Molecular mechanisms of oral immunity : Role of IL-5 in potentiation of IgA production in mucosal lymphoid cell

口腔免疫的分子机制：IL-5 在增强粘膜淋巴细胞 IgA 产生中的作用

• 批准号: 10557036
• 负责人: TAKATSU Kiyoshi
• 金额: $ 7.36万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10557036/
• 关键词: IL-5; IL-6; IgA; B-1 cell; lamina propria; Peyer's patch; gene knock-out mouse; IL-5 receptor; クラス交換; **型T細胞; リボ多糖体; γδ型T細胞

Interleukin-5 (IL-5) is Produced mainly by activated T lymphocytes and mast cells. It was originally recognized by its activity as a B cell growth factor and an IgA-enhancing factor. The IL-5 receptor (IL-5R) consists of two distinct membrane proteins, α and β chains. The binding of IL-5 occurs through the IL-5Rα, and the β chain forms a high affinity with IL-5Rα for the intracellular signal transduction pathway. IL-5, which has been shown to be an important cytokine for the mucosal immune system, possesses several immunological features which distinguish it from the systemic immune compartment. For example, IgA inductive tissues such as gut-associated lymphoreticular tissue (GALT) or Peyer's patches (PP) containing a high frequency of IgA-committed B cells [surface IgAィイD1+ィエD1 (sIgAィイD1+ィエD1) B cells and Th1/Th2 cells are interconnected with IgA effector sites including intestinal lamina propria (i-LP) via the common mucosal immune system (CMIS). IL-5 is a major cytokine which induce … More s sIgAィイD1+ィエD1 B cells to differentiate into IgA-producing plasma cells using mainly an in vitro system using PP and mitogen-stimulated splenic B cells. Further IL-2 and IL-6 have been demonstrated to be capable of enhancing IgA synthesis in vitro. An intriguing observation is that up to 40% of IgA-producing cells in the murine intestinal lamina propria arise from a pool of B-1 precursors derived from the peritoneal cavity. Peritoneal and lamina propria B-1 cells in mice have been shown to develop from a common pool and may represent a lineage separate from that of conventional PP B cells. These results suggest that B - 1 cells could be an important source for IgA-producing cells in mucosal tissues. We focused our study on exploring the role of IL-5R and B-1 cells in the development of IgA-producing cells in mucosa-associated tissues using the latter gene-disrupted murine model together with the background wild type mice.Deletion of IL-5Rα selectively influenced the mucosal IgA responses in vivo. While levels of IgA in mucosal secretions were more rduced in IL-5RαィイD1-/-ィエD1 mice than in wild type mice, the levels of IgA in serum were not changed. The frequency of IgA-producing cells was reduced in mucosal effector sites (e.g. intestinal lamina propria and nasal passage) but not in inductive sites such as PP and nasal-associated lymphoreticular, tissues (NALT) in IL-5RαィイD1-/-ィエD1 mice IgA-committed (surface IgAィイD1+ィエD1 ; sIgAィイD1+ィエD1) B-1 cells mainly resided in mucosal effector tissues, while conventional sIgAィイD1+ィエD1 B (B-2) cells formed in mucosal inductive sites of wild type mice. In contrast, in the effector tissue of IL-5RαィイD1-/-ィエD1 mice, sIgAィイD1+ィエD1 B-1 cells, but not sIgAィイD1+ィエD1 B-2 cells in the inductive site, were significantly reduced. IL-5Rα was more expressed on sIgAィイD1+ィエD1 B-1 cells than was IL-6R, while both IL-5Rα and IL-6R were expressed on sIgAィイD1+ィエD1 B-2 cells in wild type mice. sIgAィイD1+ィエD1 B-1 cells produced high levels of IgA with recombinant IL-5 (IL-5) rather than of IL-6 in vitro. Taken together, the findings demonstrate that the IL-5/IL-5R signaling pathway is critically important for the common mucosal immune system (CMIS) independent sIgAィイD1+ィエD1 B-1 cell development and for IgA responses in mucosal effector tissues in vivo. Less

白细胞介素-5（IL-5）主要由活化的T淋巴细胞和肥大细胞产生。最初通过其作为B细胞生长因子和IgA增强因子的活性来识别。IL-5受体（IL-5 R）由两种不同的膜蛋白α和β链组成。IL-5的结合通过IL-5 R α发生，β链与IL-5 R α形成高亲和力，用于细胞内信号转导途径。IL-5已被证明是粘膜免疫系统的重要细胞因子，其具有将其与全身免疫区室区分开的若干免疫学特征。例如，含有高频率IgA定型B细胞[表面伊加趋化因子D1+补体D1（sIgA趋化因子D1+补体D1）B细胞和Th 1/Th 2细胞]的肠相关淋巴网状组织（GALT）或派尔集合淋巴结（PP）等伊加诱导组织通过共同粘膜免疫系统（CMIS）与包括肠固有层（i-LP）在内的伊加效应位点相互连接。IL-5是一种主要的细胞因子， ...更多信息 s sIgA β D1+ IgA β D1 B细胞分化为IgA产生浆细胞，主要使用使用PP和促分裂原刺激的脾B细胞的体外系统。此外，已证明IL-2和IL-6能够在体外增强伊加合成。一个有趣的观察是，高达40%的IgA产生细胞在小鼠肠固有层产生的池B-1前体来源于腹膜腔。小鼠的腹膜和固有层B-1细胞已被证明是从一个共同的库中发育而来的，并且可能代表与常规PP B细胞不同的谱系。这些结果表明，B - 1细胞可能是粘膜组织中产生IgA细胞的重要来源。本研究采用基因敲除小鼠模型和野生型小鼠模型，探讨IL-5 R α和B-1细胞在粘膜相关组织中IgA产生细胞发育中的作用。IL-5 R α受体D1-/-β受体D1小鼠粘膜分泌物中伊加水平比野生型小鼠降低更多，而血清中伊加水平无变化。粘膜效应部位IgA产生细胞的频率降低（如肠固有层和鼻道），但在IL-5 R α-IFN-γ D1-/-IFN-γ D1小鼠的诱导部位，如PP和鼻相关淋巴网状组织（NALT）中，IgA-定向（表面伊加IgA IgA D1+ IgA D1 ;野生型小鼠的粘膜诱导部位主要形成sIgA β D1+ β D1）B-1细胞，而传统的sIgA β D1+ β D1 B（B-2）细胞。相比之下，在IL-5 R α β D1-/-β D1小鼠的效应器组织中，诱导部位的sIgA β D1+ β D1 B-1细胞显著减少，但sIgA β D1+ β D1 B-2细胞未显著减少。在野生型小鼠中，IL-5 R α在sIgA β D1+ β D1 B-1细胞上的表达高于IL-6 R，而IL-5 R α和IL-6 R均在sIgA β D1+ β D1 B-2细胞上表达。在体外，sIgAイD 1 + D 1 B-1细胞用重组IL-5（IL-5）而不是IL-6产生高水平的伊加。总而言之，研究结果表明，IL-5/IL-5 R信号通路对于体内常见粘膜免疫系统（CMIS）非依赖性sIgAイD 1 + D1 B-1细胞发育和粘膜效应组织中的伊加反应至关重要。少

项目成果

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