Complement receptor 2 as a novel therapeutic target to suppress germinal center-derived autoantibody production in a SLE mouse model

Abstract

Listen

Translate article

Abstract Presence of spontaneous germinal center (GCs) in SLE patients correlates with the production of pathogenic, isotype-switched antibodies (Abs) and epitope spreading. In lupus mice, spontaneous GCs are a major site for self-reactive B cells to undergo clonal selection to self-antigens. Limited efficacy of current B cell-based lupus therapies highlights the need to explore alternative targets for inhibiting auto-Ab secreting B cells (ASCs) generation. We propose that complement receptor 2 (CD21) is a novel therapeutic target to block expansion of autoimmunity and pathogenic Ab production. To test this, we set-up mix bone marrow chimeras and adoptive transfer models with 564Igi lupus mice and human CD21-transgenic mice, which allowed us to selectively block CD21 function of either B cells or FDC, or both. CD21 blockade on B cells not only restricted recently activated B cells but also memory B cells (MBC) to participate in GC-derived ASC generation. CD21 blockade on FDCs intriguingly biased MBC fate towards ASC generation, though impeded recently activated B cell capacity to participate in GC response. Dual blockade of CD21 on B cells and FDC exhibited strongest inhibitory effect on GC-derived ASC generation and auto-Ab production. As expected, blockade of ASC generation by donor B cells further correlated with reduced Ab deposition and ameliorated kidney pathology. In brief, CD21 presents itself as a promising therapeutic target to suppress pathogenic auto-Ab generation in SLE.