Background/Purpose: Age-associated B cells (ABCs) are a novel B cell subset, which expands with age in non-autoimmune mice but accumulates prematurely in autoimmune-prone strains. ABCs exhibit unique phenotypic and functional characteristics. In addition to classical B cell markers ABCs also express markers such as CD11c and CD11b. ABC differentiation depends on the transcription factor T-bet and is promoted by TLR7 stimulation. While ABCs have been proposed to play a key role in the development of autoimmune diseases and in the sex bias observed in these disorders the molecular mechanisms driving ABC formation and function are poorly understood. The SWEF proteins constitute a small family of proteins that includes SWAP-70 and its homolog DEF6, a recently identified risk variant for human SLE. The lack of SWEF proteins leads to the spontaneous development of a lupus-like syndrome, which, similarly to human SLE, preferentially occurs in female mice. We have recently shown that ABC formation is enhanced in SWEF-deficient mice (double knock-out, DKO mice) and is controlled by IL-21 and IRF5. Here we have investigated whether sex-specific differences control the accumulation and/or function of ABCs in SWEF-deficient mice.

Methods: We have evaluated the accumulation of ABCs and their ability to produce autoantibodies in male and female DKOs. We have also generated male Yaa-DKO mice, which carry a duplication of the TLR7 gene on the Y chromosome, to assess the effects of TLR7 dysregulation on the sex-bias observed in SWEF-deficient mice. T_FH cells, ABCs, Germinal center B cells (GCBs), and plasma cells (PCs), were analyzed in the spleens of WT females, WT males, DKO females, DKO males, Yaa-B6 males and Yaa-DKO male mice by FACS. To monitor the severity of the lupus phenotype, autoantibody levels were tested by ELISAs. Finally, ABCs from all genotypes were FACS-sorted and stimulated in vitro with a TLR7 ligand and autoantibody production in the culture supernatant was tested by ELISA.

Results: As compared to WT mice, ABCs accumulate to a similar extent in male and female SWEF-deficient mice. FACS-sorted ABCs from male mice, however, produced much lower titers of anti-dsDNA IgG_2c compared to ABCs from DKO female mice upon TLR7 stimulation. Yaa-DKO male mice exhibited a greater expansion of ABCs than male or female DKOs and a marked accumulation of other immune cells including T_FH cells, GCBs, and PCs. Yaa-DKO mice had significantly higher autoantibody titers and a shortened lifespan. Interestingly, in vitro stimulation of ABCs from Yaa-DKO male mice with a TLR7 ligand resulted in greatly increased autoantibody production compared to male DKOs.

Conclusion: While ABCs accumulate in a similar manner in female and male SWEF-deficient mice, they exhibit a differential ability to produce autoantibodies upon TLR7 stimulation. The functional capability of the SWEF-deficient ABCs is affected by the Yaa translocation. The enhanced autoantibody producing capability of ABCs from Yaa-DKO male mice is accompanied by increased titers of autoantibodies and a shortened lifespan. Thus TLR7 dysregulation alters the sex-bias exhibited by SWEF-deficient ABCs.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/sex-based-differences-control-abc-function-in-swef-deficient-mice/