IGM POLYMERIZATION AND J CHAIN EXPRESSION

IGM 聚合和 J 链表达

• 批准号: 3146228
• 负责人: RONALD B CORLEY
• 金额: $ 12.98万
• 依托单位: DUKE UNIVERSITY
• 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 1994-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3146228
• 关键词: B lymphocyte; antibody formation; binding proteins; blood disorder; cell differentiation; complement; cryoglobulins; disease /disorder model; gene expression; helper T lymphocyte; hemolysis; human tissue; immunoelectron microscopy; immunoglobulin M; immunoglobulin genes; interleukin 2; interleukin 5; laboratory mouse; neoplastic cell culture for noncancer research; polymerization; protein structure function; rheumatoid arthritis; western blottings

The immunoglobulin IgM is the first isotype made in immune responses and is important as a primary defense against bacteria and other microorganisms in the blood and in secretions. Secreted IgM is usually thought of as a pentameric molecule assembled from five mu2L2 monomers containing a single joining (J) chain. J chain was once believed to be required for the assembly and secretion of IgM from stimulated B cells. Recent evidence indicates that J chain is not necessary for either assembly or secretion of polymeric IgM; however, the presence of J chain may affect the final structure of the secreted polymer and, therefore, its function. Two functional forms of polymeric IgM can be secreted by B cells, the canonical pentameric form, often associated with J chain, and a hexameric form, lacking J chain. Hexameric IgM is unexpectedly efficient in complement mediated cytolysis, and has a specific activity twenty times that of the pentameric IgM. Pentameric IgM may have other primary functions; for example, the presence of J chain may be required for the interaction of polymeric IgM with secretory component. We will examine the biology of the regulation of IgM polymer formation, the role that hexameric and pentameric IgM play in the immune response, and the role that J chain plays in IgM polymerization. In particular, we will determine whether the distribution of hexameric and pentameric IgM secreted by B cells differs in T-dependent and T-independent immune responses, and if this difference correlates with the abundance of J chain produced. We will determine the basis for the higher specific activity of IgM hexamers in complement-mediated assays, by asking if this difference is due to a higher affinity of C1q for hexameric IgM. We will isolate and characterize the J chain binding protein from antibody non-secreting B cells expressing high levels of J chain protein, and follow the expression of this protein during B cell development. Finally, we will determine if the presence of absence of IgM hexamers is associated with various defects in immune status, concentrating on certain autoimmune and immunodeficiency diseases. These studies should provide novel information concerning a previously unappreciated polymeric form of IgM which may have important functions in normal and pathologic immune reactions, and the role that J chain plays in determining the predominant polymeric form of secreted IgM.

免疫球蛋白IgM是免疫反应中的第一个同种型，IS 重要的是针对细菌和其他微生物的主要防御 血液和分泌物。 分泌的IgM通常被认为是 从五个MU2L2单体组装的五聚体分子，该单体包含一个 加入（J）链。 曾经认为J链需要 来自刺激的B细胞的IgM组装和分泌。 最近的证据 表明J链对于组装或分泌不需要 聚合物IgM;但是，J链的存在可能会影响最终 分泌聚合物的结构，因此是其功能。 二 聚合物IgM的功能形式可以由B细胞分泌，即规范 五聚体形式，通常与J链和六聚体形式相关联， 缺少J链。 六聚体IgM意外有效地补充 介导的细胞解，并且具有特定活性二十倍 五聚体Igm。 五聚体IgM可能具有其他主要功能。为了 例如，相互作用可能需要J链的存在 分泌组件的聚合物IgM。 我们将研究 IgM聚合物形成的调节，六聚体和五聚体的作用 IgM在免疫反应中发挥作用，以及J链在IGM中的作用 聚合。 特别是，我们将确定分布是否 B细胞分泌的六聚体和五聚体IgM在T依赖性方面有所不同 和T非依赖性免疫反应，如果此差异与 产生的大量J链。 我们将确定 IgM六聚体在补体介导的测定中的较高特异性活性， 询问这种差异是否是由于C1Q对六聚体的亲和力较高 Igm。 我们将隔离并表征J链结合蛋白 抗体非分泌B细胞表达高水平的J链蛋白， 并在B细胞发育过程中遵循该蛋白的表达。 最后，我们将确定不存在IgM六聚体是否存在 与免疫状态的各种缺陷有关，集中于某些 自身免疫和免疫缺陷疾病。 这些研究应提供 有关先前未批准的聚合形式的新信息 IgM可能在正常和病理免疫中具有重要功能 反应以及J链在确定主要的作用 分泌IgM的聚合物形式。