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

白介素5(IL-5)主要由活化的T淋巴细胞和肥大细胞产生。它最初被认为是一种B细胞生长因子和一种免疫球蛋白A增强因子。白介素5受体(IL-5R)由两种不同的膜蛋白α和β链组成。IL-5通过IL-5Rα结合，β链与IL-5Rα形成高度亲和力的细胞内信号转导途径。IL-5是黏膜免疫系统的重要细胞因子，具有多种区别于全身免疫系统的免疫学特征。例如，肠道相关淋巴网状组织(GALT)或派耶斑块(PP)等免疫球蛋白诱导组织含有高频率的免疫球蛋白A结合的B细胞[表面免疫球蛋白ィイd1+ィエd1(SIgAィイd1+ィエd1)B细胞和Th1/Th2细胞]，它们通过共同的粘膜免疫系统与免疫球蛋白A效应部位包括肠固有层(I-LP)相连。IL-5是诱导…的主要细胞因子采用以PP和丝裂原刺激的脾B细胞为主的体外培养体系，使更多的S SIgAィイD1+ィエD1B细胞分化为产生Ig A的浆细胞。此外，IL-2和IL-6已被证明能够在体外促进IgA的合成。一个有趣的观察是，小鼠肠道固有层中高达40%的IgA产生细胞来自来自腹膜的B-1前体细胞池。小鼠的腹膜和固有层B-1细胞已被证明是从一个共同的池中发育出来的，可能代表着与传统的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的细胞的重要来源。我们利用B-1细胞和IL-5R基因缺失的小鼠模型，结合背景野生型小鼠，研究了IL-5R和B-1细胞在黏膜相关组织中对免疫球蛋白A产生细胞发育的影响。IL-5Rα的缺失选择性地影响了黏膜免疫球蛋白A的体内应答。IL-5RαィイD_1-/-ィエD_1小鼠黏膜分泌物中的免疫球蛋白A水平较野生型小鼠明显降低，而血清中的免疫球蛋白A水平无明显变化。IL-5RαィイD_1-/-ィエD_1小鼠的黏膜效应部位(肠固有层和鼻腔通道)产生免疫球蛋白A的细胞频率减少，而在PP和鼻腔相关淋巴网状组织等诱导部位则无明显变化。而在IL-5RαィイD1-/-ィエD1小鼠效应组织中，诱导部位的SIgAィイD1+ィエD1B-1细胞明显减少，而SIgAィイD1+ィエD1B-2细胞未见明显减少。IL-5Rα在SIgAィイD1+ィエD1B-1细胞上的表达高于IL-6R，而IL-5Rα和IL-6R在野生型小鼠SIgAィイD1+ィエD1B-2细胞上均有表达。SIgAィイD1+ィエD1B-1细胞在体外产生高水平的重组IL-5(IL-5)，而不是IL-6。综上所述，这些结果表明，IL-5/IL-5R信号通路对于非依赖于普通黏膜免疫系统的SIgAィイD1+ィエD1B-1细胞的发育和黏膜效应组织中的免疫球蛋白A应答至关重要。较少

项目成果

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Kariyone, A.、K. Higuchi、K. Takatsu 等人：“对 Vβ11D1+D1Th1 细胞至关重要的结核分枝杆菌 α 抗原的氨基酸残基的鉴定”。感染 67。 -4319 (1999)

Ogata, N., T.Kouro, A.Yamada, K.Takatsu. et al.: "JAK2 and JAK1 are constitutively associate with an interleukin-5 (IL-5) receptor α and βc subunit, respectively, and are activated upon IL-5 stimulation."Blood. 91. 2264-2271 (1998)

Ogata, N.、T.Kouro、A.Yamada、K.Takatsu 等人：“JAK2 和 JAK1 分别与白介素 5 (IL-5) 受体 α 和 βc 亚基组成型相关，并在IL-5 刺激。“血液。91. 2264-2271 (1998)

K. Takatsu, et al.: "Interleukin-5 induces IgG1 Isotype Switch Recombination in mouse CD38-Activated sigD-Positive B Lymphocytes"J. Immunol.. 162. 2812-2819 (1999)

K. Takatsu 等人：“Interleukin-5 在小鼠 CD38 激活的 sigD 阳性 B 淋巴细胞中诱导 IgG1 同型转换重组”。

Takatsu K.,et al.: "Deficiency of IL-5 receptor alpha-chain selectively influences the development of the common mucosal immune system independent IgA-producing B-1 cell in mucosa-associated tissues"J Immunol.. 162. 821-828 (1999)

Takatsu K.,et al.：“IL-5 受体 α 链的缺乏选择性地影响粘膜相关组织中常见粘膜免疫系统独立的 IgA 生成 B-1 细胞的发育”J 免疫学.. 162. 821-

Kinashi, T., T., Asaoka, H. Sagara, K. Takatsu, et al.: "Regulated adhesion by modulating affinity and subcellular localization of integrin VLA-5 (α5βl) in mast cells."J. Immunol.. 162. 2850-2857 (1999)

Kinashi, T., T., Asaoka, H. Sagara, K. Takatsu, et al.：“通过调节肥大细胞中整合素 VLA-5 (α5β1) 的亲和力和亚细胞定位来调节粘附。”J.Immunol.. 162 .2850-2857 (1999)