PNAS:科学家发现免疫球蛋白IgM受体

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复旦大学基础医学院免疫学系王继扬课题组在最新研究中发现了免疫球蛋白IgM的受体。免疫球蛋白IgM被誉为机体预防病毒和细菌感染的“第一道防线”，IgM与受体结合后，不仅可促进机体免疫功能增强，而且能抑制自身“有害”抗体的产生。该研究对治疗人的免疫缺陷病和自身免疫疾病有重大意义。相关成果日前在线发表于美国《国家科学院院刊》。

据了解，免疫球蛋白IgM是初次免疫应答中最早出现的抗体。IgM抗体直接与病原体结合后，可抑制病原体的活性，不让其发病、发展，并可通过特殊途径来溶解病原体，阻止感染的扩大。早在40年前，世界各地的科学家就发现B淋巴细胞表面有IgM的受体，并有证据支持这一推断，但一直没有找到该受体。

王继扬课题组运用基因敲除技术，成功培育了一种缺乏“FcμR基因”的敲除小鼠，并分析了这种小鼠在缺乏该基因的状态下，在免疫功能和自身抗体方面会产生的结果。经过3年努力，他们终于首次发现了该受体的基因FcμR。

研究发现，外来病原体侵入FcμR基因被敲除的小鼠后，出现明显的免疫缺陷状况，其抗体下降至正常小鼠的1/3以下。进一步研究表明，该免疫缺陷是由于FcμR基因敲除后，B淋巴细胞在受到外来病原体刺激后，不但不容易被激活，反而容易造成死亡。相反，缺乏FcμR基因的敲除小鼠在没有任何刺激的情况下，会产生大量有害的自身抗体，包括会产生有害的系统性红斑狼疮的抗核抗体和抗DNA抗体或诱发机体关节炎的类风湿性因子等。

相关专家表示，未来可通过激活B淋巴细胞表面的IgM受体，促进机体内有益抗体的产生，以增强人体免疫力，或采用抑制性抗体来治疗因B淋巴细胞活化异常而引起的各种免疫性疾病



doi:10.1073/pnas.1210706109
PMC:
PMID:
Critical role of the IgM Fc receptor in IgM homeostasis, B-cell survival, and humoral immune responses

Rika Ouchida, Hiromi Mori, Koji Hase, Hiroyuki Takatsu, Tomohiro Kurosaki, Takeshi Tokuhisa, Hiroshi Ohno, and Ji-Yang Wang

IgM antibodies have been known for decades to enhance humoral immune responses in an antigen-specific fashion. This enhancement has been thought to be dependent on complement activation by IgM–antigen complexes; however, recent genetic studies render this mechanism unlikely. Here, we describe a likely alternative explanation; mice lacking the recently identified Fc receptor for IgM (FcμR) on B cells produced significantly less antibody to protein antigen during both primary and memory responses. This immune deficiency was accompanied by impaired germinal center formation and decreased plasma and memory B-cell generation. FcμR did not affect steady-state B-cell survival but specifically enhanced the survival and proliferation induced by B-cell receptor cross-linking. Moreover, FcμR-deficient mice produced far more autoantibodies than control mice as they aged, suggesting that FcμR is also required for maintaining tolerance to self-antigens. Our results thus define a unique pathway mediated by the FcμR for regulating immunity and tolerance and suggest that IgM antibodies promote humoral immune responses to foreign antigen yet suppress autoantibody production through at least two pathways: complement activation and FcμR.