IGM POLYMERIZATION AND J CHAIN EXPRESSION

IGM 聚合和 J 链表达

• 批准号: 6044955
• 负责人: RONALD B CORLEY
• 金额: $ 29.86万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-03-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6044955
• 关键词: B lymphocyte; T lymphocyte; autoimmune disorder; disease /disorder model; gene expression; gene mutation; genetically modified animals; humoral immunity; immunoglobulin M; immunoglobulin genes; laboratory mouse; oxidation reduction reaction; polymerization; tissue /cell culture

IgM antibodies play important roles in protection and in adaptive immune responses. Normally, IgM is secreted as pentamers but other forms, including monomers, are sometimes produced. These are prevalent in various diseases, including chronic infections and certain autoimmune diseases. The overall goals of the proposed experiments are to help understand the role that IgM plays in immunity to pathogens and to determine if IgM monomers are beneficial or deleterious to the host. To accomplish this, 1) we will determine the effect of monomeric IgM on primary and secondary immune responses to specific antigens using a transgenic mouse model in which a mutant secretory mu chain (musC575A), which does not polymerize normally, has been expressed. We will determine the consequences, either positive or negative, of the expression of monomeric IgM in the presence and absence of pentameric IgM. 2) We will produce mice in which the endogenous secretory mu gene contains a targeted mutation such that the secretory IgM produced is non-polymeric. These mice will be evaluated for their ability to generate primary and secondary immune responses, and to clear pathogens. The repertoire of natural antibodies with specificities for particular antigens on pathogens will be compared with that of normal and secretory IgM deficient mice. 3) We will determine if the presence of high concentrations of monomeric IgM (also called low molecular weight, LMW IgM) leads to systemic autoimmune disease, either alone or in combination with wildtype IgM or antibodies of other isotypes. We will determine the role of T cells in this process. 4) We will determine if LMW IgM is an accelerator or autoimmune disease in susceptible mice. We will also determine if the presence of genes that predispose toward autoimmunity leads to increased production of LMW IgM. Finally, 5) we will determine if the redox state of B cells is altered in mice undergoing chronic infections, and/or in B cells producing LMW IgM compared with that of normal B cells. We will test the hypothesis that these changes lead to alterations in the quality control standards that regulate IgM assembly and secretion, resulting in the increased production of monomeric IgM. Together, the results of these experiments will provide novel insights into the role of IgM in natural immunity and in disease, and will also shed new light on the pathogenic effects of monomeric IgM.

IgM抗体在保护和适应性免疫反应中起重要作用。 通常，IgM被分泌为五聚物，但有时会产生包括单体在内的其他形式。 这些在各种疾病中都普遍存在，包括慢性感染和某些自身免疫性疾病。 拟议的实验的总体目标是帮助了解IGM对病原体免疫的作用，并确定IGM单体是否对宿主有益或有害。 为此，1）我们将使用转基因小鼠模型（MUSC575A）（MUSC575A）确定单体IgM对特定抗原的原发性和继发性免疫反应的影响，在该模型中，已经表达了未正常聚合的突变分泌MU链（MUSC575A）。 我们将在存在和不存在五聚体IgM的情况下确定单体IgM表达的后果。 2）我们将产生内源性分泌的MU基因包含靶向突变的小鼠，使得产生的分泌IgM是非聚合物的。 这些小鼠将评估它们产生原发性和次级免疫反应并清除病原体的能力。 将病原体特异性的天然抗体曲目与正常和分泌的IgM缺乏小鼠进行比较。 3）我们将确定高浓度的单体IgM（也称为低分子量，LMW IgM）是否会导致全身性自身免疫性疾病，无论是单独还是与其他同型的野生型IgM或抗体结合使用。 我们将确定T细胞在此过程中的作用。 4）我们将确定LMW IgM是易感小鼠的加速器还是自身免疫性疾病。 我们还将确定易于自身免疫性的基因的存在是否导致LMW IGM的产生增加。 最后，5）我们将确定与正常B细胞​​相比，患有慢性感染的小鼠和/或产生LMW IgM的B细胞中B细胞的氧化还原状态是​​否改变。 我们将检验以下假设：这些变化会导致调节IgM组装和分泌的质量控制标准的改变，从而导致单体IGM的产生增加。总之，这些实验的结果将为IgM在自然免疫和疾病中的作用提供新的见解，并且还将为单体IGM的致病作用提供新的启示。