Abstract
Natural antibody is constitutively present in the serum of all mammals. This unique IgM plays an important role in the clearance of cellular debris, the early control of viral and bacterial expansion, and the initiation of T-dependent humoral responses. Despite decades of study, the origins of natural antibody have not been precisely defined. Transfer experiments have shown a close correlation between peritoneal cells, including B1a cells, and natural antibody, but peritoneal B1 cells do not secrete adequate amounts of IgM to support the levels found in mouse serum. Here, we show that a discrete population of IgM plasmacytes in the bone marrow produces all serum IgM in resting mice. These plasmacytes originate from cells in the peritoneal cavity, but not from B1a B cells, and transfer of these progenitors completely restores serum IgM and the specific compartment of bone marrow plasmacytes in Rag1 deficient mice. This plasmacyte compartment contains a substantial fraction of non-dividing, long lived cells that do not occupy the IgG plasmacyte survival niche in the bone marrow but instead depend on IL-5. Genetic analysis of these IgM plasmacytes reveals an unmutated, clonally diverse population strongly enriched for VH11 rearrangements. We propose that these natural IgM plasmacytes represent an “innate B-cell” population descended from yolk sac progenitors, and that natural IgM plasmacytes are not the progeny of B1 B cells but instead share an earlier common ancestor.
