Fcγ受体调控途径在免疫复合物介导的SLE巨噬细胞极化中的作用

Specific autoantibodies play a central role in the pathogenesis of systemic lupus erythematosus (SLE). Our previous study has found that there is a strong and highly significant correlation between binding to BM and binding to dsDNA. Only those anti-DNA mAbs bind directly to BM antigens and that direct binding of anti-dsDNA antibody to GBM or MM is critical for the initiation of experimental lupus nephritis (LN). Accumulating data demonstrated that aberrant activated macrophages were involved in the onset and progression of SLE. Macrophages display functional polarization in response to various microenvironmental signals. But the role of specific autoantibodies of SLE in the macrophages polarization remains largely unknown. Our previous study has found that regulating expression of FcγR influences immune complex（IC）-mediated differentiation of monocyte-macrophage. Here, we study on the pathogenesis of specific autoantibodies in SLE. To explore the regulation effect of FcγR-mediated macrophage polarization by specific autoantibodies in SLE, we observe 1) Difference of macrophages polarization and activating and inhibitory FcγR expression in nephritic tissues in lupus patients versus normal individuals; 2) Regulating FcγR signaling affects the polarization of macrophages; 3) Molecular mechanisms of anti-DNA antibodies as immune complexes or directly bound IgG (in vitro to DNA or a GBM matrix) induce different macrophage polarization via FcγR; 4) Regulating FcγR signaling by immune complexes switch the polarization macrophages that have already differentiated. From the above studies, we aim to clarify the interaction of specific autoantibodies, FcγR and macrophages polarization in SLE. This study is the best attempt to provide new evidences for the pathogenesis of SLE disease.

特异性自身抗体致病在系统性红斑狼疮（SLE）的发病机制中处于中心地位。我们既往的研究发现与基底膜或系膜基质抗原高亲和力的抗dsDNA抗体在诱发狼疮性肾炎（LN）中起重要作用。越来越多的证据显示异常的巨噬细胞活化参与了SLE的发生发展过程。活化的巨噬细胞会发生功能上极化，但是SLE中特异性的自身抗体对于巨噬细胞极化的调节及机制尚不清楚。我们前期研究发现FcγR介导了免疫复合物（IC）对单核巨噬细胞功能分化的影响。本课题通过观察1）SLE患者巨噬细胞极化类型与激活型/抑制型FcγR表达的关系；2）调节FcγR对巨噬细胞极化的影响；3）IC调控FcγR介导巨噬细胞极化的分子机制；4）IC通过调控FcγR诱导巨噬细胞极化类型转换等方面，阐明特异性的自身抗体-FcγR-巨噬细胞极化化在SLE发病中的相互关系及作用,为进一步阐明SLE的发病机制提供理论和实验依据。

特异性自身抗体致病在系统性红斑狼疮（SLE）的发病机制中处于中心地位。异常的巨噬细胞活化参与了SLE的发生发展过程，但是SLE中特异性的自身抗体对于巨噬细胞极化的调节及机制尚不清楚。我们前期研究发现FcγR介导了免疫复合物（IC）对单核巨噬细胞功能分化的影响。本课题阐明SLE患者IC调节FcγR介导下游信号传导调控巨噬细胞极化的作用机制。通过研究我们发现诱导分化的M1巨噬细胞表面 FcγRIIa 和 FcγRIIIa表达升高，M2巨噬细胞表面FcγRIIb 的表达升高，免疫组化的观察结果也发现LN 患者肾组织M1、M2 巨噬细胞浸润与FcγRIIa、FcγRIIIa、FcγRIIb有相似的关系。交联FcγRIIa、FcγRIIIa诱导M1巨噬细胞分化，交联FcγRIIb诱导M2巨噬细胞分化，干扰上述FcγR后抑制IC 介导的 SLE 患者M1、M2巨噬细胞极化。调节单核细胞FcγRIIa、FcγRIIIa后胞内 Ca2+流动增加。IC 诱导 SLE M1巨噬细胞极化后胞内SHIP、 p65、IκBα 及其磷酸化蛋白的表达增加。筛选能活化 FcγRIIa 或 FcγRIIIa 的单克隆抗体能诱导M2型巨噬细胞向M1型巨噬细胞表型转化。