MECHANISMS THAT REGULATE B CELL TOLERANCE

调节 B 细胞耐受性的机制

• 批准号: 6626346
• 负责人: TIMOTHY W. BEHRENS
• 金额: $ 29.52万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-01-15 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6626346
• 关键词: B cell receptor; B lymphocyte; CD5 molecule; T cell receptor; T lymphocyte; autoantibody; autoimmunity; calcium flux; cell proliferation; gene targeting; genetically modified animals; immune tolerance /unresponsiveness; interleukin 7; laboratory mouse; passive immunization; systemic lupus erythematosus

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.

描述：被认为对 维持B细胞耐受性，包括删除自反应性细胞 在骨髓和外围，免疫球蛋白受体编辑，以及 诱导克隆语音。该实验室最近表明厌食症B 细胞表达CD5的显着表面水平，这是通常在T上发现的分子 细胞和B-1细胞的子集。 EN卵溶菌酶的繁殖（HEL） B细胞消除CD5无效背景的转基因模型导致A 体内B细胞耐受性的自发丧失。包括此的证据 CD5 - / - 小鼠血清中抗螺旋IgM抗体的水平升高 HEL特异性B细胞受体（BCR）和可溶性溶菌酶的转基因。 缺乏CD5的“ Anergic” B细胞也显示出增强的反应 体外和升高静止和之后的细胞内Ca ++水平 交联。这些数据提出了CD5负调节的假设 厌食B细胞中的免疫球蛋白受体信号传导，并功能抑制 自身免疫性B细胞反应。其他初步实验表明起作用 用于调节抗原幼稚B细胞中B细胞受体信号传导的CD5。还， 我们已经开始表征CD5 - / - Hel-ig/shel鼠标，这些小鼠会产生深刻的 容忍度的丧失。在这些老鼠中，我们假设自身抗体分泌 有效地滴定自我抗原导致厌食B细胞的逆转 表型。这里描述的实验将集中在这些体内模型， 旨在进一步表征他体内耐受性的性质 在缺乏CD5的Hel-Ig/Shel双重转基因小鼠中观察到的缺陷，至 完全评估表现出最高水平血清的CD5 - / - IG/SHEL小鼠 抗体。接下来，CD5淘汰等位基因将繁殖到可容易狼疮的SLE2上 先天性和SLE1/SLE3双重小鼠，以确定CD5缺乏症是否缺乏 这些模型的全身性红斑狼疮将增强自身免疫性 （SLE）。最后，CD5对受体编辑和诱导的影响 将探索B-1隔室。共同提出的实验应 显着提高了CD5在调节中的作用的理解 免疫反应。此外，这些实验可能会提供 有趣的新见解对导致自身免疫的机制，并带有 对抗体介导的患者的潜在治疗意义 自身免疫性疾病，例如SLE。