Altered function and differentiation of age-associated B cells contribute to the female bias in lupus mice

Abstract

Differences in immune responses to viruses and autoimmune diseases such as systemic lupus erythematosus (SLE) can show sexual dimorphism. Age-associated B cells (ABC) are a population of CD11c+T-bet+ B cells critical for antiviral responses and autoimmune disorders. Absence of DEF6 and SWAP-70, two homologous guanine exchange factors, in double-knock-out (DKO) mice leads to a lupus-like syndrome in females marked by accumulation of ABCs. Here we demonstrate that DKO ABCs show sex-specific differences in cell number, upregulation of an ISG signature, and further differentiation. DKO ABCs undergo oligoclonal expansion and differentiate into both CD11c+ and CD11c− effector B cell populations with pathogenic and pro-inflammatory function as demonstrated by BCR sequencing and fate-mapping experiments. Tlr7 duplication in DKO males overrides the sex-bias and further augments the dissemination and pathogenicity of ABCs, resulting in severe pulmonary inflammation and early mortality. Thus, sexual dimorphism shapes the expansion, function and differentiation of ABCs that accompanies TLR7-driven immunopathogenesis.

Age-associated B cells in viral infection

“…TLR7, stimulated primarily by viral single-stranded RNA, is encoded by the X chromosome and is susceptible to incomplete inactivation in females, leading to higher TLR7 expression in females [ 52 ]. In support of the theory that the ABC sex bias is due to increased TLR7 expression in females, Tlr7 duplication in male mice resulted in a significant increase in ABC frequency [ 50 ]. In addition to a sex difference in the frequency of ABCs, it was recently shown that ABCs in male versus female mice display altered functional capacities in the context of SLE [ 50 ].…”

“…In support of the theory that the ABC sex bias is due to increased TLR7 expression in females, Tlr7 duplication in male mice resulted in a significant increase in ABC frequency [ 50 ]. In addition to a sex difference in the frequency of ABCs, it was recently shown that ABCs in male versus female mice display altered functional capacities in the context of SLE [ 50 ]. In particular, ABCs from female mice secreted significantly more self-specific IgG2a/c and were enriched for interferon response pathways compared to those from males [ 50 ].…”

“…It is well established that there exist sex differences in responses to viral infection [ 49 ]. ABCs display a sex bias , in which their numbers and proportions are increased in females more so than males, during both aging [ 1 ] and autoimmunity [ 36 , 50 ]. Currently, it is not clear if ABCs display a sex bias during viral infection and, if so, what the impact might be on control of infection and resulting immunopathology between females and males.…”

“…In addition to a sex difference in the frequency of ABCs, it was recently shown that ABCs in male versus female mice display altered functional capacities in the context of SLE [ 50 ]. In particular, ABCs from female mice secreted significantly more self-specific IgG2a/c and were enriched for interferon response pathways compared to those from males [ 50 ]. It remains to be seen if these ABC functional differences between males and females are present during viral infection and if this could contribute to the well-reported sex differences to viral infections [ 49 ].…”

Molecular mechanisms controlling age‐associated B cells in autoimmunity*

“…41 These trafficking patterns can become altered in autoimmune settings where increased dissemination into the blood, lymph nodes, and tissues like the lungs and kidneys can be observed. 61 Utilization of these distinctive cytoskeletal programs by ABCs may also have broader functional implications and contribute to their ability to form more stable interactions with T cells than follicular B cells, which, together with their high level of costimulatory molecules, can enable them to act as potent APCs. 12,37,63,64 Thus, in addition to their characteristic patterns of integrins and chemokine receptors, a unique set of cytoskeletal dynamics may help shape the localization, migration, and cell-cell communication skills of ABCs.…”