Production of IgM Hexamers by Normal and Autoimmune B Cells: Implications for the Physiologic Role of Hexameric IgM

Secreted IgM is predominantly found as pentameric molecules, but IgM can also be secreted as hexamers by B cell lines. Murine hexamers activate the complement cascade more efficiently than pentamers, but the physiologic significance of hexameric IgM remains unknown. Here, we report that IgM hexamers and pentamers are cleared from the circulation with similar kinetics, suggesting that the predominance of pentameric IgM in vivo reflects the regulation of polymer assembly and secretion in responding B cells. Normal IgM-secreting B cells, particularly those from the peritoneal cavity, are capable of secreting abundant hexameric IgM in vitro. The disparity between the ability of B cells to secrete IgM hexamers in vitro and the paucity of this polymer in vivo suggest that IgM hexamers might be deleterious. In support of this, we demonstrate that the autoantibodies from a number of patients with cold agglutinin (CA) disease include both IgM hexamers and pentamers. The CA IgM hexamers lyse human erythrocytes in the presence of human complement more efficiently than CA IgM pentamers, suggesting a potential role for hexameric IgM in the pathogenesis of this autoimmune syndrome.