MECHANISMS THAT REGULATE B CELL TOLERANCE

描述：机制，这被认为是重要的， 维持B细胞耐受性，包括删除自身反应细胞， 在骨髓和外周，免疫球蛋白受体编辑， 诱导克隆无反应性。这个实验室最近表明，无反应性B 细胞表达显著的表面水平的CD 5，一种通常在T细胞上发现的分子 细胞和B-1细胞亚群。鸡蛋溶菌酶的选育 B细胞无反应性的转基因模型在CD 5无效背景下导致了 体内B细胞耐受性的自发丧失。证据包括 CD 5-/-小鼠血清中抗HEL IgM抗体水平升高 对于HEL-specific B细胞受体（BCR）和可溶性溶菌酶都是转基因的。 缺乏CD 5的“无反应性”B细胞也表现出增强的增殖反应， 体外和静息时和IgM后升高细胞内Ca++水平 交联这些数据支持了CD 5负调节 免疫球蛋白受体在无反应性B细胞中的信号传导和功能， 自身免疫B细胞应答。额外的初步实验表明， CD 5在抗原初始B细胞中调节B细胞受体信号传导。还有， 我们已经开始表征CD 5-/- HEL-Ig/sHEL小鼠， 失去宽容。在这些小鼠中，我们假设自身抗体分泌 有效地拮抗自身抗原，导致无反应性B细胞逆转 表型本文描述的实验将集中在这些体内模型中， 并被设计用于进一步表征体内耐受性的性质 在缺乏CD 5的HEL-Ig/sHEL双转基因小鼠中观察到的缺陷， 充分评价表现出极高血清抗体水平的CD 5-/-IG/sHEL小鼠 抗体的接下来，将CD 5敲除等位基因培育到狼疮倾向sle 2上， 同源和sle 1/sle 3双同源小鼠，以确定是否CD 5缺陷 将增强这些系统性红斑狼疮模型中的自身免疫 （SLE）。最后，研究了CD 5对受体编辑和诱导进入细胞的影响。 将探索B-1隔室。总之，所提出的实验应 显著地推进了对CD 5在调节 免疫反应。此外，这些实验可能会提供 有趣的新见解的机制，导致自身免疫， 对抗体介导的 自身免疫性疾病，如SLE。

DESCRIPTION: The mechanisms, which are thought to be important for the maintenance of B cell tolerance, include deletion of self-reactive cells both in the bone marrow and the periphery, immunoglobulin receptor editing, and the induction of clonal anergy. This laboratory has recently shown that anergic B cells express significant surface levels of CD5, a molecule normally found on T cells and a subset of B-1 cells. Breeding of the en egg lysozyme (HEL) transgenic model for B cell anergy onto the CD5 null background resulted in a spontaneous loss of B cell tolerance in vivo. Evidence for this included elevated levels of anti-HEL IgM antibodies in the serum of CD5-/- mice transgenic for both a HEL-specific B cell receptor (BCR) and soluble lysozyme. "Anergic" B cells lacking CD5 also showed enhanced proliferative responses in vitro and elevate intracellular Ca++ levels at rest and following IgM crosslinking. These data sup ort the hypothesis that CD5 negatively regulates immunoglobulin receptor signaling in anergic B cells and functions to inhibit autoimmune B cell responses. Additional preliminary experiments suggest a role for CD5 in regulating B cell receptor signaling in antigen naive B cells. Also, we have begun to characterize CD5-/- HEL-Ig/sHEL mice that develop a profound loss of tolerance. In these mice we hypothesize that autoantibody secretion effectively titrates self-antigen leading to a reversal of the anergic B cell phenotype. The experiments described here will focus n these in vivo models, and are designed to further characterize the nature of he in vivo tolerance defects observed in HEL-Ig/sHEL double transgenic mice lacking CD5, and to fully evaluate CD5-/-Ig/sHEL mice that exhibit the very highest levels of serum antibody. Next the CD5 knockout alleles will be bred onto lupus-prone sle2 congenic and sle1/sle3 bi-congenic mice to determine whether CD5 deficiency will enhance autoimmunity in these models for systemic lupus erythematosus (SLE). Finally, the influence of CD5 on receptor editing and induction into the B-1 compartment will be explored. Together, the experiments proposed should significantly advance understanding of the role that CD5 plays in regulating immune responses. In addition, these experiments are likely to provide interesting new insights into the mechanisms that lead to autoimmunity, with potential therapeutic implications for patients with antibody-mediated autoimmune diseases such as SLE.