MECHANISMS THAT REGULATE B CELL TOLERANCE

描述：这些机制被认为对 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，以及 克隆性无能的诱导。这个实验室最近证明了无能B 细胞表面大量表达CD5，这是一种通常在T细胞上发现的分子 细胞和B-1细胞的子集。鸡蛋溶菌酶(HEL)的选育 CD5缺失背景上的B细胞无能转基因模型导致 体内自发性B细胞耐受性丧失。这方面的证据包括 CD5-/-小鼠血清中抗HEL-IgM抗体水平升高 转基因HEL特异性B细胞受体(BCR)和可溶性溶菌酶。 缺乏CD5的无能B细胞也显示出增强的增殖反应。 静息和跟随IgM后体外培养和升高细胞内钙离子水平 交联剂。这些数据支持CD5负性调控的假设 无能B细胞免疫球蛋白受体信号转导及其抑制功能 自身免疫B细胞反应。额外的初步实验表明， CD5在调节抗原初始B细胞中的B细胞受体信号中的作用。另外， 我们已经开始描述CD5-/-HEL-Ig/Shel小鼠的特征，这些小鼠发展成一种深刻的 失去忍耐力。在这些小鼠中，我们假设自身抗体的分泌 有效地滴定自身抗原，从而逆转无能B细胞 表型。这里描述的实验将集中在这些活体模型上， 并被设计用来进一步表征体内耐受的性质 在缺乏CD5的HEL-Ig/SHEL双转基因小鼠中观察到的缺陷 全面评估血清水平最高的CD5-/-Ig/SHEL小鼠 抗体。接下来，CD5基因敲除等位基因将被培育到易患狼疮的Sle2上。 同源和sle1/sle3双基因小鼠确定CD5是否缺乏 将增强这些系统性红斑狼疮模型的自身免疫力 (SLE)。最后，CD5对受体编辑和诱导进入 将对B-1隔间进行探索。总之，提出的实验应该是 显著促进了对CD5在调节中所起作用的理解 免疫反应。此外，这些实验可能会提供 对导致自身免疫的机制的有趣的新见解， 抗体介导型患者的潜在治疗意义 自身免疫性疾病如系统性红斑狼疮。

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.