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CD4^+CD25^+调节性T细胞（Tr）介导的自身反应性T细胞控制的重要性已得到关注。近年来，Foxp3、CTLA4和GITR （TNFRSF18）等分子被鉴定为控制T-reg发育和激活的关键分子。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。与对照组相比，AIH患者T-reg比例升高。Foxp3和Ctla4的mRNA与对照组相比显著降低，这两种分子都是已知的激活T-reg功能的分子。我们检测了OKT3刺激后AIR中t - regg的功能是否受损。虽然AIH对TNF-α、IFN-γ和TGF-β的诱导作用无明显差异，但IL-10的产生明显低于对照组。我们的研究结果提示，T-reg上Foxp3和/或CTLA4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（toll-like receptor， TLR）家族在自身免疫性肝炎患者调节性T细胞中的表达研究表明，自然产生的T-reg可选择性表达若干TLR家族成员，并通过TLR信号调节T-regs的功能。我们研究了AIH患者中TLRs对T-reg的表达模式。从分离的T-reg和非T-reg部分提取总RNA，并通过实时荧光定量PCR检测TLR2、3、4、6、7、8、9的mRNA含量。在AIH和对照组中，TLR3、4、6、7、9在Tr上表达。我们的研究结果表明，通过TLRs在T-reg上表达的信号可能调节了T-reg在AIH中的功能。接下来，我们以同样的方式研究了TLRs在树突状细胞（dc）上的表达模式。AIH患者外周血中的髓系源性dc （MDDC）仅表达tlr6，而健康对照组的MDDC则表达tlr3、4、6、7、9。因此，Tr可能通过Foxp3、CTLA-4、TLR等分子受到信号调控。此外，AIH中TLR在MDDC上的不同表达模式可能对dc对Tr的功能调控有一定影响。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