REGULATION DIFFERENCES IN SUBSETS OF ANTIDNA ANTIBODIES

描述(改编自申请人的摘要)：转基因小鼠 抗双链(DS)DNA抗体的R4A Gamma2b重链， 转基因重链可与多种内源轻链配对 产生不同亲和力和细小的抗dsDNA抗体的链 具体细节。我们已经证明了产生高亲和力的B细胞 转基因抗dsDNA抗体受无能和缺失的调节 非自身免疫转基因小鼠，而在NZB/W F1小鼠品系中，高 血清中存在亲和基因编码的抗dsDNA抗体。 从小鼠的脾和骨髓细胞中产生了B细胞杂交瘤。 非自身免疫和自身免疫转基因小鼠。初步结果表明， 有三个亚群的转基因抗dsDNA分泌B细胞。一 亚群分泌一种利用Vk1的高亲和力抗dsDNA抗体 轻链，目标是无能。这些B细胞显示缺乏 等位基因排斥。另一个亚群分泌高亲和力的抗dsDNA 由非Vk1轻链编码的抗体。这些都是删除的目标。 第三个亚群分泌低亲和力的抗dsDNA抗体 监管。这些细胞表现出完整的等位基因排斥。我们想要 通过从骨髓中获得额外的杂交瘤细胞来证实这些结果 来自非自身免疫转基因小鼠的脾细胞。我们也会 我想确定为什么这些B细胞群体受到不同的调控 我们建议找出亲和力和细微的特异性差异 这些子集。我们将看看BCL-2是否可以挽救其中一个或两个子集 分泌高亲和力抗dsDNA抗体的B细胞。我们最近 获得了R4Amu重链转基因小鼠。我们会 比较B细胞分泌转基因IgM的调节 抗dsDNA抗体与分泌转基因IgG2b抗dsDNA的抗体 抗体用于确定信号转导机制是否影响耐受诱导 在这两种同种类型之间存在差异。

DESCRIPTION (Adapted from the Applicant's abstract): In mice transgenic for the R4A gamma2b heavy chain of an anti-double stranded (ds) DNA antibody, the transgenic heavy chain can pair with a variety of endogenous light chains to produce anti-dsDNA antibodies of different affinities and fine specificities. We have demonstrated that B-cells producing high affinity transgenic anti-dsDNA antibodies are regulated by anergy and deletion in non-autoimmune transgenic mice, whereas in the NZB/W F1 mouse strain, high affinity transgene encoded anti-dsDNA antibody is present in the serum. B-cell hybridomas have been generated from spleen and bone marrow cells of non-autoimmune and autoimmune transgenic mice. Initial results suggest that there are three subsets of transgenic anti-dsDNA secreting B-cells. One subset secretes a high affinity anti-dsDNA antibody that utilizes a Vk1 light chain and is targeted for anergy. These B-cells display a lack of allelic exclusion. Another subset secretes high affinity anti-dsDNA antibody encoded by non Vk1 light chains. These are targeted for deletion. A third subset secretes low affinity anti-dsDNA antibodies which escape regulation. These cells display intact allelic exclusion. We would like to confirm these results by obtaining additional hybridomas from bone marrow and spleen cells derived from non autoimmune transgenic mice. We would also like to determine why these populations of B-cells are regulated differently and we propose to identify affinity and fine specificity differences among these subsets. We will see if bcl-2 can rescue one or both of the subsets of B-cells secreting high affinity anti-dsDNA antibody. We recently generated mice transgenic for the R4Amu heavy chain transgene. We would like to compare the regulation of B-cells secreting transgenic IgM anti-dsDNA antibody with those secreting transgenic IgG2b anti-dsDNA antibody to determine if signaling mechanisms affecting tolerance induction differ between these two isotypes.