Tolerance in Polyclonal and Oligoclonal Immune Systems

等位基因和同种型（单体型）排除确定每个B细胞仅表达一种免疫球蛋白 重链和轻链配对，因此表现出单一特异性。尽管如此，B细胞表达 两条重链或两条轻链（包括单倍型）存在于健康个体和野生型小鼠中， 频率估计约为B细胞群的2%。免疫球蛋白转基因分析 小鼠已经证明，自身反应性B细胞可以绕过中枢耐受机制， 转化为成熟的B细胞。因此，这些细胞是单倍型包括 并共表达自身反应性和非自身反应性抗原受体。因为大多数 初级免疫球蛋白基因重排已显示产生自身反应特异性，我们 提出野生型小鼠中大多数包含单倍型的B细胞是自身反应性的，尽管 这些细胞在小鼠或人类中尚未被研究。本提案的目的是了解 小鼠中包含单体型的B细胞的性质和调节，并确定这些细胞是否与 自身免疫为了实现这一点，我们概述了三个具体的目标，将表征单倍型，包括 表达野生型抗体库的小鼠中的B细胞，确定这些B细胞是否 有助于自身免疫易感小鼠的自身免疫过程，并了解单倍型包括 B细胞受生理调节。包括单倍型的自身反应性B细胞将在以下两种情况下进行评价： 在体外和体内使用各种小鼠模型和各种技术，包括产生和 B细胞杂交瘤的表征和细胞过继转移的使用。因为自身免疫是一种 重大健康问题，有多种，迄今为止，知之甚少的病因学基础，分子和 需要对包括单倍型的B淋巴细胞进行细胞分析。特别是，我们预测单倍型包括 B细胞是独特的，因为它们表达的自身抗体具有表现出高亲合力的潜力 与自身抗原相互作用并产生同时结合外源抗原和自身抗原抗体。

Allelic and isotypic (haplotype) exclusion establishes that each B cell expresses only one immunoglobulin heavy and light chain pair and, consequently, exhibits a single specificity. Nevertheless, B cells expressing either two heavy or two light chains (haplotype-included) exist in healthy individuals and wild-type mice at a frequency estimated to be approximately 2% of the B cell population. Analyses of immunoglobulin transgenic mice have demonstrated that autoreactive B cells can bypass mechanisms of central tolerance and develop into mature B cells by co-expressing non-autoreactive antigen receptors. Thus, these cells are haplotypeincluded and co-express an autoreactive and non-autoreactive antigen receptor. Because the majority of primary immunoglobulin gene rearrangements have been shown to generate an autoreactive specificity, we propose that most haplotype-included B cells in wild-type mice are autoreactive although the specificity of these cells in mice or humans has not been investigated. The goal of this proposal is to understand the nature and regulation of haplotype-included B cells in mice and to determine if these cells are associated with autoimmunity. To accomplish this we outline three Specific Aims that will characterize haplotypeincluded B cells in mice expressing a wild-type antibody repertoire, determine whether these B cells contribute to the autoimmune process of autoimmune-prone mice, and to understand how haplotypeincluded B cells are physiologically regulated. Haplotype-included autoreactive B cells will be evaluated both in vitro and in vivo using various mouse models and a variety of techniques that include the generation and characterization of B cell hybridomas and the use of cell adoptive transfer. Because autoimmunity is a significant health issue that has multiple, as of yet, poorly understood etiological bases, a molecular and cellular analysis of haplotype-included B lymphocytes is warranted. In particular, we predict haplotypeincluded B cells to be unique in that the autoantibody they express have the potential to exhibit a high avidity interaction with autoantigen and produce antibodies that simultaneously bind foreign as well as self-antigens.