Modulation of B Cell Function by Prolactin

性状（申请人提供）：催乳素不仅是一种催乳激素，而且是一种免疫调节剂，与系统性红斑狼疮（SLE）的发病机制有关。高达30%的SLE患者有高泌乳素血症。此外，高催乳素血症加速疾病活动，并导致狼疮鼠模型的早期死亡。我们已经证明，高泌乳素血症可以诱导狼疮样表型在非自发性自身免疫小鼠。在致病性抗DNA抗体重链转基因的BALB/c小鼠中，用催乳素处理导致分泌高亲和力抗DNA抗体的自身反应性B细胞活化，增加抗DNA血清反应性和肾小球中IgG沉积。催乳素改变B/c小鼠B细胞发育和自身反应性B细胞负选择失调然而，相同的催乳素治疗没有打破B细胞耐受性的C57 BL/6小鼠转基因相同的重链。 我们现在建议在细胞和分子水平上进一步研究催乳素介导的自身反应性B细胞的调节。我们的目的是描述催乳素改变自身反应性B细胞负选择的机制，并确定催乳素使B细胞活化敏感的机制。我们的假设是，催乳素增强了B细胞对共刺激因子的反应，共刺激因子可以从负选择中拯救未成熟的B细胞，并可以激活成熟的滤泡B细胞。 为了了解催乳素在不同遗传背景小鼠中诱导的表型差异，并确定对催乳素介导的自身免疫易感性或抗性的遗传基础，我们将在BALB B/c和C57 BL/6小鼠中进行上述所有实验，并分析每种品系B细胞中受催乳素上调或下调的基因。 这些研究将进一步加深我们对催乳素调节B细胞库的机制的理解，并可能有助于为SLE患者开发新的靶向治疗方法。通过确定催乳素敏感性或抵抗性的遗传因素，这些研究可能有助于确定一个SLE患者的催乳素反应性疾病的子集。

DESCRIPTION (provided by applicant): Prolactin is not only a lactogenic hormone, but also an imrnunomodulator, implicated in the pathogenesis of systemic lupus erythematosus (SLE). Up to 30% of patients with SLE have hyperprolactinemia. In addition, hyperprolactinemia accelerates disease activity and causes early mortality in murine models of lupus. We have demonstrated that hyperprolactinemia can induce a lupus-like phenotype in non-spontaneously autoimmune mice. In BALB/c mice transgenic for the heavy chain of the pathogenic anti-DNA antibody, treatment with prolactin leads activation of autoreactive B cells that secrete high affinity anti-DNA antibodies, increased anti-DNA serum reactivity and IgG deposition in the glomeruli. Prolactin alters B cell development and dysregulated negative selection of autoreactive B cells in BALB/c mice. However, the same treatment with prolactin did not break B cell tolerance in C57BL/6 mice transgenic for the same heavy chain. We are now proposing to further investigate prolactin-mediated modulation of autoreactive B cells at the cellular and molecular level. Our aims are to characterize the mechanisms by which prolactin alters negative selection of autoreactive B cells and to determine mechanisms by which prolactin sensitizes B cells for activation. It is our hypothesis that prolactin enhances the B cell response to costimulatory factors that can rescue immature B cells from negative selection and can activate mature, follicular B cells. To understand the phenotypic differences induced by prolactin in mice with different genetic backgrounds and to determine the genetic basis for susceptibility or resistance to prolactin-mediated autoimmunity, we will perform all of the experiments above in both BALB/c and C57BL/6 mice and will analyze genes that are up- or down-regulated by prolactin in B cells of each strain. These studies will further our understanding of the mechanisms by which prolactin modulates the B cell repertoire, and may help develop novel targeted therapeutic approaches for patients with SLE. By determining the genetic factors that underlie either sensitivity or resistance to prolactin, these studies may help identify a subset of SLE patients who have prolactin responsive disease.