Type I interferon enhanced double negative 2 B cell differentiation and lupus autoantibody production

Abstract

Abstract Systemic Lupus Erythematosus (SLE) is characterized by high level of type I interferon (IFN) and abnormal expansion of effector B cells including IgD−CD27−double negative (DN), CD21−T-bet+DN2 B cells, and antibody secreting cells (ASCs). It remains unclear as to the role of type I and type II interferon (IFN) to promote DN2 B cell differentiation. The in vivo effects of type I IFN signaling in promoting DN B cells were accessed using the BXD2 mouse model of lupus which exhibit a low Th1 response, compared to normal B6 mice. Compared to normal B6 mouse, there was a significantly elevated percent of DN B cells in the BXD2 mice, but this was reduced in BXD2 mice that are deficient in IFNAR1 (BXD2-Ifnar1−/−). Compared to wild-type BXD2 mice, there was a lower level of IgG autoantibodies specific to DNA, histone and Smith (Sm) in BXD2-Ifnar1−/− mice. BXD2-Ifnar1−/− B cells presented impaired differentiation into the DN and the DN2 populations under an in vitro stimulation condition in the presence of IFNb and a TLR7 agonist. To determine if type I IFN stimulation can direct differentiation of healthy B cells to these effector B cells without the influence of type II IFN, B cells purified from healthy individuals were stimulated under a DN stimulation condition (anti-Ig+IL-21+BAFF+TLR7) in the presence and absence of IFNb. We found that IFNb significantly increased the percentage and of DN and DN2 B cells, but decreased the percentage of CD27+CD38+ plasmablasts/plasma. Under the same condition, IFNb increased the secretion of autoantibodies specific to DNA, histone and Sm. Our results suggest that type I IFN signaling stimulates DN2 B cell differentiation and can promote the abnormal expansion of these B cells in vivo independent of type II IFN.