Role of innate immunity on initiation of autoimmune diseases and its regulation

树突状细胞（DC）上toll样受体（TLRs）对病原体的识别导致DC成熟，启动适应性免疫和/或自身免疫反应。在本研究中，我们研究了先天免疫在自身免疫性疾病发生中的作用。HTLV-1已被确定为引发和/或延续干燥综合征（SS）和类风湿性关节炎（RA）过程的病原体。首先，我们分析了HTLV-1感染的T细胞系和HTLV-1相关脊髓病/热带痉挛性麻痹（HAM/TSP）患者外周血CD4^+T细胞中干扰素(IFN)-γ和HTLV-1 p19抗原表达与p38 MAPK活化之间的关系。提示p38 MAPK信号通路的激活可能参与了HAM/TSP患者HTLV-1前病毒载量高的IFN-γ表达上调。此外，我们还证实了税介导的Bcl-xL表达抑制了HTL -1血清阳性受试者活化T淋巴细胞的凋亡。这些结果促进了自身免疫性疾病如SS和RA的发病。接下来，我们发现TLR2、TLR3和TLR4在SS小唾液腺的腺泡和导管细胞以及浸润的单核细胞上表达。当人唾液腺（HSG）受到肽聚糖（PDG）、聚I: C或脂多糖（LPS）刺激时，HSG细胞系通过磷酸化MAP激酶增加CD54的表达和IL-6的产生。我们在原发性SS患者的血清中发现了特异性识别颗粒酶B蛋白酶产生的La蛋白片段的自身抗体。与健康对照组相比，原发性SS患者NK细胞数量、NK细胞杀伤活性、活化受体CD2和NKG2D的表达均显著降低，NKp36的表达及NK细胞凋亡百分比均显著升高。我们的数据表明，NK细胞数量的减少，可能是凋亡死亡的结果，可能导致原发性SS患者NK细胞活性受损。我们研究了SLE患者外周血树突状细胞（DCs）的表型特征。在SLE患者中，髓样DC （CD11c^+, CD11c- bdca -3^+）和浆细胞样DC （BDCA-2^+）均减少。这些DC亚群的改变可能驱动SLE的自身免疫。皮下注射表达TSHR的重组腺病毒感染的dc可诱导小鼠Graves样甲状腺功能亢进。白矾百日咳毒素几乎完全抑制了IFN-γ的分泌以及抗体和疾病的诱导，而多核胞酸（poly I: C）增强了脾细胞IFN-γ的分泌，但没有改变疾病的发病率。最后，我们报道，通过在B: 16和19位（A^<16,19>改变的肽配体（APL））上的氨基酸取代或截断肽c端氨基酸（B: 9-21）来消除B: 9-23肽的CTL表位，两者都缺乏与K^d分子的结合，当与强效粘膜佐剂霍乱毒素（CT）共同给药时，鼻内诱导的糖尿病抑制作用显著。这些研究表明，清除B: 9-23肽的CTL表位对于预防粘膜诱导的糖尿病至关重要。APL独特地抑制抗胰岛体液和细胞自身免疫，保护和缓解糖尿病。我们目前的研究有助于澄清病因和/或发病机制，并为自身免疫性疾病的治疗提供新的策略。少

Pathogen recognition by Toll-like receptors (TLRs) on dendritic cells (DCs) leads to DC maturation, the initiation of adaptive immunity and/or autoimmune response. In the present study, we investigated the role of innate immunity on initiation of autoimmune diseases. HTLV-1 has been identified as a causative agent which initiates and/or perpetuates the process of Sjogren's syndrome (SS) and rheumatoid arthritis (RA). At first, we analyzed the relationship between the expression of interferon (IFN)-γ and HTLV-1 p19 antigen and activation of p38 MAPK in HTLV-1-infected T cell lines and peripheral blood CD4^+T cells from patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). It is suggested that activation of p38 MAPK signaling pathway might be involved in the up-regulation of IFN-γ expression with high HTLV-1 proviral load in HAM/TSP patients. Furthermore, we demonstrated that Tax-mediated Bcl-xL expression inhibited apoptosis of activated T lymphocytes in HTL … More V-1-seropositive subjects. These results consequently promotes the onset of autoimmune disorders such as SS and RA. Next, we showed the expression of TLR2, TLR3 and TLR4 on the acinal and ductal cells, and infiltrated mononuclear cells from minor salivary glands of SS. When a human salivary glands (HSG) were stimulated by peptidoglycan (PDG), poly I : C, or lipopolysaccharide (LPS), HSG cell line augmented the expression of CD54 and production of IL-6, through the phosphorylation of MAP kinase. We found autoantibodies in sera from primary SS patients that specifically recognize fragments of the La protein that are produced by the granzyme B protease. NK cell number, NK cell killing activity, and the expression of activating receptor CD2 and NKG2D were significantly decreased, and the expression of NKp36, as well as the percentage of apoptotic NK cells were significantly increased in primary SS patients compared with healthy controls. Our data suggest that reduced NK cell numbers, a probably result of apoptotic death, may contribute to impaired NK cell activity in patients with primary SS. It was undertaken to investigate the phenotypic characteristics of peripheral blood dendritic cells (DCs) in SLE patients. Both myeloid DCs (CD11c^+, CD11c-BDCA-3^+) and plasmacytoid DC (BDCA-2^+) were reduced in SLE patients. These altermations of the DC subset may drive the autoimmune in SLE. Subcutaneous injections of DCs infected with recombinant adenovirus expressing the TSHR in syngeneic female mice inuced Graves'-like hyperthyroidism. IFN-γ secretion and induction of antibodies and disease were almost completely suppressed by co-administration of alum pertussis toxin, whereas polyribocytidytic acid (poly I : C) enhanced splenocyte secretion of IFN-γ without changing disease incidence. Finally, we report that the elimination of CTL epitope from B : 9-23 peptide by aminoacid substitution at position B : 16 and 19 (A^<16,19> altered peptide ligand (APL)), or truncation of the C-terminal aminoacids from the peptide (B : 9-21), both of which lacks binding to the K^d molecule, provided significant intranasally induced suppression of diabetes when co-administrated with a potent mucosal adjuvant cholera toxin (CT). These study indicated that elimination of the CTL epitope from B : 9-23 peptide was critically important for mucosally induced diabetes prevention. A^<16,19> APL uniquely suppresses anti-islet humoral and cellular autoimmunity with protection and remission of diabetes. Our present study contributes the clarification of etiology and/or pathogenesis, and leads to new strategies for treatments in autoimmune diseases. Less