TLR7-induced ABCs and DN B-cell-derived PBs are associated with enhanced XCI escape of TLR7, suggesting positive selection of biallelic B cells upon cognate TLR engagement.
ABCs are more frequent in PBMCs from females of reproductive age than in age-matched males.
ABCs with dysregulated XCI at the TLR7 locus are positively selected during TLR7-driven differentiation, but not in response to TLR9 stimulation.
A similar trend of selection was observed for biallelic CXorf21/TASL cells.
IgD-CD27- double-negative (DN) B cells, which contain ABCs, are the immediate precursors of CD27hiIRF4+ plasmablasts in response to TLR stimulation.
Female B cells were more prone than male B cells to generate plasmablasts only in response to TLR7 stimulation, not TLR9 stimulation.
The female sex bias in PB generation was associated with enhanced expression from both X chromosomes of TLR7 and, to a lesser extent, CXorf21 in TLR7-stimulated PBs.
This study looked at a type of immune cell called age-associated B cells (ABCs), which are linked to autoimmune diseases, aging-related conditions, and chronic infections. These cells are more common in women. Two genes on the X chromosome, TLR7 and CXorf21/TASL, help drive these cells. Normally one of a female's two X chromosomes is largely silenced, but these genes can sometimes escape silencing, so both copies are active. The researchers found that ABCs were more frequent in blood from women of reproductive age than in men of the same age. In lab experiments starting from naïve B cells, cells with both copies of TLR7 active were preferentially selected when stimulated through TLR7, but not through TLR9. A similar trend was seen for CXorf21/TASL. They also found that double-negative B cells, a group that includes ABCs, were the direct precursors of antibody-secreting plasmablasts. Female B cells made more plasmablasts than male cells only under TLR7 stimulation, and this was linked to increased activity of both X-copies of TLR7 and, to a lesser extent, CXorf21. This research suggests that incomplete X chromosome silencing at TLR7 may help explain why women are more prone to autoimmune diseases involving these B cells. The findings come from cell-based experiments, so they point to a mechanism rather than showing direct effects on disease in people.
Faz-Lopez B, Nieucel M, Cenac C, Langlais A, Sailler L, Miquel C, et al.. (2026). TLR7 stimulation promotes altered X chromosome inactivation maintenance at the TLR7 and CXorf21/TASL loci in female age-associated B cells and plasmablasts.. Journal of immunology (Baltimore, Md. : 1950). https://doi.org/10.1093/jimmun/vkag290