Roles of regulatory T cells (Tr) and dendritic cells (DCs) in the pathogenesis of autoimmune hepatitis(AIH)

(1)自身免疫性肝炎患者调节性T细胞功能受损CD 4 ^+ CD 25 ^+调节性T细胞（Tr）介导的自身反应性T细胞调控的重要性一直受到关注。和GITR（TNFRSF 18）被鉴定为控制T细胞发育和活化的关键分子。我们研究了这些关键分子在T-reg上的表达模式是否存在差异，以及T-reg在1型自身免疫性肝炎（AIH）患者中的功能是否存在差异。AIH患者T-reg阳性率明显高于对照组。与对照组相比，AIH患者Foxp 3和Ctla 4的mRNA显著降低，这两种分子都被认为激活了T-reg的功能。我们检测了OKT 3刺激后AIR中T-reg的功能是否受损。虽然在TNF-α、IFN-γ和TGF-β的诱导作用上没有明显差异，但IL-10的产生有显著差异， ...更多信息 AIH组明显低于对照组。本研究结果提示，T-reg上Foxp 3和/或CTLA 4表达的遗传差异可能导致T-reg功能受损，最终导致AIH外周耐受的突破。(2)Toll样受体（TLR）家族在自身免疫性肝炎患者调节性T细胞上的表达研究表明，天然产生的T-reg选择性表达TLR家族的几个成员，并且通过TLR的信号调节T-reg的功能。我们研究了AIH患者T-reg上TLRs的表达模式。从分离的T-reg和非T-reg组分中提取总RNA，并通过真实的时间PCR评估TLR 2、3、4、6、7、8、9的mRNA的量。在AIH和对照组中，TLR 3、4、6、7、9在Tr.提示T-reg表面TLRs信号可能参与了自身免疫性肝炎中T-reg功能的调节。接下来，我们以相同的方式研究了树突状细胞（DC）上TLR的表达模式。AIH患者外周血中的髓源性DC（MDDC）仅表达TLR 6，而健康对照者表达TLR 3、4、6、7、9。因此，Tr可能通过Foxp 3、CTLA-4和TLR等分子受到信号调节。另外，AIH中MDDC表面TLR表达模式的不同可能对DC调节Tr的功能有一定影响。少

(1) Impaired regulatory T cell functions in patients with autoimmune hepatitisThe importance of CD4^+CD25^+regulatory T cell (Tr)-mediated control of self-reactive T cells has been focused on. Recently, several molecules including Foxp3, CTLA4, and GITR (TNFRSF18) were identified as key molecules which control the development and activation of T-reg. We investigated whether there were any difference in the expression pattern of these key molecules on T-reg, and whether there were any difference in the function of T-reg in the patients with type 1 autoimmune hepatitis (AIH). The proportion of T-reg was increased in AIH compared with controls. mRNA for Foxp3 and Ctla4, both molecules are known to activate the function of T-reg, were significantly decreased in AIH compared with controls. We tested if the function of T-reg in AIR was impaired or not after stimulation by OKT3. Although no obvious difference in induction of TNF-α, IFN-γ, and TGF-β was identified, production of IL-10 was sign … More ificantly lower in AIH than in controls. Our results implies the possibility that genetical difference in the expression of Foxp3 and/or CTLA4 on T-reg might lead to the impaired function of T-reg, and finally to the breakthrough of peripheral tolerance in AIH.(2) Expression of toll-like receptor (TLR) family on regulatory T cells in patients with autoimmune hepatitisIt has been shown that naturally arising T-reg selectively express several members of the TLR family, and that signals through TLRs modulate the function of T-regs. We investigated the expression pattern of TLRs on T-reg in the patients with AIH. Total RNA was extracted from isolated T-reg and non-T-reg fractions and the amount of mRNA for TLR2, 3, 4, 6, 7, 8, 9 were evaluated by real time PCR. In AIH, as well as controls, TLR3, 4, 6, 7, 9 were expressed on Tr. Our results implies the possibility that the signals through TLRs expressed on T-reg might regulate the function of T-reg in AIH. Next we investigated the expression pattern of TLRs on dendritic cells (DCs) in the same manner. Myeloid derived DCs (MDDC) in the peripheral blood of patients with AIH expressed only TLR 6 whereas those of healthy controls expressed TLR 3, 4, 6, 7, 9. Thus Tr might regulated by the signal through the molecules like Foxp3, CTLA-4, and TLR. Further, different expression pattern of TLR on MDDC in AIH might have some influence on functional regulation of Tr by DCs. Less