自體免疫疾病

1、自體免疫疾病器官特異性非器官特異性自體免疫疾病肌肉腎臟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類風(fēng)濕性關(guān)節(jié)炎(RA)類風(fēng)濕性關(guān)節(jié)炎(RA)類風(fēng)濕性關(guān)節(jié)炎是一種重要的自體免疫疾病，可導(dǎo)致關(guān)節(jié)破壞變形，骨骼變化以及全身性的病變。類風(fēng)濕性關(guān)節(jié)炎的骨骼變化包括發(fā)炎關(guān)節(jié)旁的骨缺乏，軟骨侵蝕。 類風(fēng)濕性關(guān)節(jié)炎是一種全身性的變化，患者不但關(guān)節(jié)疼痛，可能關(guān)節(jié)會逐漸變形。 過去十年來，類風(fēng)濕關(guān)節(jié)炎在冶療上的改變有著明顯的進步。我們不再視其為一

12、僅局限于關(guān)節(jié)的慢性病變；反之，卻視為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類風(fēng)濕性關(guān)節(jié)炎(RA)Rheumatoid arthritis類風(fēng)濕性關(guān)節(jié)炎(RA)類風(fēng)濕性關(guān)節(jié)炎(RA)類風(fēng)濕關(guān)節(jié)炎的早期關(guān)節(jié)破壞類風(fēng)濕性關(guān)節(jié)炎的臨床病程變異性極大只有小于1/5 的病人在發(fā)病10-12年內(nèi)沒有出現(xiàn)關(guān)節(jié)破壞或變形在發(fā)病頭六年內(nèi)關(guān)節(jié)破壞進展最快 (1st2nd3rd.)在發(fā)病頭兩年內(nèi)對于關(guān)節(jié)功能

15、的影響最顯著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僵直性脊椎關(guān)節(jié)炎(AS)全身紅斑性狼瘡好發(fā)于20-40歲之年輕女性女性與男性之比例約為10:1侵犯多個器官系統(tǒng) 臨床表現(xiàn)千變?nèi)f化難以捉摸全身紅斑性狼瘡全身紅斑性狼瘡全身紅斑性狼瘡與自體抗體患者體內(nèi)常出現(xiàn)許多自體抗體最常出現(xiàn)之自體抗體為抗核抗體(ANA)自體抗體為造成導(dǎo)致器官傷害的重要原因有些自體抗體為追蹤病情之重要指針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器官特異性自體免疫疾病對應(yīng)抗原的種類疾 病自 體 抗 原橋本氏甲狀腺炎 (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胰島素抗性糖尿病Insulin, insulin receptors愛迪生病 (Addisons disease)Adrenal cortex惡性貧血 (Pernicious anemia)Intrinsic factor, parietal cells重癥肌無力Acetycholine receptors多發(fā)性硬化癥 (Multiple sclerosis)Myelin basic proteinGoodpas

26、tures 病Basement membrane (lung and glomeruli)尋常性天皰瘡 (pemphigus vulgaris)Intracellular cement水泡性類天皰瘡 (Bullous pemphigoid)Basement membrane (skin)非分節(jié)性白斑癥 (Non-segmental vitiligo)Membrane proteins on keratinocyte and melanocyte自體免疫抗體與全身性自體免疫疾病之相關(guān)自體免疫抗體相關(guān)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.