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

• Published in: European journal of immunology Vol. 48; no. 3; pp. 509 - 521
• Main Authors: Aranburu, Alaitz, Höök, Nina, Gerasimcik, Natalija, Corleis, Bjorn, Ren, Weicheng, Camponeschi, Alessandro, Carlsten, Hans, Grimsholm, Ola, Mårtensson, Inga‐Lill
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.03.2018
• Subjects: Autoantibodies; Autoimmune diseases; Autoimmunity; CD21−/low B cells; Complementarity-determining region 3; Deoxyribonucleic acid; DNA; H‐CDR3 repertoire; Immunoglobulin M; Lupus; Lymphocytes B; Memory B cells; Memory cells; SLE animal model; Somatic hypermutation; Systemic lupus erythematosus; T cell receptors; Autoimmunity; CD21−/low B cells; SLE animal model; H-CDR3 repertoire; Memory B cells
• ISSN: 0014-2980; 1521-4141; 1521-4141
• DOI: 10.1002/eji.201747127

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. Age‐associated B cells (ABCs; CD21−/low) accumulate with age in both mice and humans, and are expanded in autoimmunity, e.g. SLE. In an autoimmune mouse model, the ABCs express a restricted H‐CDR3 repertoire and consist mainly of autoreactive IgM+ memory B cells recognising nuclear antigens, e.g. DNA, Sm antigen.