自体免疫疾病

1、自体免疫疾病器官特异性非器官特异性自体免疫疾病肌肉肾脏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 ParametersESRAcute p

2、hase reactantsImmunoglobulinsComplement componentsInflammatory mediators: cytokines, prostanoids ESR are determined by the three forcesSurface free energy (Van de Waals force):cohesive forceElectrical charge associated with RBC: repulsive forceDielectric constant of the medium: dissipates the forceC

3、alculation Equation for ESR Vs=2/9x(Ps-PL)R2/n x gVs= the limiting velocity of the sphereR= the radius of the spherePs and PL= the densities of the sphere and of the liquidg= the acceleration due to gravityn= the viscosity of the liquidSerum Proteins and Drugs That Affect the ESR RateESR increaseESR

4、 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 Tissue Damage Caused by:Acute i

5、nfections: i.e., bacterial or parasiticTrauma: i.e., blunt, surgery, and burnsIschemic necrosis: i.e., acute myocardial infarctionMalignant disease: I.e., tumor growth and metastasisConnective tissue disease: i.e., rheumatoid arthritis, rheumatic fever and othersAcute abdominal inflammation: i.e. ch

6、olecystitis and pancreatitisVaccination: I.e., typhoidFunctional Properties of Human Acute Phase ProteinsFunctional GroupProteinFunctionHost defense proteinsC-reactive protein (CRP)Complement activation, opsonicationMannan-binding protein (MBP)Complement activation, opsonizationComplement proteins C

7、3, C4, C5 Factor B, C9 Factor H, C4bpIncreased vascular permeability, opsonization, bacterial killingFibrinogenFormation of hemostatic plugs, wound healingProteinase inhibitors 1-Proteinase inhibitor ( 1 -PI)Control of extracellular matrix degradation 1 -Antichymotrypsin ( 1 -Achy)Control of extrace

8、llular matrix degradation 2 -Antiplasmin ( 2-AP)Control of plasminC1 inhibitor (C1 INH)Control of complement and contace system activationAntioxidantsCeruloplaasminInhibition of oxy radical formationHemopexin (Hx)Binding of heme, inhibition of lipid peroxidationHaptoglobulin (HP)Binding of hemoglobu

9、lin, inhibition of lipid peroxidationFunction unknownSerum amyloid A (SAA) 1 -Acid glycoproteinC-Reactive Protein (CRP)Normal plasma protein, concentration from 0.068-8.8 mg/mlAcute phase reactant, concentration up to 500mg/mlSynthesized by hepatocytesMolecular weight 105,500 daltonsFive identical n

10、on-glycosylated, non-covalently associated subunitsAmino acid sequence homologous with serum amyloid A component (SAA)Rheumatic Disease in Which Elevated C-Reactive Protein Levels may OccurGoutRheumatoid arthritisJuvenile rheumatoid arthritisPsoriatic arthritisAnkylosing spondylitisReiters syndromeP

11、olymyalgia rheumatica-giant cell arteritisSystemic vasculitisWegeners granulomatosisBehcets syndromeSystemic lupus erythematosusc ACR类风湿性关节炎(RA)类风湿性关节炎(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

12、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)A chronic, systemic, autoimmune, inflammatory disease of unknown etiologyCharacterized by persistent intense immunological activityinflammatory and erosive synovitis ,usually involving peripheral joint in a symmetric fashionlocal destruction o

13、f bone and cartilagea variety of systemic manifestation.The most common inflammatory joint diseaseNormal SynoviumRheumatoid Synoviumc ACRc Arthritis & Rheumatism FoundationPage No.20/52Clinical features of Rheumatoid Arthritis in the handEarlyWasting small musclesExtensor tendon sheath swellingFusif

14、orm swelling of PIP jointsMCP joint synovitis with swellingLateDeformityUlnar deviationSwan-neck deformitySubluxation of MCPJ2. Loss of function类风湿性关节炎(RA)Rheumatoid arthritis类风湿性关节炎(RA)类风湿性关节炎(RA)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变异性极大只有小于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

15、的影响最显着Markers of severe disease activity in RA1. General polyarthritis involving both small and large joints2. Extra-articular disease, especially nodules and vasculitis3. Persistently elevated ESR or CRP with active synovitis4. RF-positive with high titier5. Radiologically erosions within two years

16、 of disease onset6. HLA-DR4 positiveMajor extra-articular features of RACommonAnemiaLymphadenopathyRheumatoid nodulesMuscle wastingEpiscleritis and keratoconjuntivitisPeripheral sensory polyneuropathyUncommonPleural effusionPulmonary fibrosisPericardial effusionSystemic vasculitisSplenomegalyRheumat

17、oid FactorsAn autoantibody reactive with denatured human or rabbit IgGGeneration of RFs in the following conditions:Autoimmune disorders: RA, SLE, Sjogrens syndrome, vasculitisChronic inflammationChronic infectionMalignancyagingSome Disease Commonly Associated with Rheumatoid FactorRheumatic Disease

18、s Filariasis 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 sa

19、lmonellosis 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 diseas

20、e Kala-azar Sarcoid Malaria Other chronic pulmonary diseases SchistosomiasisFalse Positive Rheumatoid Factor TestSarcoidosis 10 %Syphilis 10 %Hepatitis 25 %Viral infection 15 %Leprosy 25 %Subacute bacterial endocarditis 50 %Old age ( 65y/o) 35 %Biomarkers in Rheumatoid ArthritisRheumatoid factorAnti

21、-CCP (anti-cyclic 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 ManagementPain relief and inflammation reductionActivities of daily living and quality of lifeLongterm joint damage control or prevention

22、 Disease process interruption or modificationTherapy related side effects avoidance僵直性脊椎关节炎(AS)全身红斑性狼疮好发于20-40岁之年轻女性女性与男性之比例约为10:1侵犯多个器官系统 临床表现千变万化难以捉摸全身红斑性狼疮全身红斑性狼疮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最常出现之自体抗体为抗核抗体(ANA)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Antinuclear Antibody (ANA) DiseaseDiseasePatients with AN

23、As (%)Systemic lupus erythematosus99Drug-induced lupus100Systemic sclerosis97Mixed connective tissue disease93Polymyositis and dermatomyositis78Sjogrens syndrome96Specific AutoantibodiesOrgan specific autoantibodiesAutoantibodies for systemic autoimmune disoedersAutoantibodies in systemic lupus eryt

24、hematosus器官特异性自体免疫疾病对应抗原的种类疾 病自 体 抗 原桥本氏甲状腺炎 (Hashimotos thyroiditis)Thyroid peroxidase (microsomal antigen)ThyroglobulinThyroid-stimulating immunoglobulin葛雷氏病 (Graves disease)Thyroid peroxidaseThyroglobulinThyroid-stimulating immunoglobulin (TSI)Thyroid growth-stimulating ikmmunoglobulin (TGSI)Thyr

25、otropinbinding-inhibitory immunoglobulin (TBII)第一型糖尿病Insulin, insulin receptors, islet cells胰岛素抗性糖尿病Insulin, insulin receptors爱迪生病 (Addisons disease)Adrenal cortex恶性贫血 (Pernicious anemia)Intrinsic factor, parietal cells重症肌无力Acetycholine receptors多发性硬化症 (Multiple sclerosis)Myelin basic proteinGoodpas

26、tures 病Basement membrane (lung and glomeruli)寻常性天疱疮 (pemphigus vulgaris)Intracellular cement水泡性类天疱疮 (Bullous pemphigoid)Basement membrane (skin)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相关之疾病Anti-dsDNASLEAnti-SmSLEAnti-laminSLEAnti-histo

27、neSLE, Drug-induced lupusAnti-U1 RNPSLE, MCTDAnti-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-SclSclerodermaA

28、nti-Jo-1 (tRNA synthetase)PolymyositisAnti-cardiolipinAnti-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

29、, 48. Poly (A) polymerase3. DsDNA19. HIV-gp120 C3 convertaseC1q49. 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.