Modulation of B Cell Function by Prolactin

描述（由申请人提供）：催乳素不仅是一种致乳激素，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患者有高泌乳素血症。此外，在狼疮小鼠模型中，高泌乳素血症加速疾病活动并导致早期死亡。我们已经证明，高催乳素血症可以诱导狼疮样表型在非自发自身免疫小鼠。在转基因致病性抗dna抗体重链的BALB/c小鼠中，催乳素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IgG的沉积。泌乳素改变BALB/c小鼠B细胞发育和自身反应性B细胞的失调负选择。然而，同样的催乳素处理并没有破坏转基因C57BL/6小鼠对相同重链的B细胞耐受性。

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.