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

树突状细胞（DC）上的Toll样受体（TLR）识别病原体导致DC成熟，启动适应性免疫和/或自身免疫应答。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已被鉴定为引发和/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相关性脊髓病/热带痉挛性截瘫（HAM/TSP）患者外周血CD 4 ^+T细胞中干扰素（IFN）-γ和HTLV-1 p19抗原的表达与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患者高HTLV-1前病毒载量时IFN-γ表达的上调。此外，我们证明Tax介导的Bcl-xL表达抑制HTL中活化的T淋巴细胞的凋亡， ...更多信息 V-1-血清阳性受试者。因此，这些结果促进了自身免疫性疾病如SS和RA的发作。接下来，我们显示了TLR 2，TLR 3和TLR 4在腺泡和导管细胞上的表达，以及从SS的小唾液腺浸润的单个核细胞。人唾液腺（HSG）细胞经肽聚糖（PDG）、poly I：C或脂多糖（LPS）刺激后，通过磷酸化MAP激酶，增加CD 54的表达和IL-6的产生。我们在原发性SS患者血清中发现了自身抗体，其特异性识别由颗粒酶B蛋白酶产生的La蛋白片段。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CD 2和NKG 2D的表达均显著降低，NKp 36的表达和NK细胞凋亡百分比显著升高。我们的数据表明，NK细胞数量减少，可能是凋亡性死亡的结果，可能有助于原发性SS患者NK细胞活性受损。目的探讨系统性红斑狼疮（SLE）患者外周血树突状细胞（DC）的表型特征。SLE患者髓样DC（CD 11 c ^+、CD 11 c-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的自身免疫性。皮下注射表达TSHR的重组腺病毒感染的DCs诱导同系雌性小鼠发生Graves样甲状腺功能亢进。IFN-γ的分泌和抗体和疾病的诱导几乎完全抑制了共同管理的明矾百日咳毒素，而聚核糖胞苷酸（聚I：C）增强脾细胞分泌IFN-γ，而不改变疾病的发病率。最后，我们报道了通过在位置B：16和19处的氨基酸取代来消除来自B：9-23肽的CTL表位。（A）<16，19>改变的肽配体（APL）），或从肽的C-末端氨基酸截短（B：9-21），两者都缺乏与K^d分子的结合，当与有效的粘膜佐剂霍乱毒素（CT）共同给药时，提供了显著的鼻内诱导的糖尿病抑制。这些研究表明，从B：9-23肽中消除CTL表位对于粘膜诱导的糖尿病预防是至关重要的。APL独特地抑制抗胰岛体液和细胞自身免疫，具有保护和缓解糖尿病的作用。我们目前的研究有助于阐明病因和/或发病机制，并导致新的策略治疗自身免疫性疾病。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