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Liver Is a Generative Site for the B Cell Response to Ehrlichia Muris

40 Pages Posted: 14 Feb 2019 Sneak Peek Status: Review Complete

See all articles by Nikita Trivedi

Nikita Trivedi

University of Pittsburgh - Department of Immunology

Muhamuda Kader

University of Pittsburgh - Department of Pathology

Aditya Radhakrishnan

Juno Therapeutics

Chris Clouser

Juno Therapeutics

Aaron Rosenfeld

Drexel University

Francois Vigneault

Juno Therapeutics

Uri Hershberg

Drexel University - School of Biomedical Engineering

Nahed Ismail

University of Pittsburgh - Department of Pathology

Mark Shlomchik

University of Pittsburgh - Department of Immunology

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Abstract

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.

Suggested Citation

Trivedi, Nikita and Kader, Muhamuda and Radhakrishnan, Aditya and Clouser, Chris and Rosenfeld, Aaron and Vigneault, Francois and Hershberg, Uri and Ismail, Nahed and Shlomchik, Mark, Liver Is a Generative Site for the B Cell Response to Ehrlichia Muris (February 14, 2019). Available at SSRN: https://ssrn.com/abstract=3334429 or http://dx.doi.org/10.2139/ssrn.3334429
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Nikita Trivedi

University of Pittsburgh - Department of Immunology

Pittsburgh, PA 15261
United States

Muhamuda Kader

University of Pittsburgh - Department of Pathology

Pittsburgh, PA
United States

Aditya Radhakrishnan

Juno Therapeutics

Seattle, WA
United States

Chris Clouser

Juno Therapeutics

Seattle, WA
United States

Aaron Rosenfeld

Drexel University

3141 Chestnut St
Philadelphia, PA 19104
United States

Francois Vigneault

Juno Therapeutics

Seattle, WA
United States

Uri Hershberg

Drexel University - School of Biomedical Engineering

3141 Chestnut St
Philadelphia, PA 19104
United States

Nahed Ismail

University of Pittsburgh - Department of Pathology

Pittsburgh, PA
United States

Mark Shlomchik (Contact Author)

University of Pittsburgh - Department of Immunology ( email )

Pittsburgh, PA 15261
United States

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