Jackson et al. propose a role for B cell–intrinsic IFN-γ receptor signaling in spontaneous germinal center activation and autoantibody production.

Arkatkar et al. report that B cell–derived IL-6 is critical for T follicular helper cell differentiation, spontaneous germinal center formation, and class-switched autoantibody production during humoral autoimmunity.

The single nucleotide polymorphism, rs1990760, in the cytosolic viral sensor, IFIH1, results in an amino-acid change (p.A946T) and is associated with multiple autoimmune diseases. The impact of this polymorphism on both viral-sensing and autoimmune pathogenesis remains poorly understood. Here, we find that human PBMCs and cell lines with the risk variant, IFIH1T946, exhibit heightened, basal and ligand-triggered type I interferon (IFN-I) production. Consistent with these findings, IFIH1T946 knock-in mice display enhanced basal IFN-I expression, survive a lethal viral challenge, and exhibit increased penetrance in autoimmune models including a combinatorial impact with other risk variants. Further, IFIH1T946 mice manifest an embryonic survival defect consistent with enhanced responsiveness to RNA self-ligands. Together, our data support a model wherein autoimmune risk variant-driven, ligand-triggered IFN-I production functions to protect against viral challenge, likely accounting for its selection within human populations, but provides this advantage at the cost of modestly promoting the risk for autoimmunity.

Mice overexpressing B cell activating factor of the TNF family (BAFF) develop systemic autoimmunity characterized by class-switched anti-nuclear antibodies. Transmembrane activator and CAML interactor (TACI) signals are critical for BAFF-mediated autoimmunity, but the B cell developmental subsets undergoing TACI-dependent activation in settings of excess BAFF remains unclear. We now report that, whereas surface TACI expression is usually limited to mature B cells, excess BAFF promotes the expansion of TACI-expressing transitional B cells. TACIhi transitional cells from BAFF-Tg mice are characterized by an activated, cycling phenotype; and the TACIhi cell subset is specifically enriched for autoreactivity, expresses activation-induced cytidine deaminase (AID) and T-bet and exhibits evidence of somatic hypermutation. Consistent with a potential contribution to BAFF-mediated humoral autoimmunity, TACIhi transitional B cells from BAFF-Tg mice spontaneously produce class-switched autoantibodies ex vivo. These combined findings highlight a novel mechanism whereby BAFF promotes humoral autoimmunity via direct, TACI-dependent activation of transitional B cells.

Problem Chlamydia trachomatis (CT) is the leading sexually transmitted bacterial infection in humans and is associated with reproductive tract damage. However, little is known about the involvement and regulation of microRNAs (miRs) in genital CT. Methods We analyzed miRs in the genital tract (GT) following C. muridarum (murine strain of CT) challenge of wild type (WT), and CD4+ T cell deficient (CD4−/−) C57BL/6 mice at days 6 and 12 post challenge. Results At day 6, miRs significantly downregulated in the lower GT were miR-125b-5p, −16, −214, −23b, −135a, −182, −183, −30c, and −30e while −146 and −451 were significantly upregulated, profiles not exhibited at day 12 post bacterial challenge. Significant differences in miR-125b-5p (+5.06 fold change), −135a (+4.9), −183 (+7.9), and −182 (+3.2) were observed in C. muridarum infected CD4−/− compared to WT mice. In silico prediction and mass spectrometry revealed regulation of miR-135a and −182 and associated proteins i.e, Heat Shock Protein B1 and Alpha-2HS-Glycoprotein. Conclusion This study provides evidence on regulation of miRs following genital chlamydial infection suggesting a role in pathogenesis and host immunity.