Age-associated B cells expanded in autoimmune mice are memory cells sharing H-CDR3-selected repertoires

Abstract

Age-associated B cells (ABCs) represent a distinct cell population expressing low levels of CD21 (CD21−/low). The Ig repertoire expressed by ABCs in aged mice is diverse and exhibits signs of somatic hypermutation (SHM). A CD21−/low B-cell population is expanded in autoimmune diseases, e.g. systemic lupus erythematosus, as well as in lupus-prone NZB/W mice and in mice lacking a pre-B cell receptor (SLC−/−). However, the nature of the CD21−/low B cells (hereafter ABCs) in autoimmunity is not well understood. Here we show that in young SLC−/− mice, the vast majority of the ABCs express memory B-cell (MBC) markers in contrast to wild-type controls. A similar population is present in lupus-prone MRL mice before and at disease onset. In SLC−/− mice, a majority of the ABCs are IgM+, their VH genes have undergone SHM, show clonal diversification and clonal restriction at the H-CDR3 level. ABC hybridomas, established from SLC−/− mice, secrete typical lupus autoantibodies, e.g. anti-Smith antigen, and some of those that bind to DNA comprise a H-CDR3 that is identical to previously described IgM anti-DNA antibodies from lupus-prone mice. Together, these results reveal that ABCs in autoimmune mice are comprised of autoreactive MBCs expressing highly restricted H-CDR3 repertoires.