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.
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