejection : cytotoxic lymphocyte (CTLs, CD8+ T), CD4+ T , macrophages Antibody-Mediated Rejection : Direct pathway: Alloan

5、tibodies directed against graft MHC molecules Indirect pathway: other alloantigens bind to the graft endothelium and cause injury (and secondary thrombosis) via complement activation and recruitment of leukocytes.,Mechanisms of Graft Rejection,Classification,1. Hyperacute Rejection Occurs within min

6、utes to a few hours after transplantation 2. Acute Rejection Occurs within days, weeks, months even years. 3. Chronic Rejection Occurs in months to years,Hyperacute Rejection,Mechanisms Antidonor antibodies (MHC or ABO antigens) are present in the circulation of the host before transplant. In any ev

7、ent, transplantation in this setting results in immediate rejection because the circulating antibodies rapidly bind to the endothelium of the grafted organ, with subsequent complement fixation and vascular thrombosis.,Gross: Cyanotic, mottled, flabby and soft, swollen Widespread hemorrhagic cortical

8、 necrosis May excrete only a few drops of bloody fluid,MORPHOLOGY,LM: (1) Widespread acute arteritis and arteriolitis: Fibrinoid necrosis of walls Thrombosis (2) Ischemic necrosis,Acute Rejection,It is the most common type of transplant rejection in a nonimmunosuppressed host or may appear months or

9、 even years later in the presence of adequate immunosuppression It is mainly conducted by cellular rejection in the early stage. However, humoral (體液) rejection also participate in the later stage.,1. Acute cellular rejection : most commonly seen within the first months after transplantation extensi

10、ve interstitial CD4+ and CD8+ T-cell infiltration with edema and mild interstitial hemorrhage 2. Acute humoral rejection- antibody-mediated rejection: also called as blood vessel type rejection. necrotizing vasculitis with endothelial cell necrosis; neutrophilic infiltration; deposition of antibody,

11、 complement, and fibrin; and thrombosis,Acute Rejection,Histologically, cellular rejection is marked by an interstitial mononuclear cell infiltrate with associated edema and parenchymal injury humoral rejection is associated with vasculitis.,Acute cellular rejection,T-cell infiltration with edema an

12、d mild interstitial hemorrhage,Blood vessel type rejection,necrotizing vasculitis,Chronic Rejection,It is usually the result from acute rejection, and not respond to standard immunosuppression therapy. Gross: shrunk kidney. Microscope: dominated by vascular changes (smooth muscle cell proliferation

13、and extracellular matrix synthesis), interstitial fibrosis, and loss of renal parenchyma,血管閉塞性動(dòng)脈內(nèi)膜炎,Diseases of Autoimmunity,Tolerance (unresponsiveness) to self-antigens is a fundamental property of the immune system, breakdown is the basis of autoimmune diseases,Systemic Lupus Erythematosus (SLE),

14、Characteristics: 1. Predominantly in young women. 2. Mainly conducted by humoral immunity. 3. Multiple organs damage, multisystem autoimmune disease 4. Variant clinical manifestation: Acute or insidious onset that may involve virtually any organ in the body, affects principally the skin, kidneys, se

15、rosal membranes, joints, and heart 5. A fairly common disease, a strong (approximately 9 : 1) female preponderance, affecting 1 in 700 women of childbearing age.,Etiology and Pathogenesis,The fundamental defect in SLE is a failure to maintain self-tolerance. A large number of autoantibodies is produ

16、ced that can damage tissues either directly or in the form of immune complex deposits Antibodies include: 1. Antinuclear Antibodies (1) antibodies to DNA (2) antibodies to histones (3) antibodies to nonhistone proteins bound to RNA (4) antibodies to nucleolar antigens 2. Other Autoantibodies Antibod

17、ies against blood cells Antiphospholipid antibodies,Etiology and Pathogenesis,1. Genetic Factors (1) There is a high rate of concordance (25%) in monozygotic twins versus dizygotic twins (1% to 3%). (2) Family members have an increased risk of developing SLE. And up to 20% of clinically unaffected f

18、irst-degree relatives may reveal autoantibodies. (3) Positive association between SLE and polymorphism of HLA-DQ locus.,Etiology and Pathogenesis,2. Nongenetic Factors (1) Most patients treated with procainamide (普魯卡因胺) for more than 6 months develop ANAs (抗核抗體）and 20% appear SLE. (2) Sex hormones,

19、especially estrogens. (3) Exposure to ultraviolet light. 3. Immunologic Factors Intrinsic B-cell hyperactivity was considered a central feature of SLE pathogenesis.,Mostly type III hypersensitivity reaction,Morphology,LE body: ANAs attack the damaged cells nuclear, the cell lost its chromatin patter

20、n, and become homogeneous, to produce so-called LE body (hematoxylin body). The neutrophil or macrophage that has engulfed the LE body is referred as to LE cell 2. The Basic Morphologic Changes: (1) Acute stage: acute necrotizing vasculitis Fibrinoid necrosis of blood vessel wall (2) Chronic stage:

21、perivascular fibrosis, producing Onion-skin lesions,Involved Organs,Kidney: Kidney involvement is one of the most important clinical features of SLE. Renal failure being the most common cause of death. SLE glomerolonephritis: occur in about 60% SLE patients. The typical lesions are fibrinoid necrosi

22、s, wire loop and so on. If detected by immuno-fluorescence and electron microscope, almost all cases show some renal abnormality.,World Health Organization （WHO）morphologic classification, 5 patterns of glomerular disease in SLE (none of which is specific to the disease): class I, normal by light, e

23、lectron, and immunofluorescence microscopy (less than 5% of SLE patients); class II, mesangial lupus glomerulonephritis; class III, focal proliferative glomerulonephritis; class IV, diffuse proliferative glomerulonephritis; class V, membranous glomerulonephritis.,wire loop,Immunofluorescence “滿(mǎn)堂亮”,2

24、. Skin: Involved in a vast majority of patients. A characteristic erythematous are butterfly pattern in about half. Histologically, there is liquefactive degeneration of the basal layer of the epidermis, edema at the dermoepidermal junction, and mononuclear infiltrates around vessels and skin append

25、ages. Immunofluorescence microscopy reveals deposition of Ig and complement at the dermoepidermal junction,Involved Organs,liquefactive degeneration of the basal layer of the epidermis and edema at the dermoepidermal junction,immunofluorescence stained for IgG reveals deposits of Ig along the dermoe

26、pidermal junction.,3. Heart: Nonbacterial verrucous endocarditis; pericarditis; and myocarditis.,Involved Organs,1- to 4-mm warty deposits Myocarditis in the form of a nonspecific mononuclear cell infiltrate, and valvular lesions Pericardium and pleura, in particular, are serosal membranes that show

27、 a variety of inflammatory changes,4. Others: more than 90% patients have joint involvement: nonspecific mononuclear cell infiltration in the synovial membranes. Erosion of the membranes and destruction of articular cartilage CNS involvement is also very common: vascular lesions causing ischemia or

28、multifocal cerebral microinfarcts spleen may be moderately enlarged, central arteries characteristically show thickening and perivascular fibrosis, producing onion-skin lesions. lung may reveal interstitial fibrosis, along with pleural inflammation; liver shows nonspecific inflammation of the portal

29、 tracts.,Involved Organs,Clinical and pathological correlations The manifestations are extremely variable because of multiple organs damaged. The diagnosis of SLE is obvious in a young woman with a classic butterfly rash over the face, fever, arthritis, pleuritic chest pain, and photosensitivity（光敏）

30、 ANAs can be found in virtually 100% of patients; anti-dsDNA antibodies and antibodies to Smith (Sm) antigen are considered highly diagnostic of SLE. Serum complement levels are low 90% five-year and 80% ten-year survivals Renal failure, intercurrent（伴發(fā)的） infections, and diffuse CNS involvement are

31、major causes of death.,Acquired Immuno-Dificiency Syndrom (AIDS),Concept: AIDS is a retroviral disease caused by the human immunodeficiency virus (HIV). It is characterized by infection and depletion of CD4+ T lymphocytes, and by profound immunosuppression leading to opportunistic infections, second

32、ary neoplasms, and neurologic manifestations,Originated from Africa, but first described in the United States in 1981 1985年，一位到中國(guó)旅游的外籍人士患病入住北京協(xié)和醫(yī)院后很快死亡，后被證實(shí)死于艾滋病。這是我國(guó)第一次發(fā)現(xiàn)艾滋病病例。 more than 22 million people have died of AIDS; about 42 million people are living with the disease; estimated 5 million in

33、fections each year; 95% of HIV infections are in developing countries, Africa alone carrying more than 50% of the HIV burden AIDS represents the fifth most common cause of death in adults between the ages of 25 and 44,Epidemiology of AIDS,Five groups at risk for developing AIDS: 1. Homosexual or bis

34、exual males 2. Intravenous drug abusers 3. Recipients of blood and blood components 4. Hemophiliacs（血友病患者） 5. Heterosexual contacts of members of other high-risk group 6. about 10% of cases the risk factors are unknown or not reported,Three Major Transmission Routes,1. Sexual transmission: accountin

35、g for more than 75% cases in the world. 2. Parenteral （注射）transmission: Including three groups (1) intravenous drug abusers (2) hemophiliacs receiving factor or (3) random recipients of blood transfusion 3. Mother-to-infant transmission: vertical transmission rate worldwide vary from 25% to 30%.,Eti

36、ology of AIDS,HIV has two genetically different but antigenically related forms. HIV-1 is the more common type associated with AIDS in the United States, Europe, and Central Africa HIV-2 causes a similar disease principally in West Africa,Retroviruse HIV-1 virion is spherical and contains an electro

37、n-dense, cone（圓錐）-shaped core surrounded by a lipid envelope derived from the host cell membrane,Pathogenesis of AIDS,The two major targets of HIV infection are the immune system and the CNS Life Cycle of HIV: The CD4 molecule is a high-affinity receptor for HIV infection. The virus bind and entry t

38、he cells. Then produce new virus in the CD4+ cells. The infected cells were killed, and the virus will infect other CD4+ cells. The loss of CD4+ cells. The cytokines production reduced so that the whole immuno-system break-down.,Progression of HIV Infection: acute infection of mucosal T cells and DC

39、s; viremia with dissemination of virus; latent infection of cells in lymphoid tissue; continuing viral replication and progressive loss of CD4+ T cells,Mechanisms of T-cell Depletion in HIV Infection,Three phase (1) an early acute phase (2) a middle chronic phase (3) a final crisis phase,Natural History of HIV Infection,In the absence of treatment, most patients with HIV infection develop AIDS after a chronic phase lasting 7 to 10 years,Morphology of AIDS,The clinical manife