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

先天免疫在自身免疫性疾病发生中的作用及其调控

• 批准号: 15390316
• 负责人: EGUCHI Katsumi
• 金额: $ 8.96万
• 依托单位: Nagasaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390316/
• 关键词: innate immunity; adaptive immunity; HTLV-I; toll-like receptor; dendritic cell; NK cell; autoimmune disease; regulatory T cell; Toll-like receptor (TLR); 関節リウマチ; シェーグレン症候群; Natural killer (NK)細胞; アポトーシス; 生物学的製剤; 初代培養唾液腺細胞; TLR-3; poly(I:C)

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

树突状细胞(DC)上的Toll样受体(TLRs)识别病原体，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已被确定为启动和/或延续干燥综合征(SS)和类风湿关节炎(RA)过程的病原体。首先，我们分析了HTLV-1相关脊髓病/热带痉挛截瘫(HAM/TSP)患者外周血中干扰素-γ和HTLV-1p19抗原表达与p38MAPK活化的关系。提示p38MAPK信号通路的激活可能与HAM/TSP患者高前病毒载量的干扰素-γ表达上调有关。此外，我们还证实了Tax介导的bclxl表达抑制了hTL…中活化的T淋巴细胞的凋亡。更多V-1血清阳性的受试者。因此，这些结果促进了自身免疫性疾病的发生，如SS和RA。接下来，我们显示了TLR2、TLR3和TLR4在SS的腺泡和导管细胞上的表达，并见于SS的小涎腺中的单个核细胞。人唾液腺细胞株在多肽聚糖(PDG)、聚I：C或脂多糖(LPS)刺激下，通过MAP激酶的磷酸化，促进CD54的表达和IL-6的产生。我们在原发SS患者的血清中发现了特异性识别颗粒酶B蛋白产生的La蛋白片段的自身抗体。与正常对照组比较，SS患者外周血中NK细胞数、NK细胞杀伤活性、活化受体CD2和NKG2D的表达显著降低，NKp36的表达和NK细胞的凋亡率显著升高。我们的数据表明，NK细胞数量减少，可能是细胞凋亡死亡的结果，可能是原发SS患者NK细胞活性受损的原因之一。研究系统性红斑狼疮(SLE)患者外周血树突状细胞(DC)的表型特征。SLE患者髓系DC(CD11c^+、CD11c-BDCA-3^+)和浆细胞型DC(BDCA-2^+)均减少。这些DC亚群的改变可能推动了SLE的自身免疫。皮下注射表达TSHR基因的重组腺病毒感染的树突状细胞可诱发Graves‘样甲亢。联合应用百日咳明矾毒素可完全抑制干扰素-γ的分泌、抗体和疾病的诱导，而多聚核糖核酸(Poly I：C)可促进脾细胞分泌干扰素-γ，但不改变发病率。最后，我们报道通过B：16和19位氨基酸替换(A^&lt；16，19&gt；改变的多肽配体(APL))消除B：9-23多肽的CTL表位，或截断B：9-23多肽的C-末端氨基酸(B：9-21)，两者都缺乏与K^d分子的结合，在与有效的粘膜佐剂霍乱毒素(CT)联合给药时，提供了显著的鼻内诱导抑制糖尿病的作用。这些研究表明，消除B：9-23多肽的CTL表位对于预防粘膜诱导的糖尿病至关重要。APL独一无二地抑制抗胰岛体液和细胞自身免疫，保护和缓解糖尿病。我们的研究有助于阐明自身免疫性疾病的病因和/或发病机制，并为治疗自身免疫性疾病提供新的策略。较少

项目成果

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Shigeno M: "Interferon-α sensitizes human hepatoma cells to TRAIL-induced apoptosis through DR5 upregulation and NF-κB inactivation"Oncogene. 22(11). 1653-1662 (2003)

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