GPR40在 B 淋巴细胞活化及类风湿性关节炎中的功能及机制研究

GPR40 is a specific receptor of fatty acids, and it is also highly expressed in human and mouse B lymphocytes. We found that GPR40 deficiency had no significant influence on the development of B cells in mice. However, under antigen stimulation, GPR40-deficient B lymphocytes demonstrated a higher level of activation and antibody secretion. Using bone marrow chimeric mice, we found that GPR40-deficient mice had increased serum Ig and enhanced germinal center formation in spleen after immunization. We also found a higher incidences of collagen-induced arthritis (CIA) in GPR40-deficient mice than in wild type mice. These results indicate that GPR40 is very likely to play a negative regulatory role in B cell activation and then affect the humoral immunity process and the onset of rheumatoid arthritis (RA). We will study the role of GPR40 on BCR downstream signaling transductions upon the activaiton of different antigens in vitro to reveal the molecular mechanisms of GPR40 function in B cells. On the other hand, GPR40 conditional knock-out mice will be developed to further explore the function of GPR40 in humoral immunity and the pathogenesis of RA. In addition, we will also investigate the relationship between GPR40 and RA incidence in clinical to provide a theoretical basis for further investigation into effective molecular targets for the treatment of RA.

G蛋白偶联受体40（GPR40）是一种特异性脂肪酸受体，在人及小鼠的B淋巴细胞中均有特异性的高表达。利用商品化GPR40-/-小鼠，我们发现GPR40的缺陷虽然没有对B细胞的发育产生显著影响，但GPR40缺陷的B淋巴细胞在受到抗原刺激后，具有更高的活化及抗体分泌水平。在骨髓嵌合小鼠中我们也发现，GPR40缺陷小鼠具有更高的血清Ig水平，其胶原诱导的关节炎（CIA）发病率及发病程度亦高于野生型小鼠。以上结果提示，GPR40很可能在B细胞的活化过程中发挥了负向调控作用，进而影响了整体体液免疫及类风湿性关节炎的发病。本课题拟重点研究GPR40在B细胞活化过程中发挥的作用及其分子机制；并通过构建条件敲除小鼠，进一步探讨GPR40在B细胞中的特异性缺陷对小鼠体液免疫及RA发病的影响；此外，我们也将探讨GPR40与临床RA发病的相关性，为寻找治疗RA有效分子靶点提供基础理论依据。

G蛋白偶联受体40（GPR40）是一种特异性脂肪酸受体，在人及小鼠的B淋巴细胞中均有特异性的高表达。利用构建的GPR40-CD19特异性缺陷小鼠，我们发现GPR40的缺陷影响了B淋巴细胞在外周向浆细胞的分化，且GPR40缺陷的B淋巴细胞在受抗原刺激后，具有更高的活化及抗体分泌水平。在条件缺陷小鼠的抗原免疫实验中我们发现，GPR40缺陷小鼠具有更高的血清Ig水平，其胶原诱导的关节炎（CIA）发病率及发病程度亦高于野生型小鼠。此外，在灭活新冠病毒疫苗接种的GPR40-CD19及其野生对照小鼠中，我们发现GPR40缺陷的小鼠其血清中抗新冠的IgM型抗体有所提升，而IgG型抗体并无差异。以上结果都提示，GPR40在B细胞的活化过程中发挥了负向调控作用，从而进一步揭示 GPR40 的在 B 淋巴细胞中的功能，特别是深入阐释其在 B 细胞中的免疫调节功能及其发挥作用的分子机制，为体液免疫相关的自身免疫性疾病和病毒感染相关研究提供了新的线索。

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