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Function and Regulation of B-cell Subsets in Experimental Autoimmune Arthritis
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för cell- och molekylärbiologi, Kemisk biologi.ORCID-id: 0000-0002-2651-3109
2015 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2015. , s. 57
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1305
Nyckelord [en]
B cells, marginal zone, autoimmune arthritis, spleen, lymph node, antigen presentation, Fc gamma receptor IIb, complement receptors 1 and 2, mast cells
Nationell ämneskategori
Immunologi
Forskningsämne
Biologi med inriktning mot molekylär immunologi
Identifikatorer
URN: urn:nbn:se:uu:diva-265024ISBN: 978-91-554-9382-0 (tryckt)OAI: oai:DiVA.org:uu-265024DiVA, id: diva2:862262
Disputation
2015-12-10, C8:301, BMC, Husargatan 3, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2015-11-18 Skapad: 2015-10-20 Senast uppdaterad: 2016-01-13
Delarbeten
1. Function and regulation of self-reactive marginal zone B cells in autoimmune arthritis
Öppna denna publikation i ny flik eller fönster >>Function and regulation of self-reactive marginal zone B cells in autoimmune arthritis
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2015 (Engelska)Ingår i: Cellular & Molecular Immunology, ISSN 1672-7681, E-ISSN 2042-0226, Vol. 12, nr 4, s. 493-504Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Polyreactive innate-type B cells account for many B cells expressing self-reactivity in the periphery. Improper regulation of these B cells may be an important factor that underlies autoimmune disease. Here we have explored the influence of self-reactive innate B cells in the development of collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis. We show that splenic marginal zone (MZ), but not B-1 B cells exhibit spontaneous IgM reactivity to autologous collagen II in naive mice. Upon immunization with heterologous collagen II in complete Freund's adjuvant the collagen-reactiveMZ B cells expanded rapidly, while the B-1 B cells showed a modest anti-collagen response. The MZ B cells were easily activated by toll-like receptor (TLR) 4 and 9-ligands in vitro, inducing proliferation and cytokine secretion, implying that dual engagement of the B-cell receptor and TLRs may promote the immune response to self-antigen. Furthermore, collagen-primed MZ B cells showed significant antigen-presenting capacity as reflected by cognate T-cell proliferation in vitro and induction of IgG anti-collagen antibodies in vivo. MZ B cells that were deficient in complement receptors 1 and 2 demonstrated increased proliferation and cytokine production, while Fc gamma receptor IIb deficiency of the cells lead to increased cytokine production and antigen presentation. In conclusion, our data highlight self-reactive MZ B cells as initiators of the autoimmune response in CIA, where complement and Fc receptors are relevant in controlling the self-reactivity in the cells.

Nyckelord
arthritis, complement receptors, Fc receptors, marginal zone B cells, mice
Nationell ämneskategori
Immunologi
Identifikatorer
urn:nbn:se:uu:diva-264328 (URN)10.1038/cmi.2015.37 (DOI)000360939000012 ()25958842 (PubMedID)
Forskningsfinansiär
VetenskapsrådetReumatikerförbundet
Tillgänglig från: 2015-10-15 Skapad: 2015-10-09 Senast uppdaterad: 2017-12-01Bibliografiskt granskad
2. Nodal marginal zone B cells in mice: a novel subset with dormant self-reactivity
Öppna denna publikation i ny flik eller fönster >>Nodal marginal zone B cells in mice: a novel subset with dormant self-reactivity
2016 (Engelska)Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikel-id 27687Artikel i tidskrift (Refereegranskat) 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.

Nationell ämneskategori
Immunologi
Identifikatorer
urn:nbn:se:uu:diva-265022 (URN)10.1038/srep27687 (DOI)000377368700001 ()27277419 (PubMedID)
Forskningsfinansiär
Reumatikerförbundet
Tillgänglig från: 2015-10-20 Skapad: 2015-10-20 Senast uppdaterad: 2017-12-01Bibliografiskt granskad
3. Activated mast cells promote a pro-inflammatory phenotype of B cells
Öppna denna publikation i ny flik eller fönster >>Activated mast cells promote a pro-inflammatory phenotype of B cells
Visa övriga...
(Engelska)Artikel i tidskrift (Refereegranskat) Submitted
Nationell ämneskategori
Immunologi
Identifikatorer
urn:nbn:se:uu:diva-265023 (URN)
Tillgänglig från: 2015-10-20 Skapad: 2015-10-20 Senast uppdaterad: 2016-01-13

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