45 CD11c-hi T-bet+ B cells contribute to the pathogenesis of SLE through generation of autoreactive plasma cells

Background

The etiology of systemic lupus erythematosus (SLE) is unclear, though dysregulated B cells play a key role. Several unconventional B cell subsets that associate with autoantibodies have been described in SLE. The aim of this study was to further evaluate B cell subsets in SLE and their connection to autoreactive specificities and disease manifestations.

Methods

The frequency and phenotype of CD11c+Tbet+B cells were determined by flow cytometry. Autoantibodies were measured at the UT Southwestern core facility. The presence of CD11c+B cells in nephritic kidney was determined with IHC. IgH repertoires and mutational frequencies as well as transcriptome profile of CD11c+B cells were analyzed from RNA isolated from CD11c+B cells from SLE patients and compared to other B cell subsets from the same individual. Purified B cells from HD or SLE donors were cultured with either CD3-activated T cells or IL-21 co-stimulation and evaluated for B cell phenotype or production of auto-antibodies.

Results

We found a CD11c hi T-bet +B cell subset highly expanded in SLE with a unique expression profile including chemokine receptors consistent with migration to target tissues. Notably, these cells were enriched for autoreactive specificities, present in nephrotic kidney and significantly correlated with specific clinical manifestations. IL-21 was a potent inducer of CD11c hi T-bet +B cells that further promoted the differentiation of these cells into Ig-secreting plasma cells. IgH repertoire analysis showed CD11c hi T-bet +B cells displayed a diverse repertoire with high levels of somatic hypermutation similar to memory B cells and plasma cells. This diverse repertoire suggests that CD11c hi T-bet +B cells accumulate in response to a plethora of antigens overtime, including self-antigens in SLE.

Conclusions

These results show that CD11c-hi T-bet +B cells are polyclonally expanded, and highly somatically hypermutated in SLE. Furthermore, IL-21 may be involved in their expansion and differentiation into autoreactive plasma cells, which in turn may contribute to autoimmune manifestations in SLE.

Funding Source(s):

This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging and National Institute of Arthritis and Musculoskeletal and Skin Diseases and MedImmune, LLC.