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.
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