IGM POLYMERIZATION AND J CHAIN EXPRESSION

IGM 聚合和 J 链表达

• 批准号: 2607794
• 负责人: RONALD B CORLEY
• 金额: $ 24.91万
• 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 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2607794
• 关键词: B lymphocyte; antibody formation; disease /disorder model; enzyme linked immunosorbent assay; gene expression; immunodeficiency; immunoglobulin A; immunoglobulin M; immunoglobulin genes; laboratory mouse; plasma cells; polymerization; protein structure function; tissue /cell culture

IgM constitutes a major component of the natural antibody repertoire and is the first antibody secreted in primary immune responses. IgM is efficient in activating complement and can bind to the polymeric Ig receptor to be transcytosed into exocrine secretions. Both of these functions are properties of the polymeric form of IgM, and thus the processes that control oligomerization are crucial to IgM function. IgM is secreted in two functional polymeric forms, pentamers and hexamers. Unlike pentamers, hexamers do not contain J chain. Hexamers are more than an order of magnitude more efficient than pentamers in activating the classical complement pathway. In this studies, several aspects of the assembly, secretion, and function of IgM will be examined. 1) The abundance of hexameric and pentameric IgM secreted by B cells in antigen- specific immune responses will be determined. We will ask if the abundance of these different polymers can be modulated, and what the consequences of such modulation might be. The role of IgM hexamers and pentamers in protecting a host against challenge by infectious agents will be investigated. 2) The mechanism(s) of IgM polymer assembly and the subcellular compartment(s) in which polymerization occurs will be determined, and the effect that J chain abundance and other factors have on IgM oligomerization will be characterized. We will examine the mechanism by which IgM monomers escape retention and are secreted by plasma cells. 3) The developmental control of IgM assembly in cells of the B lineage will be evaluated. We will determine if pre-B and B cells are capable of polymerizing IgM intracellularly. We will examine the mechanism by which the secretory IgM is retained in B cells, and determine if this mechanism is similar to that which mediates retention of unassembled secretory IgM in plasma cells. 4) The mechanism by which J chain regulates the assembly process will be resolved by determining whether J chain is added by a regulated or stochastic process to assembling polymers. 5) We will determine the function of J chain by producing mutant mice deficient in this protein, and assessing the immune status of these mice. The presence of IgM and lgA in blood and secretions will be determined, and the type of polymers present in natural and immune IgM will be evaluated. The mutant mice will be followed for the spontaneous development of autoimmunity. Taken together, these studies will help clarify the biologic functions of IgM in normal and pathologic immune responses, and determine how the assembly and secretion of different forms of polymeric and monomeric IgM are regulated. They will make significant contributions to our understanding of the process of assembly and transport of oligomeric proteins and the "quality control" mechanisms by which polymerization and protein trafficking are regulated.

IgM构成了天然抗体库的主要组成部分， 是初级免疫反应中分泌的第一种抗体。 Igm是 有效激活补体，可以与聚合物Ig结合 受体被转换为外分泌分泌物。这两个 函数是IgM聚合物形式的特性，因此 控制寡聚的过程对于IgM功能至关重要。 Igm是 分泌有两种功能性聚合物形式，五聚体和六聚体。与众不同 五聚体，六聚体不包含J链。六聚体不仅仅是 比五聚会在激活中的数量级要高。 古典补体途径。在这项研究中， 将检查IgM的组装，分泌和功能。 1） B细胞在抗原中分泌的六聚体和五聚体IgM的丰度 将确定特定的免疫反应。我们会问是否丰富 可以调制这些不同的聚合物，以及 这种调制可能是。 IgM Hexamers和Pentamers在 保护主人免受传染性特工的挑战将是 调查。 2）IgM聚合物组件的机制和 聚合发生的亚细胞室将是 确定，J链丰度和其他因素具有 在IgM上，将表征寡聚。我们将检查 IgM单体逃脱保留并分泌的机制 浆细胞。 3）IgM组装在细胞中的发育控制 B谱系将进行评估。我们将确定前B和B细胞是否是 能够在细胞内聚合IgM。我们将检查机制 通过将分泌的IgM保留在B细胞中，并确定是否 机制类似于介导未组装的保留率的机制 浆细胞中的分泌IgM。 4）J链调节的机制 组装过程将通过确定J链是否为 由调节或随机过程添加到组装聚合物中。 5）我们 将通过产生不足的突变小鼠来确定J链的功能 在该蛋白质中，并评估这些小鼠的免疫状态。这 将确定血液和分泌物中IgM和LGA的存在，并且 将评估天然和免疫IgM中存在的聚合物类型。 将遵循突变小鼠的自发发展 自身免疫性。综上所述，这些研究将有助于阐明生物学 IgM在正常和病理免疫反应中的功能，并确定 不同形式的聚合物的组装和分泌如何 单体IgM受调节。他们将为 我们对寡聚组装和运输过程的理解 蛋白质和聚合和“质量控制”机制 蛋白质运输受到调节。