FcγRIIb signaling by germinal B cells following Borrelia burgdorferi infection

Abstract

Tick-borne infection with Borrelia burgdorferi (Bb) causes Lyme disease in humans and persistent infection of mice, its natural reservoir host. IgG responses critically control Bb tissue burden but do not clear the infection. We previously showed induction of germinal centers (GC) in mice after Bb infection followed by their rapid collapse within 30 days, despite ongoing infection. This was consistent with the lack of long-lived and high-affinity antibody responses in these mice. Our recent experiments showed that serum IgG from Bb-infected mice bound more strongly to the inhibitory FcγRIIb on B cells, as well as recombinant FcγRIIb than those from uninfected mice, as assessed by flow cytometry and ELISA, respectively. The data prompted us to investigate whether the interaction between Bb infection-induced IgG and FcγRIIb results in the suppression of GC. Indeed, Bb-infected mice lacking FcγRIIb signaling (FcγRIIb−/−) maintained GC B cells and CD4 TFH for at least 90 days after infection, and GC B cells showed reduced apoptosis, as assessed by staining for Annexin V. Furthermore, transfer of serum from Bb-infected wild type but not AID−/−sIgM−/− mice lacking IgG, IgM and from non-infected wild type mice, into 14-day Bb-infected wild type mice resulted in reduced GC at day 21. However, despite GC maintenance and the resulting increases in Bb-specific, T cell-dependent IgG responses, enhanced antibody affinity maturation was not observed and Bb tissue burdens of FcγRIIb−/− and control mice were comparable. The data show the importance for FcγRIIb in the regulation of GC during Bb infection, while additional mechanisms currently under investigation seem to underlie their functional deficits, enabling the establishment of Bb persistence.