1、文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。课件与相关阅读课件与相关阅读文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Autoimmunity:immune response against self-antigens(components)Autoimmune disease,AID:Diseases induced by inappropriate response of the immune system against self-compone
2、ntsGeneral principles:-Significant health burden,5%of population(USA)-Multiple factors contribute to autoimmunity,-Including genetic predisposition（遗传倾向）,infections -Fundamental problem is the failure of self-toleranceProblems:Failure to identify target antigens,heterogeneous（异质性）disease manifestati
3、ons,disease usually presents long after initiationDefinition文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Characters of AID 1High titer auto-antibody in serum and/or self-reactive T cells against self-components.2 Damage to organs and tissue destruction caused by auto-antibody&self-reactive T cells.3Repeat
4、,Chronic,Persistent,Progress 4Animal model replication and transferable.5Inherited tendency,female susceptible.6 No obvious reasons.文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Organ-specific vs Systemic Autoimmune DiseasesFor most of the AIDs,There is a major affected organ but also affect others文档仅供参考，不
5、能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Broadly separated by the type of effector mechanism(similar to hypersensitivity classification scheme)Three classes:Type II:Antibody against cell-surface antigen or matrix antigens Type III:Immune-complex disease Type IV:T cell-mediated diseaseClassification of Autoimm
6、une Diseases文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Antibody-mediated Diseases I -Tissue InjuryType IIType III文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Antibody-mediated Diseases II -w/o tissue injuryAcetylcholine:乙酰胆碱重症肌无力重症肌无力文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Type II Antibody-mediated Diseases贫血贫
7、血血小板减少血小板减少寻常型天疱疮寻常型天疱疮血管炎血管炎肺出血肾炎综合征肺出血肾炎综合征急性风湿热急性风湿热重症肌无力重症肌无力甲状腺亢进甲状腺亢进胰岛素耐受糖尿病胰岛素耐受糖尿病恶性贫血恶性贫血文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Graves Disease甲状腺亢进甲状腺亢进文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Graves Disease：Antibody mediated Disease文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。In this disease,auto
8、antibodies to the Acetylcholine receptor（乙酰胆碱受体）block neuromuscular transmission from cholinergic neurons by blocking the binding of acetylcholine and by causing downregulation(degradation)of its receptor.Progressive weakening of skeletal muscles,manifested by difficulty in chewing,swallowing and br
9、eathing,and eventually death from respiratory failure.Myasthenia Gravis（重症肌无力）文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Type III：Immune-Complex mediated diseases肾小球肾炎文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Immune-Complex Formation and DepositionDeposition to Kidney,Joint and vascular Lesions文档仅供参考，不能作为科
10、学依据，请勿模仿；如有不当之处，请联系网站或本人删除。“red wolf”:reddish facial rash on the cheeks Antibodies to a vast array of tissues,RBCs,platelets,leukocytes Antibodies against several nuclear antigens (Mostly native DS-DNA and histones)The disease attacks many organs and causes fever,joint pain and damage to the central
11、 nervous system,heart and kidneys.Kidney lesion causes the most mortality from SLE Women:men=10:1 Aged between 20-40 yrsSystemic lupus erythematosus(SLE)文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Rheumatoid factors(a group of autoantibodies,IgM)react with determinants in the Fc region of IgGRheumatoid f
12、actors bind to circulating IgG,forming IgM-IgG complexes that are deposited in the joints.Immune complexes then activate complement cascade.Major symptoms:chronic inflammation of jointsMost affecting women from 40-60 yrs oldRheumatoid arthritis文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Type IV T cell-me
13、diated Diseases Direct T cell cytotoxicity via CD8+CTL Self-destruction of tissue cells induced by cytokines,eg,TNFa Recruitment and activation of macrophages leading to bystander tissue destruction 文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Type IV T cell-mediated Diseases麸质过敏症文档仅供参考，不能作为科学依据，请勿模仿；如有不当
14、之处，请联系网站或本人删除。T cell response to antigens expressed in the-cells of the islets(Proinsulin/Insulin,GAD,I-A2)T cell response is Th1“like”,makes g-IFN and helps recruit a tissue/cell destruction response 90%islet destruction needed for the disease to be expressed Patients also have auto-antibodies to i
15、slet antigensType I DiabetesT cell-directed attack against the-cells of the pancreatic islet文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。胰高血糖素 生长抑素文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Tetramer flow study:reveal the presence of proIns and GAD-reactive CD4 T cells in PBMC of T1D patients文档仅供参考，不能作为科学依据，请勿
16、模仿；如有不当之处，请联系网站或本人删除。Involves demyelinization（脱髓鞘）of central nervous system tissue Symptoms may be mild,such as numbness in the limbs,or severe,such as paralysis or loss of vision.T-cell mediated autoimmune disease Cause of MS:not well understood Failure of clonal deletion,from neuro-antigen sensiti
17、zation Molecular mimicry to a neuro-epitope following virus infectionMultiple sclerosis(MS)文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Multiple sclerosis(MS)文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Why do autoimmune disease occur?Answer:Failure in self-tolerance 文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Types
18、 of Tolerance Central Tolerance happens during lymphocyte development.Negative selection or clonal deletion of T and B cells that have receptors for self-antigens.Selected on thymic epithelial MHC against highly reactive clones against self antigen.95%of immature lymphocyte die in thymus/bone marrow
19、.Peripheral Tolerance-occurs in the periphery after lymphocyte development.Ignorance:low dose or immunologically privileged sites;Anergy:Lack of co-stimulatory molecules during T cell activation;Clonal contraction and AICD:Both LPR Fas deficient,Gld FasL deficient have autoimmune phenotypes.Cannot r
20、egulate duration of response Suppression:specific immune regulation through regulatory T cells,Consequences:apoptosis,anergy,inactivation文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Central T cell Tolerance achieved by Negative selection T cells that are strongly activated by self MHC plus self peptides n
21、eed to be eliminated in the thymus.(High affinity)文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Peripheral tolerance through different mechanisms 文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Overview of Autoimmunity文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Informative Single-gene models of autoimmunityAIRE(APECED）：
22、Negative selectionFas/FasL(ALPS):peripheral deletion of T and B cellsFoxP3(IPEX):TregCTLA-4(mouse KO):anergy;TregIL2,IL-2R(mouse KO):TregMany other reportedBUT：not seems to be the basis of most autoimmune diseases文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Autoimmunity is so complicated,how can we figure
23、 out how it happens?Answer:1)Use genetics Genetic Reasons2)Animal models Genetic Reasons and environment trigger文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Genetic basis of autoimmunity Genetic predisposition of autoimmune diseases Increased incidence in twins Identification of disease-associated genes b
24、y breeding and genomic approaches Multiple genes are associated with autoimmunity single mutation causes autoimmunity-rare MHC genes Major genetic association with autoimmune diseases Disease-associated alleles may be found in normal individuals Non-MHC genes Many loci identified by genomic methods,
25、animal studies Mutations in complement genes predispose to lupus文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。HLA(or MHC)is the strongest genetic factor for susceptibility to autoimmune diseaseRelated:Different susceptibilities of AIs for different mouse strains文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Popula
26、tion StudyFamily StudyHLA and susceptibility to autoimmune disease文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。HLA and susceptibility to autoimmune diseaseHow HLA confer susceptibility and/or protection1.Capacity to present antigens and to induce positive selection but not negative selection(central)2.Som
27、e HLAs are more potent in presenting self-antigens(peripheral)3.Linked to other non-MHC disease causing genes(indirect)4Other unknown reasons文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Non-MHC genes associated withautoimmune disease in HUMANS Single gene disorders:AIRE,FoxP3,Fas/FasL,CTLA-4,CD25(IL-2R)PT
28、PN22:phosphatase,polymorphism in Lupus,Type 1 Diabetes,Rheumatoid Arthritis,mechanism of action?NOD2:intracellular toll receptor,Microbial sensor in intestinal epithelial cells,polymorphism associated with 25%of Crohns disease and Uveitis(eye autoimmunity)ATG16:autophagy gene,associated in IBD(resis
29、tance to microbes?)IL-23R:receptor for Th17-inducing cytokine,affect Th17 responses Complement genes in Lupus文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Susceptibility loci associated with autoimmunity文档仅供参考，不能作为科学依据，请勿模仿；如有不当之
30、处，请联系网站或本人删除。GWAS(Genome Wide Association Study)SNP array Massive sequencingGenome wide,Fast Becoming Cost-effective文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。GWAS T1D as an example文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。GWAS Diagram Browser文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Explore Disease mechanism
31、s(genetic and environmental)Test Treatment drug or strategySpontanuous Disease models:NOD mouse-model of type 1 diabetes NZBxNZW mouse-model of Lupus KBxN mouse-model of rheumatoid ArthritisInducible Disease models：EAE-induced model of multiple sclerosis whereby disease is induced by injecting prote
32、ins of the myelin sheath with adjuvantKnock-outs:Knockouts that get autoimmunity Combined Kos with spontanuous/inducible modelsNext step:Animal models of autoimmunity文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。EAE mouse model of human multiple sclerosis文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。EAE mouse mod
33、el of human multiple sclerosisDaysMean Disease ScoreAnti-NKG2A/C/E Fab2 MechanismTreatmentThakker P et al JI 2007Lu L et al Immunity 2007文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。NOD mice represent spontaneous diabetes 文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。B7.1/B7.2 KOs get worse diabetesin the NOD ba
34、ckground decrease in Treg文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Development of autoimmune diseaseCause：Loss of self-tolerance What triggers autoimmune diseases?文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Proposed mechanisms for triggering autoimmunityAltered antigen or antigen presentationViral Infection
35、文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Altered antigen or antigen presentation-Release of sequestered antigensMyelin basic protein(MBP):Sequestered from immune system by blood-brain barrierSperm antigens.EyeHeart-muscle antigensPhysical accident Or infection文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Alt
36、ered antigen or antigen presentationInappropriate expression of class II MHC molecules on non-APCs*High expression of MHC I and II on the pancreatic beta cells of individuals with insulin-dependent diabetes mellitus(IDDM).*Expression of MHC II on thyroid acinar(腺泡)cells(in Graves disease).*IFN-from
37、trauma or viral infection.文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Infections and autoimmunity Infections trigger autoimmune reactions Clinical prodromes（先驱症状）,animal models Autoimmunity develops after infection(i.e.the autoimmune disease is precipitated by infection but is not directly caused by the
38、infection)Some autoimmune diseases are reduced or prevented by infections Increasing incidence of type 1 diabetes,multiple sclerosis in developed countries;experimental-NOD mice:mechanism unknown The“hygiene hypothesis”(originally proposed to describe effects of infections on asthma)文档仅供参考，不能作为科学依据，
39、请勿模仿；如有不当之处，请联系网站或本人删除。Viral infections and autoimmune diseaseBy stander activationMolecular Mimicry文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Autoreactive T cells can be activated through a mechanism of molecular mimicry that involves cross-reactive recognition of a viral antigen that has similarity to
40、 self antigen.Molecular mimicry 文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Epitope mimicry(human and microbial proteins)Protein A.A.Position A.A.SequenceCMV IE2 7988 PDPLGRPDEDHLA-DR 6069 VTELGRPDAEPolio V.VP2 7079 STTKESRGTT乙酰胆碱受体乙酰胆碱受体 176185 TVIKESRGTK乳头瘤乳头瘤V.E2 7685 SLHLESLKDS胰岛素受体胰岛素受体 6675 VYGLESL
41、KDLHIV P24 160167 GVETTTPS人人IgG顶恒定区顶恒定区 466473 GVETTTPS麻疹麻疹V.P3 1320 LECIRALK促肾上腺皮质激素促肾上腺皮质激素 1825 LECIRACK文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Helicobacter pylori and gastric autoimmunityH.pylori induces the expansion of H.pylori-specific Th1 cells that cross-react with H+,K+-ATPase epitopes.H.py
42、lori-H+,K+-ATPase cross-reactive Th1 cells could mediate destruction of gastric mucosa.幽门螺旋杆菌文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。(1)Microbial infection stimulates Toll-like receptors(TLRs)and other pattern-recognition receptors on antigen-presenting cells(APCs),leading to the production of pro-in
43、flammatory mediators,which in turn can lead to tissue damage.(2)Self antigen that is released from damaged tissue can be taken up by activated APCs,processed and presented to autoreactive T cells.(3)Alternatively,an infection can lead to microbial superantigen-induced activation of a subset of T cel
44、ls,some of which could be specific for self antigen.Bystander Activation文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Further tissue destruction by activated T cells and inflammatory mediators causes the release of more self antigen from tissues.Bd|The T-cell response can then spread to involve T cells spe
45、cific for other self antigens in a process known as epitope spreading.Epitope spreading文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Epitope spreading responsible for the relapse of disease文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Gut microbiota and autoimmune diseaseGut Bacteria Affect Multiple Sclerosis 文档仅
46、供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Gut microbiota and autoimmune disease文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Endocrine factors Most autoimmune disease do not occur with equal frequency in males and females.For example Graves and Hashimotos are 4-5 times,and SLE 10 times,more common in females whi
47、le Ankylosing Spondylitis is 3-4 more frequent in males.These differences are believed to be the result of hormonal influences.A second well documented hormonal effect is the marked reduction in disease severity seen in many autoimmune conditions during pregnancy.Rheumatoid arthritis is perhaps the
48、classic example of this effect.In some cases there is also a rapid exacerbation(rebound)after giving birth.文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。What would be the ideal way to treat autoimmune disease?Answer:remove only the antigen-specific responseReality:Unable to remove the antigen-specific resp
49、onse in general Mainstay of treatment:anti-inflammatories(corticosteroid)and global immunosuppression(cyclosporine)if symptoms are severe enough to warrant itTreatment of Autoimmune Diseases文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Corticosteroid文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Corticosteroid环氧合酶
50、膜联蛋白前列腺素白三烯文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Cyclosporin文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Cyclosporin文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Immune Therapy of Autoimmune diseases文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系网站或本人删除。Therapeutic approaches for immune disorders文档仅供参考，不能作为科学依据，请勿模仿；如有不当之处，请联系
