Background/Purpose: Systemic lupus erythematous is characterized by the production of pathogenic autoantibodies that drive inflammation and tissue damage.  Defining the B cell subsets that give rise to these autoantibodies may reveal therapeutic strategies that target pathogenic B cells while sparing responses to immunization and infection.  T-bet+ B cells are thought to be pathogenic in lupus, while B-1 B cells have been suggested to play both protective and pathogenic roles, depending on the study.  Both subsets have been implicated in the Lyn-deficient mouse model of lupus.  We sought to identify the specificity of plasma cells (PCs) generated by T-bet+ B cells and B-1 cells in Lyn-/- mice.    

Methods: To identify PCs derived from particular B cell subsets we used a cre-inducible tomato reporter that labels cells that express cre and their progeny.  We used Tbx21-cre to induce the reporter in T-bet+ B cells, and Ighg3-cre to label B-1 cells and their progeny.  Reporter expressing PCs and their unlabeled counterparts were sorted from the spleens of Tbx21-cre.tomato.Lyn-/- and Ighg3-cre.tomato.Lyn-/- mice and cultured overnight.  Supernatants were analyzed for autoreactivity by autoantigen array. 

Results: PCs derived from T-bet+ B cells were a dominant source of many IgG autoantibodies, including those targeting DNA and RNA containing antigens.  In contrast, IgG produced by Ighg3-labeled PCs was consistently under-enriched in several of these specificities, including ssDNA, dsDNA, genomic DNA, SmD1, and TIF1 gamma.  IgM autoantibodies were generally more evenly distributed among B cell subsets, but T-bet+ B cell derived PCs were particularly enriched in IgM against RNA containing antigens. 

Conclusion: T-bet+ B cells are more important than B-1 cells for the production of many IgG autoantibodies in the Lyn-/- lupus model.  Ongoing studies will determine whether B-1 cells play other protective or pathogenic roles in autoimmune disease. 

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/b-cell-subset-contribution-to-autoantibodies-in-lupus/