The newly identified population of BM B-1 cells shows many

of the phenotypic characteristics of splenic B-1 cells but is distinct from B-1 cells in the peritoneal cavity, which generate at best very small amounts of IgM. Antibody-secreting spleen and BM B-1 cells are distinct also from terminally differentiated plasma cells generated from antigen-induced conventional B cells, as they express high levels of surface IgM and CD19 and lack expression of CD138. Overall, these data identify populations of non-terminally differentiated B-1 cells in spleen and BM as the most significant producers of natural IgM. A significant proportion of circulating serum antibodies are “natural antibodies”, mainly of the IgM isotype, i.e. antibodies that are produced even in the complete absence of any antigenic stimulation as seen in gnotobiotic animals 1–3. Natural antibodies are often polyreactive and will bind to multiple antigens, with overall low PI3K Inhibitor Library affinities (Kd=10−3 to 10−7 mol/L) 4. Despite their low affinities, these antibodies are important in host defense. Following infection with viral or bacterial pathogens, pre-existing IgM antibodies directly

neutralize and inhibit early pathogen replication, in part via complement GPCR Compound Library cost binding, and thereby increase survival from infection 5–10. Natural IgM also enhances the ensuing pathogen-specific IgG responses 6, 11, possibly via the formation of antibody-antigen complexes for their deposition on follicular DCs 6, 12. Analogous “natural” poly-specific IgA antibodies exist at mucosal surfaces where they might act as a first layer of immune defense 13, 14. Thus, natural antibodies constitute an important component of pre-existing protective immunity. Another function of natural antibodies is N-acetylglucosamine-1-phosphate transferase their involvement in the maintenance of tissue integrity and homeostasis. Natural antibodies facilitate uptake of apoptotic cells via binding to surface antigens such as phosphatidylcholine (PtC), Annexin IV 15, phosphorylcholine

16 and malondialdehyde, the latter a reactive aldehyde degradation product of polyunsaturated lipids 16–19 and xenoantigens 20. This seems to facilitate increased phagocytosis by immature DCs 18, while also limiting tissue inflammation 18. Consistent with this, the genetic ablation of secreted IgM results in increased autoimmunity, with accelerated, pathogenic IgG responses and resulting disease progression 21. Similarly, inappropriate and/or enhanced local secretion of natural IgM secretion and ensuing IgM–self antigen complex formation can result in local activation of the complement cascade and tissue damage, as seen during ischemia-reperfusion injury 15, 22. Natural antibody binding to self-antigens seem to be involved also in atherosclerosis development, where these antibodies contribute to plaque formation via their binding to oxidation-specific epitopes on low-density lipoproteins and cardiolipins 16, 19.