1、自体免疫疾病器官特异性非器官特异性自体免疫疾病自体免疫疾病肌肉肾脏皮肤关节Pathological Factors in Rheumatic Disorders Rheumatic diseases are multisystem disorders caused by tissue damage resulting from autoantibodies,cytotoxic T lymphocytes,complement-fixing immune complex deposition,and inflammatory mediatorsInflammatory ParametersnES
2、RESRnAcute phase reactantsAcute phase reactantsnImmunoglobulinsImmunoglobulinsnComplement componentsComplement componentsnInflammatory mediators:cytokines,Inflammatory mediators:cytokines,prostanoidsprostanoids ESR are determined by the three forces Surface free energy(Van de Waals force):cohesive f
3、orce Electrical charge associated with RBC:repulsive force Dielectric constant of the medium:dissipates the forceCalculation Equation for ESR Vs=2/9x(Ps-PL)R2/n x gVs=2/9x(Ps-PL)R2/n x gVs=the limiting velocity of the sphereVs=the limiting velocity of the sphereR=the radius of the sphereR=the radius
4、 of the spherePs and PL=the densities of the sphere and Ps and PL=the densities of the sphere and of the liquidof the liquidg=the acceleration due to gravityg=the acceleration due to gravityn=the viscosity of the liquidn=the viscosity of the liquidSerum Proteins and Drugs That Affect the ESR RateESR
5、 increaseESR decrease Fibrinogen ACTH Immunoglobulins Cortisone Dextran Ethambutol Methyldopa Quinine Procainamide Salicylate Oral contraceptives Penicillamine Methylsergide Theophylline Trifluperidol Vitamine AAcute Phase ReactantsThe Acute Phase Response Follows Cell Injury and The Acute Phase Res
6、ponse Follows Cell Injury and Tissue Damage Caused by:Tissue Damage Caused by:Acute infections:i.e.,bacterial or parasiticAcute infections:i.e.,bacterial or parasiticTrauma:i.e.,blunt,surgery,and burnsTrauma:i.e.,blunt,surgery,and burnsIschemic necrosis:i.e.,acute myocardial Ischemic necrosis:i.e.,a
7、cute myocardial infarctioninfarctionMalignant disease:I.e.,tumor growth and Malignant disease:I.e.,tumor growth and metastasismetastasisConnective tissue disease:i.e.,rheumatoid Connective tissue disease:i.e.,rheumatoid arthritis,rheumatic fever and othersarthritis,rheumatic fever and othersAcute ab
8、dominal inflammation:i.e.cholecystitis Acute abdominal inflammation:i.e.cholecystitis and pancreatitisand pancreatitisVaccination:I.e.,typhoidVaccination:I.e.,typhoidFunctional Properties of Human Acute Phase ProteinsFunctional GroupProteinFunctionHost defense proteinsC-reactive protein(CRP)Compleme
9、nt activation,opsonicationMannan-binding protein(MBP)Complement activation,opsonizationComplement proteins C3,C4,C5 Factor B,C9 Factor H,C4bpIncreased vascular permeability,opsonization,bacterial killingFibrinogenFormation of hemostatic plugs,wound healingProteinase inhibitors 1-Proteinase inhibitor
10、(1-PI)Control of extracellular matrix degradation 1-Antichymotrypsin(1-Achy)Control of extracellular matrix degradation 2-Antiplasmin(2-AP)Control of plasminC1 inhibitor(C1 INH)Control of complement and contace system activationAntioxidantsCeruloplaasminInhibition of oxy radical formationHemopexin(H
11、x)Binding of heme,inhibition of lipid peroxidationHaptoglobulin(HP)Binding of hemoglobulin,inhibition of lipid peroxidationFunction unknownSerum amyloid A(SAA)1-Acid glycoproteinC-Reactive Protein(CRP)Normal plasma protein,concentration from Normal plasma protein,concentration from 0.068-8.8 mg/ml0.
12、068-8.8 mg/mlAcute phase reactant,concentration up to Acute phase reactant,concentration up to 500mg/ml500mg/mlSynthesized by hepatocytesSynthesized by hepatocytesMolecular weight 105,500 daltonsMolecular weight 105,500 daltonsFive identical non-glycosylated,non-Five identical non-glycosylated,non-c
13、ovalently associated subunitscovalently associated subunitsAmino acid sequence homologous with serum Amino acid sequence homologous with serum amyloid A component(SAA)amyloid A component(SAA)Rheumatic Disease in Which Elevated C-Reactive Protein Levels may OccurGoutRheumatoid arthritisJuvenile rheum
14、atoid arthritisPsoriatic arthritisAnkylosing spondylitisReiters syndromePolymyalgia rheumatica-giant cell arteritisSystemic vasculitisWegeners granulomatosisBehcets syndromeSystemic lupus erythematosusc ACRc ACR类风湿性关节炎类风湿性关节炎(RA)(RA)类风湿性关节炎类风湿性关节炎(RA)(RA)类风湿性关节炎是一种重要的自体免疫疾病，可导致关节破坏变形，骨骼变化以及全身性的病变。类风
15、湿性关节炎的骨骼变化包括发炎关节旁的骨缺乏，软骨侵蚀。类风湿性关节炎是一种全身性的变化，患者不但关节疼痛，可能关节会逐渐变形。过去十年来，类风湿关节炎在冶疗上的改变有着明显的进步。我们不再视其为一仅局限于关节的慢性病变；反之，却视为一甚富侵略性的全身性疾患。Rheumatoid Arthritis(RA)Rheumatoid Arthritis(RA)A chronic,systemic,autoimmune,A chronic,systemic,autoimmune,inflammatory disease of unknown inflammatory disease of unknown
16、 etiologyetiologyCharacterized by Characterized by persistent intense immunological persistent intense immunological activityactivityinflammatory and erosive inflammatory and erosive synovitis,usually involving synovitis,usually involving peripheral joint in a symmetric peripheral joint in a symmetr
17、ic fashionfashionlocal destruction of bone and local destruction of bone and cartilagecartilagea variety of systemic a variety of systemic manifestation.manifestation.The most common inflammatory joint The most common inflammatory joint diseasediseaseNormal SynoviumNormal SynoviumRheumatoid Synovium
18、Rheumatoid Synoviumc ACRc ACRc Arthritis&Rheumatism Foundationc Arthritis&Rheumatism FoundationPage No.20/52Clinical features of Rheumatoid Clinical features of Rheumatoid Arthritis in the handArthritis in the handEarlyEarly Wasting small muscles Extensor tendon sheath swelling Fusiform swelling of
19、PIP joints MCP joint synovitis with swellingLateLate Deformity Ulnar deviation Swan-neck deformity Subluxation of MCPJ2.Loss of function类风湿性关节炎类风湿性关节炎(RA)(RA)Rheumatoid arthritisRheumatoid arthritis类风湿性关节炎类风湿性关节炎(RA)(RA)类风湿性关节炎类风湿性关节炎(RA)(RA)类风湿关节炎的早期关节破坏类风湿关节炎的早期关节破坏类风湿性关节炎的临床病程类风湿性关节炎的临床病程 变异性极大 只
20、有小于1/5 的病人在发病10-12年内没有出现关节破坏或变形 在发病头六年内关节破坏进展最快(1st2nd3rd.)在发病头两年内对于关节功能的影响最显着Markers of severe disease activity in RAMarkers of severe disease activity in RA1.General polyarthritis involving both small and 1.General polyarthritis involving both small and large large jointsjoints2.Extra-articular di
21、sease,especially nodules and 2.Extra-articular disease,especially nodules and vasculitisvasculitis3.Persistently elevated ESR or CRP with active 3.Persistently elevated ESR or CRP with active synovitissynovitis4.RF-positive with high titier4.RF-positive with high titier5.Radiologically erosions with
22、in two years of 5.Radiologically erosions within two years of disease onsetdisease onset6.HLA-DR4 positive6.HLA-DR4 positiveMajor extra-articular features of RACommonAnemiaLymphadenopathyRheumatoid nodulesMuscle wastingEpiscleritis and keratoconjuntivitisPeripheral sensory polyneuropathyUncommonPleu
23、ral effusionPulmonary fibrosisPericardial effusionSystemic vasculitisSplenomegalyRheumatoid FactorsAn autoantibody reactive with denatured human An autoantibody reactive with denatured human or rabbit IgGor rabbit IgGGeneration of RFs in the following conditions:Generation of RFs in the following co
24、nditions:Autoimmune disorders:RA,SLE,SjogrenAutoimmune disorders:RA,SLE,Sjogrens s syndrome,vasculitissyndrome,vasculitisChronic inflammationChronic inflammationChronic infectionChronic infectionMalignancyMalignancyagingagingSome Disease Commonly Associated with Rheumatoid FactorRheumatic Diseases F
25、ilariasis Rheumatoid arthritisChronic Bacterial infections Systemic lupus erythematosus Tuberculosis Scleroderma Leprosy Mixed connective tissue disease Yaws Sjogrens syndrome SyphilisViral Infections Brucellosis Acquired immunodeficiency syndromes Subacute bacterial endocarditis Mononucleosis salmo
26、nellosis HepatitisNeoplasms Influenza Tumors after radiation therapy or chemotherapy After vaccination(may yield falsely elevatedOther Hyperglobulinemic States titers of antivival antibodies)Hypergammaglobulinemic purpuraParasitic Infections Cryoglobulinemia Trypanosomiasis Chronic liver disease Kal
27、a-azar Sarcoid Malaria Other chronic pulmonary diseases SchistosomiasisFalse Positive Rheumatoid Factor Test Sarcoidosis 10%Syphilis 10%Hepatitis 25%Viral infection 15%Leprosy 25%Subacute bacterial endocarditis 50%Old age(65y/o)35%Biomarkers in Rheumatoid Arthritis Rheumatoid factor Anti-CCP(anti-cy
28、clic citrullinated peptides)Ab The presence of anti-CCP Ab is the most accurate biomarker for RA in both selected and unselected cohorts Goals of RA Management Pain relief and inflammation reduction Activities of daily living and quality of life Longterm joint damage control or prevention Disease pr
29、ocess interruption or modification Therapy related side effects avoidance僵直性脊椎关节炎僵直性脊椎关节炎(AS)(AS)全身红斑性狼疮全身红斑性狼疮好发于好发于20-4020-40岁之年轻女性岁之年轻女性女性与男性之比例约为女性与男性之比例约为10:110:1侵犯多个器官系统侵犯多个器官系统 临床表现临床表现千变万化难以捉摸千变万化难以捉摸全身红斑性狼疮全身红斑性狼疮侵犯多個身體系統的自體免疫疾病紅斑性狼瘡常見的表徵肌肉骨系統 95%關節炎 95%無菌性壞死7%肌肉炎5%全身红斑性狼疮全身红斑性狼疮最最初初的的表表徵徵關
30、節炎及關節痛關節炎及關節痛 53%皮膚表徵皮膚表徵 錢幣狀錢幣狀9%臉頰紅斑臉頰紅斑9%腎炎腎炎6%發燒發燒5%黏膜炎黏膜炎 肋膜炎肋膜炎 心內膜炎心內膜炎 5%抽筋抽筋3%雷諾氏症候雷諾氏症候3%貧血貧血 2%血小板減少血小板減少2%假性梅毒試驗陽性假性梅毒試驗陽性 1%黃疸黃疸 1%其他症狀其他症狀17%全身红斑性狼疮与自体抗体全身红斑性狼疮与自体抗体患者体内常出现许多自体抗体患者体内常出现许多自体抗体最常出现之自体抗体为抗核抗体最常出现之自体抗体为抗核抗体(ANA)(ANA)自体抗体为造成导致器官伤害的重要原因自体抗体为造成导致器官伤害的重要原因有些自体抗体为追踪病情之重要指针有些自体抗
31、体为追踪病情之重要指针Antinuclear Antibody(ANA)DiseaseDiseasePatients with ANAs(%)Systemic lupus erythematosus99Drug-induced lupus100Systemic sclerosis97Mixed connective tissue disease93Polymyositis and dermatomyositis78Sjogrens syndrome96Specific AutoantibodiesnOrgan specific autoantibodiesOrgan specific auto
32、antibodiesnAutoantibodies for systemic autoimmune Autoantibodies for systemic autoimmune disoedersdisoedersnAutoantibodies in systemic lupus Autoantibodies in systemic lupus erythematosuserythematosus器官特异性自体免疫疾病对应抗原的种类疾疾 病病自自 体体 抗抗 原原桥本氏甲状腺炎桥本氏甲状腺炎(Hashimotos thyroiditis)Thyroid peroxidase(microsoma
33、l antigen)ThyroglobulinThyroid-stimulating immunoglobulin葛雷氏病葛雷氏病(Graves disease)Thyroid peroxidaseThyroglobulinThyroid-stimulating immunoglobulin(TSI)Thyroid growth-stimulating ikmmunoglobulin(TGSI)Thyrotropinbinding-inhibitory immunoglobulin(TBII)第一型糖尿病第一型糖尿病Insulin,insulin receptors,islet cells胰岛
34、素抗性糖尿病胰岛素抗性糖尿病Insulin,insulin receptors爱迪生病爱迪生病(Addisons disease)Adrenal cortex恶性贫血恶性贫血(Pernicious anemia)Intrinsic factor,parietal cells重症肌无力重症肌无力Acetycholine receptors多发性硬化症多发性硬化症(Multiple sclerosis)Myelin basic proteinGoodpastures 病病Basement membrane(lung and glomeruli)寻常性天疱疮寻常性天疱疮(pemphigus vulg
35、aris)Intracellular cement水泡性类天疱疮水泡性类天疱疮(Bullous pemphigoid)Basement membrane(skin)非分节性白斑症非分节性白斑症(Non-segmental vitiligo)Membrane proteins on keratinocyte and melanocyte自体免疫抗体与全身性自体免疫疾病之相关自体免疫抗体自体免疫抗体相关之疾病相关之疾病Anti-dsDNASLEAnti-SmSLEAnti-laminSLEAnti-histoneSLE,Drug-induced lupusAnti-U1 RNPSLE,MCTDAn
36、ti-SSA/RoSLE,Sjogrens syndromeAnti-SSB/LaSLE,Sjogrens syndromeAnti-PCNA/cyclinSLEAnti-ribosomal PNP-SLEAnti-Scl-70/topoisomerase ISclerodermaAnti-KuSLE,sclerodermaAnti-centromere/kinetochoreCRESTAnti-RNA polymerase ISclerodermaAnti-PM-SclSclerodermaAnti-Jo-1(tRNA synthetase)PolymyositisAnti-cardioli
37、pinAnti-phospholipid sydnromeAnti-neutrophil cytoplasmic antigenWegeners granulomatosis,other vasculitisList of Autoantibodies Reported in SLEAgainst:1.ANA17.PCNA/Cyclin33.Ribosomal-P47.Poly(ADP ribose)2.SsDNA18.HTLV-134.Ca nephritic factor,48.Poly(A)polymerase3.DsDNA19.HIV-gp120 C3 convertaseC1q49.
38、Protein kinase N II4.Z-DNA20.Mycobacteria35.Antiendothelial50.Prothymosin 5.Poly I21.Laminin36.Fibronectin51.Replication protein A6.Poly G22.Heat shock protein(90kD)37.Golgi apparatus52.Sp 1007.Poly(dt)23.Klebsiella38.Mitotic spindle apparatus53.RA-338.Histones24.Vimentin39.Mi/Ma/Mc54.Nucleosomes9.C
39、ardiolipin25.Heparan sulfate40.Annexin XI55.Ubiquitine10.ENA26.LAC/Fac II,VIII,XII)41.DNA polymerase,56.Glycosaminoglycans11.RNP/hn RNP27.Lymphocytes(LCTA,Ts,NK)-RNA polymerase I-III57.Lipocortin-112.Sm28.Erythrocytes(Coombs)42.HMG-1,2,1758.Pyruvate dehydrogenase13.SS-A/Ro29.Platelets43.L759.Anti-P
40、ribosomal protein14.SS-B/La30.Leukocytes44.Nuclear helicase15.RNA31.Neuronal45.Nucleosides16.Ku/Ki(SL)32.Glycolipids46.C-myc全身红斑性狼疮全身红斑性狼疮常见慢性并发症常见慢性并发症1.1.肾炎及肾脏衰竭肾炎及肾脏衰竭2.2.中枢神经病变中枢神经病变3.3.感染症感染症4.4.贫血及血小板降低贫血及血小板降低全身红斑性狼疮的活动性与复发全身红斑性狼疮的活动性与复发活动性活动性 (SLE activity)(SLE activity)复发复发 (flare up)(flare
41、 up)常见症状常见症状:发烧发烧,关节炎关节炎,水肿加重水肿加重,红斑红斑,癫痫发作癫痫发作,呼吸困难呼吸困难起伏不定起伏不定,难以捉摸难以捉摸影响全身红斑性狼疮复发的因素影响全身红斑性狼疮复发的因素阳光曝晒 紫外线怀孕压力与情绪感染全身红斑性狼疮活动性的追踪全身红斑性狼疮活动性的追踪1.1.抗抗DNADNA抗体抗体2.2.补体补体 C3,C4C3,C43.3.发炎指针发炎指针,血球血球 及肾功能及肾功能免疫学检查与全身红斑性狼疮活动性临床症状临床前期之复发Algorithm for the use of antinuclear antibodies(ANAs)in the diagnosi
42、s of connective tissue disordersAnti-Neutrophil Cytoplasmic Anti-Neutrophil Cytoplasmic Antibodies(ANCA)Antibodies(ANCA)cANCA:anti-proteinase 3(serine cANCA:anti-proteinase 3(serine proteinase)proteinase)pANCA:anti-myeloperoxidase(MPO)pANCA:anti-myeloperoxidase(MPO)Disease-Association of ANCADisease
43、 entity Anti-PR3 Disease entity Anti-PR3 Anti-MPOAnti-MPO (%)(%)(%)(%)WegenerWegeners granulomatosis 85 s granulomatosis 85 1010Microscopic polyangiitis 45 Microscopic polyangiitis 45 4545Idiopathic crescenticIdiopathic crescentic glomerulonephritis 25 glomerulonephritis 25 6565Churg-Strauss symdrome 10 Churg-Strauss symdrome 10 6060Polyarteritis nodosum 5 Polyarteritis nodosum 5 1515
