Age-Related Changes in B1a Derived IgM Repertoire Affect their Atheroprotective Function.

Perivascular adipose tissue (PVAT) harbors immune cells and locally regulates atherosclerosis. The B1a cells present in PVAT secrete IgM in young mice. This IgM has been shown to confer atheroprotection by binding to ox-LDL and other oxidation specific epitopes (OSEs). The impact of aging on B1a-B cells in PVAT, the PVAT B-1a cell IgM repertoire and how aged B-1a cells affect atherosclerosis has not been explored. We sequenced the V-D-J gene segments of IgM in aged B-1a cells from hyperlipemic mice with atherosclerosis. Results demonstrated greater N-additions as well as changes in the usage of the VDJ gene regions in PVAT B1a cells when compared to the B1a cells residing in peritoneal cavity: the primary niche of B1a cells where they self-renew. Further, our previous results have shown similar changes in IgM repertoire in secondary antibody producing sites like spleen and bone marrow. ELISA demonstrated that these changes in IgM repertoire during aging reflect in the systemic IgM pool. The ratio of atheroprotective IgM (IgM to OSEs) to total IgM was significantly decreased with age when 10-, 50- and 100-week-old ApoE−/− mice plasma IgM levels were compared. Further, when B1a cells from young and aged CD45.2 Apoe−/− mice were adoptively transferred to PCSK9 injected CD45.1 STEM mice, those that received B1a from young mice had lower atherosclerosis compared to those that received B1a cells from aged mice. With these results we conclude that with age B1a derived IgM repertoire substantially changes to be less atheroprotective. "Supported by grants from NIH (RO1 HL107490 and RO1 HL136098 (CM); Ro1AI154539 (NH)); and AHA (award number 18CDA34110392 (PS))."