系统性红斑狼疮患者泌乳素对调节性B细胞的调控作用及其影响自身抗体分泌的研究

Systemic lupus erythematosus (SLE) is an autoimmune disease involving multiple systems of the patient. It often occurs in women of reproductive age and its pathogenesis has not been elucidated. The disease is mainly manifested as activation of B cells and increased production of autoantibodies. We previously revealed an increasing prolactin (PRL) level in blood, which was related to the autoantibodies secretion of B cells. But the effects of PRL on differentiation and function regulation of regulatory B cells (Breg), a subset of B cells with suppressive activity, in SLE is still not clear. Our study showed that there were Breg both in peripheral blood of SLE patients and MRL/lpr mice, but the immune suppression function of the cells were damaged. Based on this, we hypothesized that PRL may play a different role on different B cells. On one hand it may promote B cells differentiation to plasma cells and increasing antibodies production, on the other hand it may hinder the differentiation and suppressive activity of Breg , so as to promote the disease development. This study intends to understand the correlation between PRL and Breg in vivo of SLE, the effects of PRL on the differentiation and function regulation of Breg in vitro, and the Breg differentiation and autoantibodies production in MRL/lpr lupus mice after treatment with anti-PRL-Receptor antibody were also analyzed. The study could help us understanding the impact effect of PRL on Breg and autoantibodies production, providing a new target used for the treatment of SLE.

系统性红斑狼疮(SLE)是一种累及多系统的自身免疫病，好发于育龄期女性，发病机制未阐明。该病主要表现为B细胞活化，自身抗体产生增多。我们前期揭示:SLE患者外周血泌乳素(PRL)水平升高，且与B细胞分泌自身抗体相关，但PRL对SLE具有免疫抑制作用的调节性B细胞(Breg)的分化和功能调控作用尚不清楚;SLE患者外周血和MRL/lpr狼疮鼠中存在Breg，但免疫抑制功能受损。基于此我们推测PRL对不同B细胞发挥不同调控作用，一方面促进B细胞向浆细胞分化导致抗体分泌增加，另一方面阻碍Breg分化行使免疫抑制功能，从而促进病情发展。本课题拟研究:SLE体内PRL与Breg的相关性，体外PRL对Breg分化和功能的调控;并通过MRL/lpr狼疮鼠研究抗PRL受体抗体对体内Breg分化和自身抗体产生的影响。该研究可深入了解PRL对Breg的调节作用及对自身抗体产生的影响，为SLE治疗提供新靶点。

系统性红斑狼疮(SLE)是一种累及多系统的自身免疫病，好发于育龄期女性，其发生机制尚不清楚。本课题研究了SLE患者外周血泌乳素（PRL）与调节性B细胞（Breg）的相关性、体外PRL对Breg分化和功能的调控，并通过MRL/lpr狼疮鼠研究抗PRL受体抗体对体内Breg分化和自身抗体产生的影响及变化情况。SLE患者全血、中性粒细胞、单核细胞、B细胞、CD4+T细胞中泌乳素表达水平均升高，且SLE患者PRL作用于Breg，可导致Breg免疫抑制功能受损，进而Breg对效应性B细胞的负向免疫调节作用减弱，可使SLE患者自身抗体产生增加，病情活动加剧。通过MRL/lpr狼疮小鼠模型在体验证上述作用，通过PRL受体中和抗体来治疗MRL/lpr狼疮鼠。观察到：经过治疗的小鼠，其外周血中IL-10、抗ds-DNA抗体等自身抗体水平有所下降；HE染色、PAS染色和免疫荧光显示狼疮小鼠肾小球肿大、新月状、急性肾小球肾炎、节段性纤维蛋白样坏死和肾小球系膜细胞增生等病变明显改善。治疗后，狼疮小鼠脾脏肿大、淋巴结增大情况明显好转，脾细胞总数和T细胞总数明显下降。该研究表明体外PRL作用于Breg，导致Breg免疫抑制功能受损，进而Breg对效应性B细胞的负向免疫调节作用减弱，使SLE患者自身抗体产生增加，病情活动加剧。并在SLE小鼠模型中进一步验证了两者之间的相关性。该研究深入了解PRL对Breg的调节作用及对自身抗体产生的影响，为SLE治疗提供新靶点。