Toll样受体信号在自身免疫病发生中的细胞学机制

Studies over the past decade have demonstrated the important roles of Toll-like receptors (TLRs) in the pathogenesis of autoimmune diseases. It seems that both the production of autoantibodies and the self-perpetuated inflammation response are required steps for the occurrence of systemic autoimmune diseases, exemplified as systemic lupus erythematosis (SLE). As a major pattern recognition receptor (PPR) family, TLRs are expressed in multiple immune and non-immune cell types at steady state, and could be induced in more cell types upon environmental change. The frequent occurrence of autoantibodies against DNA- or RNA-associated autoantigens is related to the nucleic acid binding properties of TLR7 and 9. To what extent and by what mechanisms the TLR signaling from different cells contribute to the development of autoimmune diseases in vivo is not clear yet. Taking the advantage of a common adapter protein MyD88 downstream of both TLR7 and 9 signaling, we propose to use conditional MyD88 deletion to study the different mechanisms that the TLR signaling might be involved in during the pathogenesis of autoimmune diseases by engaging a network of immune cells and soluble mediators..Mice lack Lyn, an Src family kinase, which in vivo mainly inhibits immunoreceptor tyrosine-based activating motif (ITAM) mediated signaling, is a well-established murine SLE model. lyn-/- mice spontaneously develop auto-antibody, immune complex deposition, and nephritis, similar to the characters seen in human SLE patients. By mating cell-specific MyD88-/- including B-MyD88-/- and DC-MyD88-/- to lyn-/- background, we will be able to examine the roles of TLR signaling in B cells and dendritic cells (DCs), especially their relevance to SLE pathogenesis. Comparing autoantibody production and kidney pathology among lyn-/- B-MyD88-/-, lyn-/- DC-MyD88-/- lyn-/- and lyn-/- will allow us to determine whether TLR signaling from B cell and DCs is required for the progress of the disease. Further exploration of the potential underlying mechanisms, such as germinal center response, TFH activation, pro-inflammatory cytokine secretion, and etc. will reveal the cellular mechanisms by which TLR signaling might play a role. In addition, we will further explore the potential contribution of endogenous TLR ligands to SLE occurrence by generating TLR7 and TLR9 conditional transgenic mice. It has been shown that duplication of TLR7 predisposes mice to SLE, indicating a proper level of TLR expression might be important in keeping the balance between pathogen defense and self destruction. We are particularly interested in the initiation process of the autoimmune diseases, which might be amplified or exaggerated by overexpression of TLRs. Detailed examination of some earliest events in SLE from TLR7/9 cell-type specific transgenic mice will enable us to understand the physiological triggering factors in human autoimmune diseases.

自身免疫性疾病是免疫系统针对自身成分发生异常反应和破坏引起的一大类疾病，是导致青壮年人群生活和劳动能力下降乃至死亡的一类主要疾病。近年的研究发现由Toll样受体（TLRs）活化的天然免疫信号对免疫细胞的异常活化和炎症反应都起着重要作用。但是，目前关于TLR信号在体内如何活化不同类型免疫细胞并导致自身免疫病的机制并不十分清楚。我们将首先通过在小鼠系统性红斑狼疮模型中选择性地消除B细胞、树突状细胞等免疫细胞TLR信号的方法来研究这些细胞的TLR信号分别在自身抗体产生、生发中心反应、T细胞活化及促炎因子分泌等几个自身免疫病发生的关键环节中的作用。另外，我们还将通过构建TLR的细胞特异性转基因小鼠来研究不同免疫细胞在识别内源性TLR配体和活化自身免疫反应中的作用。我们的研究将有助于揭示TLR信号在破坏免疫耐受和导致自身免疫病中的作用机理。

系统性红斑狼疮（SLE）是一种发病率较高、病情危害严重的自身免疫病，其特征性临床表现为高滴度的抗核抗体和伴随的肾脏病理改变。天然免疫受体不仅在抗感染中起重要作用，而且可能也参与了自身免疫病的发生。本项目中，我们利用小鼠SLE模型分别研究了树突样细胞（DC）和B细胞中的Toll样受体（TLR）信号如何影响自身免疫病的发生。我们发现，在DC或B细胞中选择性敲除MyD88后，SLE小鼠的抗核抗体水平明显降低，肾脏病理改善。更为有趣的是，我们发现SLE小鼠脾脏中出现自发的生发中心，而B细胞MyD88敲除后自发生发中心消失，提示B-MyD88可能通过促进生发中心反应而促进自身抗体产生。为此，我们在SLE小鼠中敲除与生发中心特异性相关的SAP分子，发现其抗核抗体也明显下降，证实了我们的猜想。这些结果已发表，我们将在今后的研究中进一步探索生发中心如何参与自身免疫病。这项研究将有助于推动人类SLE疾病发病机理的研究，以及为寻找新的治疗靶标提供线索。