Modulation of B Cell Function by Prolactin

描述(申请人提供)：催乳素不仅是一种催乳素，也是一种免疫调节剂，与系统性红斑狼疮(SLE)的发病机制有关。高达30%的SLE患者有高催乳素血症。此外，在狼疮小鼠模型中，高催乳素血症会加速疾病活动，并导致早期死亡。我们已经证明，高催乳素血症可以在非自发自身免疫的小鼠中诱导狼疮样表型。在转致病性抗DNA抗体重链的BALB/c小鼠中，催乳素治疗可激活分泌高亲和力抗DNA抗体的自身反应性B细胞，增加抗DNA血清反应性和肾小球中的IgG沉积。催乳素改变BALB/c小鼠B细胞发育和自身反应性B细胞的异常负选择。然而，同样的催乳素处理并没有破坏转基因相同重链的C57BL/6小鼠的B细胞耐受性。 我们现在建议在细胞和分子水平上进一步研究催乳素对自身反应性B细胞的调节作用。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，这些共刺激因子可以将未成熟的B细胞从负选择中拯救出来，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的小鼠中诱导的表型差异，并确定对催乳素介导的自身免疫的易感性或抵抗力的遗传基础，我们将在BALB/c和C57BL/6小鼠中进行上述所有实验，并分析每个品系的B细胞中由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。通过确定对催乳素敏感或抵抗的遗传因素，这些研究可能有助于识别患有催乳素反应性疾病的SLE患者的子集。

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.