Liver Is a Generative Site for the B Cell Response to Ehrlichia Muris
40 Pages Posted: 14 Feb 2019 Sneak Peek Status: PublishedMore...
Murine infection with Ehrlichia muris models human Ehrlichiosis, with prominent liver involvement. Although Ehrlichia is an obligate intracellular pathogen, B cells are important for protection. The B cell response is dominated by plasmablasts (PBs), with few if any germinal centers (GC), and generates protective IgM memory B cells (MBC) that express T-bet and include some B cells express V region mutation. Here we address the origins, specificity, and location of these mutated MBC, revealing several novel features of the E. muris response and B cell memory in general. We first identified B cells within infected livers and demonstrated that they were proliferating and — via laser capture microdissection — undergoing somatic hyper mutation (SHM) in local liver foci. Similarly, splenic extrafollicular (EF) foci were undergoing active proliferation and mutation. In addition to PBs, we identified proliferating B cell blasts but no GC B cells. Vh region high throughput sequencing (HTS) revealed substantial trafficking of B cell clones between the spleen and liver that was often followed by localized clonal expansion. A subset of responding B cells persisted as memory cells in the spleen and liver of infected mice, even after antigen clearance, including a novel tissue-resident liver MBC. These data demonstrate that liver is a generative site of B cell responses that include V region mutation, MBC generation, and MBC residency.
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