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 myeloid markers such as CD11c. ABC differentiation depends on T-bet and is promoted by TLR7 stimulation and cytokines like IFN-g and IL-21. While ABCs have been proposed to play a key role in the development of autoimmune diseases, the mechanisms regulating ABC formation and function are poorly understood. The SWEF proteins are 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 females. We have recently shown that ABC formation is enhanced in SWEF-deficient mice (=DKO mice). Given that alterations in cholesterol homeostasis can promote autoimmunity, here we have investigated whether the accumulation and/or function of ABCs in SWEF-deficient mice could be affected by changes in the expression of the LDL receptor (LDLR) and/or a High Cholesterol Diet (HCD).

Methods: We have generated DKO mice, which also lack the LDLR (LDLRKO-DKOs), to assess the effects of metabolic dysregulation on the development of autoimmunity in DKO mice. Mice were fed either chow or a HCD. T_FH cells, ABCs, germinal center B cells (GCBs), and plasma cells (PCs), were analyzed in the spleens of DKO females and males, LDLRKO-DKO females and males and control mice (WT, LDLRKO females and males) by FACS. To monitor the severity of the lupus phenotype, autoantibody levels were tested by ELISAs and end-organ inflammation was assessed by histology.

Results: As compared to wt mice, DKO mice exhibit an accumulation of T_FH cells, ABCs, GCBs, and PCs (F >M). DKO female mice with a concomitant deletion of the LDLR (LDLRKO-DKOs) fed a chow diet displayed a similar expansion of ABCs, GCBs, and PCs to DKO female mice. As compared to DKO females, LDLRKO-DKO females on a chow diet however displayed increased focal chronic inflammation of skeletal muscles and joints. Feeding a HCD to LDLRKO-DKO female mice did not substantially affect the expansion of ABCs, GCBs, and PCs. Interestingly, as compared to DKO males on a chow diet, DKO males fed a HCD exhibited a marked increase in ABCs, GCBs, and PCs, which was associated with an increased production of autoantibodies. LDLRKO-DKO males on either a chow or a HCD exhibited an increase in PCs and a more variable increase in ABCs and GCBs.

Conclusion: ABCs accumulate to a similar manner in female DKO mice irrespective of the concomitant absence of the LDLR. Lack of the LDLR in DKO female mice, however, leads to increased tissue inflammation.  A HCD can promote marked expansion of ABCs in DKO male mice and promote the production of autoantibodies. Thus, alterations in cholesterol homeostasis can affect ABC accumulation and other autoimmune parameters in a sex-specific manner.

« Back to 2019 ACR/ARP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/alterations-in-cholesterol-homeostasis-regulate-autoimmunity-age-associated-b-cells/