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Nodal marginal zone B cells in mice: a novel subset with dormant self-reactivity
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, 27687Article in journal (Refereed) Published
Abstract [en]

Marginal zone (MZ) B cells, representing a distinct subset of innate-like B cells, mount rapid T-independent responses to blood-borne antigens. They express low-affinity polyreactive antigen receptors that recognize both foreign and self-structures. The spleen is considered the exclusive site for murine MZ B cells. However, we have here identified B cells with a MZ B-cell phenotype in the subcapsular sinuses of mouse lymph nodes. The nodal MZ (nMZ) B cells display high levels of IgM, costimulators and TLRs, and are represented by naive and memory cells. The frequency of nMZ B cells is about 1-6% of nodal B cells depending on mouse strain, with higher numbers in older mice and a trend of increased numbers in females. There is a significant expansion of nMZ B cells following immunization with an autoantigen, but not after likewise immunization with a control protein or with the adjuvant alone. The nMZ B cells secrete autoantibodies upon activation and can efficiently present autoantigen to cognate T cells in vitro, inducing T-cell proliferation. The existence of self-reactive MZ B cells in lymph nodes may be a source of autoantigen-presenting cells that in an unfortunate environment may activate T cells leading to autoimmunity.

Place, publisher, year, edition, pages
2016. Vol. 6, 27687
National Category
Immunology
Identifiers
URN: urn:nbn:se:uu:diva-265022DOI: 10.1038/srep27687ISI: 000377368700001PubMedID: 27277419OAI: oai:DiVA.org:uu-265022DiVA: diva2:862233
Funder
Swedish Rheumatism Association
Available from: 2015-10-20 Created: 2015-10-20 Last updated: 2017-12-01Bibliographically approved
In thesis
1. Function and Regulation of B-cell Subsets in Experimental Autoimmune Arthritis
Open this publication in new window or tab >>Function and Regulation of B-cell Subsets in Experimental Autoimmune Arthritis
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

B lymphocytes play a significant role in autoimmune arthritis, with their function stretching beyond autoantibody production to cytokine secretion and presentation of autoantigen. However, the involvement and activation of different B-cell subset in the autoimmune response is not fully clear. The main focus of this thesis has been to understand the contribution of marginal zone (MZ) B cells in the induction of collagen-induced arthritis (CIA), a mouse model for rheumatoid arthritis (RA).

We show that MZ B cells in the spleen of naïve mice display a natural self-reactivity to collagen type II (CII), the autoantigen used for immunization of CIA. The CII-reactive MZ B cells expand rapidly following immunization with CII, and produce IgM and IgG antibodies to CII. They also very efficiently present CII to cognate T cells in vitro and in vivo. Moreover, absence of regulatory receptors such as CR1/2 or FcγRIIb on the MZ B cells increases their proliferation and cytokine production in response to toll-like receptor, but not B-cell receptor, activation. Further, FcγRIIb-deficient MZ B cells present CII to T cells more efficiently than wild-type MZ B cells. We additionally demonstrate for the first time the existence of a small population of nodal MZ B cells in mouse lymph nodes. Similar to splenic MZ B cells, the nodal MZ B cells expand after CIA induction, secrete IgM anti-CII antibodies and can present CII to cognate T cells. Finally, we show that mast cells, associated with ectopic B cell follicles in inflamed RA joints, in coculture with B cells promote their expansion, production of IgM and IgG antibodies as well as upregulation of CD19 and L-selectin. Coculture with mast cells further causes the B cells to upregulate costimulators and class II MHC, important molecules for antigen-presenting function.

In summary, my findings suggest that splenic and nodal self-reactive MZ B cells participate in breaking T-cell tolerance to CII in CIA. B-cell intrinsic regulation is needed to keep such autoreactive B cells quiescent. Mast cells can potentiate B-cell responses locally in the arthritic joint, thus feeding the autoimmune reaction.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 57 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1305
Keyword
B cells, marginal zone, autoimmune arthritis, spleen, lymph node, antigen presentation, Fc gamma receptor IIb, complement receptors 1 and 2, mast cells
National Category
Immunology
Research subject
Biology with specialization in Molecular Immunology
Identifiers
urn:nbn:se:uu:diva-265024 (URN)978-91-554-9382-0 (ISBN)
Public defence
2015-12-10, C8:301, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2015-11-18 Created: 2015-10-20 Last updated: 2016-01-13

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Palm, Anna-Karin E.Kleinau, Sandra

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