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Function and regulation of self-reactive marginal zone B cells in autoimmune arthritis

Cellular & Molecular Immunology volume 12, pages 493–504 (2015)Cite this article

Abstract

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 naı¨ve mice. Upon immunization with heterologous collagen II in complete Freund’s adjuvant the collagen-reactive MZ 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 Fcγ 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.

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Acknowledgements

This work was supported by grants from the Swedish Research Council, the King Gustaf V:s 80-years Foundation, the Swedish Rheumatism Association and the O. & E. Ericsson’s Foundation. We thank Cecilia Carnrot for technical assistance. Flow cytometric experiments and sorting were performed with equipment maintained by the Science for Life Lab BioVis Platform, Uppsala.

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Authors and Affiliations

  1. Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden

    Anna-Karin E Palm, Heike C Friedrich, Anja Mezger, Maya Salomonsson & Sandra Kleinau

  2. Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA

    Linda K Myers

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  1. Anna-Karin E Palm
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Correspondence to Sandra Kleinau.

Additional information

Supplementary Information accompanies the paper on Cellular & Molecular Immunology’s website (http://www.nature.com/cmi).

Supplementary Figures 1 and 2 show the sorting strategy and post-sort purity checks for marginal zone, follicular, and B-1 B cells.

Supplementary Figure 3 shows the surface expression of CD80, CD86, and class II MHC on marginal zone and follicular B cells, as determined by flow cytometry.

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Palm, AK., Friedrich, H., Mezger, A. et al. Function and regulation of self-reactive marginal zone B cells in autoimmune arthritis. Cell Mol Immunol 12, 493–504 (2015). https://doi.org/10.1038/cmi.2015.37

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