免疫細(xì)胞與自身免疫病2課件

1、免疫細(xì)胞與自身免疫病北京協(xié)和醫(yī)院趙麗丹免疫系統(tǒng)固有免疫適應(yīng)性免疫免疫系統(tǒng)的構(gòu)成T細(xì)胞PAMP/PRRsB細(xì)胞物理屏障、濾過樹突狀細(xì)胞DCNK細(xì)胞吞噬細(xì)胞其他：NKT/TB1CTL抗體抗菌肽補(bǔ)體激活吞噬作用溶菌酶cytokine激活補(bǔ)體調(diào)理吞噬ADCC穿孔素顆粒酶高效、特異、自身MHC限制Fas誘導(dǎo)凋亡自身免疫病 免疫系統(tǒng)識(shí)別“自我”和“非我”免疫耐受免疫應(yīng)答病原清除移植排斥自身反應(yīng)性T/B細(xì)胞自身抗體免疫穩(wěn)態(tài)對自身組分的持續(xù)免疫攻擊自身免疫病可檢出自身抗體損傷和功能障礙遷延、反復(fù)發(fā)作轉(zhuǎn)歸與自身免疫反應(yīng)強(qiáng)度相關(guān)免疫抑制機(jī)制的缺陷免疫抑制機(jī)制增強(qiáng)移植耐受腫瘤發(fā)生DC dentrtic cell專職

2、的APC（攝取加工、呈遞Ag）誘導(dǎo)和維持中樞、外周免疫耐受（參與胸腺中T細(xì)胞的陰性選擇有關(guān)，并參與調(diào)節(jié)T細(xì)胞的發(fā)育分化）成熟DC高表達(dá)MHC-II和共刺激分子B7、CD40，能夠刺激初始T細(xì)胞活化和增殖遞呈抗原供B細(xì)胞識(shí)別，通過體細(xì)胞突變發(fā)生親和力成熟。DC固有免疫和適應(yīng)性免疫的橋梁DC in rheumatic diseaseRA的滑膜組織和滑液中含有豐富DC，在局部細(xì)胞因子環(huán)境中發(fā)生表型和功能分化成熟，促進(jìn)滑膜炎癥反應(yīng)和T細(xì)胞免疫應(yīng)答。DC的狀態(tài)可影響免疫激活和免疫抑制的平衡 tolerogenic DC vs immunogenic DC Immature DC mature DC T細(xì)

3、胞在胸腺中的發(fā)育陽性選擇和陰性選擇Auto-reactive T cellTreg subsetsDevelopment of Treghow Treg suppress immune responseTh17- IL-17 secreting T cellsTh17 in rheumatic diseaseIL-17可作用于成骨細(xì)胞誘導(dǎo)其表達(dá)RANKL，RANKL與表達(dá)于破骨細(xì)胞前體的RANK結(jié)合促進(jìn)后者分化為破骨細(xì)胞，參與RA的骨和軟骨破壞。CD4IL-17HC SLEB細(xì)胞在風(fēng)濕病中的免疫效應(yīng)活化的B細(xì)胞1 抗原呈遞,提供共刺激信號(hào)，活化T細(xì)胞；2 產(chǎn)生自身抗體，介導(dǎo)II型、III型超敏

4、反應(yīng)；3 調(diào)節(jié)其他免疫細(xì)胞如DC4 產(chǎn)生的致炎性細(xì)胞因子： TNF-（腫瘤壞死因子） IL-6（白介素-6） Lymphotoxin（淋巴毒素） IFN-（ -干擾素）Anti-DNAAnti-SSA RA滑膜中的B淋巴細(xì)胞RA關(guān)節(jié)滑膜可出現(xiàn)彌漫性或?yàn)V泡樣淋巴細(xì)胞浸潤，甚至可形成生發(fā)中心，其中的B細(xì)胞可分化為漿細(xì)胞并產(chǎn)生RF。B細(xì)胞在類風(fēng)濕關(guān)節(jié)炎發(fā)病機(jī)制的作用 環(huán)節(jié)B細(xì)胞在SLE發(fā)病機(jī)制中的作用Summary of abnormal immune responses and immunoregulation in SLET、B細(xì)胞是自身免疫病的靶細(xì)胞CTLA4-IgAnti-CD20不同發(fā)育階

5、段B細(xì)胞的影響Anti-CD20的作用機(jī)制CD20的表達(dá)不調(diào)變（modulate），與抗體結(jié)合后不內(nèi)化（internalize）血循環(huán)中未發(fā)現(xiàn)游離的CD20分子。 DANCERBAFF：a novel member of TNF ligand family 1999年 *BAFF (B cell Activation Factor from the TNF Family) *BLyS (B Lymphocyte Stimulator) *TALL-1(TNF and Apoptosis Ligand-related Leukocyte- expressed Ligand 1) *THANK (

6、 a TNF Homologue that Activates apoptosis，NF-B and c-Jun NH2-terminal Kinase ) *TNSF13B ( TNF-superfamily member 13B ) *zTNF4*BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med 1999.*TALL-1 is a novel member of the TNF family that is down-regulated by mitog

7、ens. J Leukoc Biol 1999.*Identification and characterization of a novel cytokine, THANK, a TNF homologue that activates apoptosis, nuclear factor-kappaB and c-Jun NH2-terminal kinase. J Biol Chem 1999.*BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science 1999.BAFF與其受

8、體 BCMA: B cell maturation antigen BAFF-R: BAFF receptor, BR3 TACI: transmembrane activator and calcium modulator and cyclophilin ligand interactorDavid L. Vaux Clin Invest. 2002, 109:1718.Functions of BAFF：調(diào)控B細(xì)胞成熟:B細(xì)胞向T2期分化和/或T2期B細(xì)胞存活必需的信號(hào)促進(jìn)Ig類別轉(zhuǎn)換輔助T細(xì)胞活化參與自身免疫: 過表達(dá)時(shí)可使T2期自身反應(yīng)性B細(xì)胞逃逸陰性選擇，導(dǎo)致多種自身免疫現(xiàn)象。Rol

9、e of BAFF in SLE mice model BAFF轉(zhuǎn)基因小鼠B細(xì)胞增生、高丙球血癥、循環(huán)免疫復(fù)合物、高滴度抗dsDNA自身抗體、蛋白尿和免疫復(fù)合物在腎臟沉積等狼瘡樣表現(xiàn)；狼瘡鼠模型MRL/Mp-lpr/lpr和NZB/W F1中，發(fā)病時(shí)血清BAFF水平增高，與腎臟損害相關(guān)。control BAFF Tg BAFF Tg controlJ Exp Me, 1999, 190(11): 16971710；Proc Natl Acad Sci USA 2000, 97:3370-3375；Nature 2000, 404:995-999.BAFF antagonist in lupus

10、 mice modelBR3-Fc treatedImmunity, 2002,17(4):515-524；J Clin Invest，2006,116(3):724-734；controlBackground人類CTD中BAFF的研究及BAFF拮抗治療Antagonist of BAFF in RA patientsPhase 1：LymphoStat-B in SLE Patients綜述匯報(bào)CTLA4-Ig融合蛋白是第一種抑制協(xié)同刺激信號(hào)的生物制劑Abatacept (CTLA4-Ig融合蛋白)Abatacept (CTLA4-Ig) 對RA的治療作用ATTAIN試驗(yàn)：Abatacept Trial in the Treatment of Anti-TNF Inadequate (RA) RespondersAbatacept (CTLA4-Ig) in SLE RituximabAbatacep