Natural IgM is produced by B1a cell-derived bone marrow plasma cells that do not share a survival niche with IgG AFC.

Abstract Natural antibody makes up the majority of serum IgM and provides protection against both infection and autoimmunity. The B1 lineage is required for natural IgM, but the location and identity of the cells that secrete natural IgM are uncertain. B1-8i VHDJH knock-in mice lack virtually all B1a cells, but have normal B2 cell development and support robust splenic B2 populations. The loss of B1a cells is associated with a 10-fold reduction in serum IgM, whereas serum IgG levels are normal. We examined B1-8i mice and found a 10-fold reduction in the number of IgM AFC in the BM, while BM IgG AFC populations were normal. As B1 cells themselves do not secrete substantial amounts of antibody, our observation indicates that the BM is the major source of natural serum IgM, and that BM IgM plasmacytes require the presence of B1a cells. By FACS and histology, we determined that IgM-secreting cells in BM are CD5- CD138high and appear as differentiated plasma cells, not small B1a cells. Examination of BM revealed that while cytoplasmic IgG+ cells preferentially co-localize with eosinophils, cytoplasmic IgM+ cells do not. This localization correlated with an enhanced survival of IgG AFC, but not IgM AFC, from sorted CD138high BM cells cultured with IL-6. We propose that B1a cell-derived BM plasma cells produce natural serum IgM, and that these cells occupy a survival niche distinct from IgG AFC.