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Arthritis Research & Therapy
Published in: Arthritis Research & Therapy 1/2016

Open Access 01-12-2016 | Research article

Collagen epitope expression on B cells is sufficient to confer tolerance to collagen-induced arthritis

Authors: Sofia E. M. Andersson, Tove Eneljung, Sara Tengvall, Pernilla Jirholt, Anna Stern, Louise Henningsson, Bibo Liang, Katrin Thorarinsdottir, Jan Kihlberg, Rikard Holmdahl, Inga-Lill Mårtensson, Kenth Gustafsson, Inger Gjertsson

Published in: Arthritis Research & Therapy | Issue 1/2016

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Abstract

Background

The mechanisms underlying tolerance induction and maintenance in autoimmune arthritis remain elusive. In a mouse model of rheumatoid arthritis, collagen type II (CII)-induced arthritis, we explore the contribution of B cells to antigen-specific tolerance.

Methods

To generate expression of the CII-peptide specifically on B-cell major histocompatibility complex type II, lentiviral-based gene therapy including a B-cell-specific Igk promoter was used.

Results

Presentation of the CII-peptide on B cells significantly reduced the frequency and severity of arthritis as well as the serum levels of CII -specific IgG antibodies. Further, both frequency and suppressive function of regulatory T cells were increased in tolerized mice. Adoptive transfer of regulatory T cells from tolerized mice to naïve mice ameliorated the development of CII-induced arthritis.

Conclusion

Our data suggest that endogenous presentation of the CII-peptide on B cells is one of the key contributors to arthritis tolerance induction and maintenance.
Appendix
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Literature
1.
Snir O, Widhe M, Hermansson M, von Spee C, Lindberg J, Hensen S, et al. Antibodies to several citrullinated antigens are enriched in the joints of rheumatoid arthritis patients. Arthritis Rheum. 2010;62(1):44–52.CrossRefPubMed
2.
Schellekens GA, de Jong BA, van den Hoogen FH, van de Putte LB, van Venrooij WJ. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J Clin Invest. 1998;101(1):273–81.CrossRefPubMedPubMedCentral
3.
Hedberg H. Depression of synovial fluid complement activity and rheumatoid factor positivity. Acta Med Scand. 1970;188(5):409–13.PubMed
4.
Rantapaa-Dahlqvist S, de Jong BA, Berglin E, Hallmans G, Wadell G, Stenlund H, et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 2003;48(10):2741–9.CrossRefPubMed
5.
Mok CC. Rituximab for the treatment of rheumatoid arthritis: an update. Drug Des Devel Ther. 2014;8:87–100.
6.
Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM. B cells regulate autoimmunity by provision of IL-10. Nat Immunol. 2002;3(10):944–50.CrossRefPubMed
7.
8.
Flores-Borja F, Bosma A, Ng D, Reddy V, Ehrenstein MR, Isenberg DA, et al. CD19+CD24hiCD38hi B cells maintain regulatory T cells while limiting TH1 and TH17 differentiation. Sci Transl Med. 2013;5(173):173ra123.CrossRef
9.
Morlacchi S, Soldani C, Viola A, Sarukhan A. Self-antigen presentation by mouse B cells results in regulatory T-cell induction rather than anergy or clonal deletion. Blood. 2011;118(4):984–91.CrossRefPubMed
10.
Sagoo P, Perucha E, Sawitzki B, Tomiuk S, Stephens DA, Miqueu P, et al. Development of a cross-platform biomarker signature to detect renal transplant tolerance in humans. J Clin Invest. 2010;120(6):1848–61.CrossRefPubMedPubMedCentral
11.
Brunsberg U, Gustafsson K, Jansson L, Michaelsson E, Ahrlund-Richter L, Pettersson S, et al. Expression of a transgenic class II Ab gene confers susceptibility to collagen-induced arthritis. Eur J Immunol. 1994;24(7):1698–702.CrossRefPubMed
12.
13.
Yanaba K, Hamaguchi Y, Venturi GM, Steeber DA, St. Clair EW, Tedder TF. B Cell Depletion Delays Collagen-Induced Arthritis in Mice: Arthritis Induction Requires Synergy between Humoral and Cell-Mediated Immunity. J Immunol. 2007;179(2):1369–80.CrossRefPubMed
14.
Nagler-Anderson C, Bober LA, Robinson ME, Siskind GW, Thorbecke GJ. Suppression of type II collagen-induced arthritis by intragastric administration of soluble type II collagen. Proc Natl Acad Sci U S A. 1986;83(19):7443–6.CrossRefPubMedPubMedCentral
15.
Terato K, Ye XJ, Miyahara H, Cremer MA, Griffiths MM. Induction by chronic autoimmune arthritis in DBA/1 mice by oral administration of type II collagen and Escherichia coli lipopolysaccharide. Br J Rheumatol. 1996;35(9):828–38.CrossRefPubMed
16.
Dzhambazov B, Nandakumar KS, Kihlberg J, Fugger L, Holmdahl R, Vestberg M. Therapeutic vaccination of active arthritis with a glycosylated collagen type II peptide in complex with MHC class II molecules. J Immunol. 2006;176(3):1525–33.CrossRefPubMed
17.
Gjertsson I, Laurie KL, Devitt J, Howe SJ, Thrasher AJ, Holmdahl R, et al. Tolerance induction using lentiviral gene delivery delays onset and severity of collagen II arthritis. Mol Ther. 2009;17(4):632–40.CrossRefPubMedPubMedCentral
18.
Eneljung T, Tengvall S, Jirholt P, Henningsson L, Holmdahl R, Gustafsson K, et al. Antigen-specific gene therapy after immunisation reduces the severity of collagen-induced arthritis. Clin Dev Immunol. 2013;2013:345092.CrossRefPubMedPubMedCentral
19.
Tengvall S, Eneljung T, Jirholt P, Turesson O, Wing K, Holmdahl R, et al. Gene Therapy Induces Antigen-Specific Tolerance in Experimental Collagen-Induced Arthritis. PLoS One. 2016;11(5), e0154630.CrossRefPubMedPubMedCentral
20.
Laurie KL, Blundell MP, Baxendale HE, Howe SJ, Sinclair J, Qasim W, et al. Cell-specific and efficient expression in mouse and human B cells by a novel hybrid immunoglobulin promoter in a lentiviral vector. Gene Ther. 2007;14(23):1623–31.CrossRefPubMed
21.
Henningsson L, Eneljung T, Jirholt P, Tengvall S, Lidberg U, van den Berg WB, et al. Disease-dependent local IL-10 production ameliorates collagen induced arthritis in mice. PLoS One. 2012;7(11), e49731.CrossRefPubMedPubMedCentral
22.
Perfetto SP, Chattopadhyay PK, Roederer M. Seventeen-colour flow cytometry: unravelling the immune system. Nat Rev Immunol. 2004;4(8):648–55.CrossRefPubMed
23.
Michaelsson E, Andersson M, Engstrom A, Holmdahl R. Identification of an immunodominant type-II collagen peptide recognized by T cells in H-2q mice: self tolerance at the level of determinant selection. Eur J Immunol. 1992;22(7):1819–25.CrossRefPubMed
24.
Rosloniec EF, Whittington KB, Brand DD, Myers LK, Stuart JM. Identification of MHC class II and TCR binding residues in the type II collagen immunodominant determinant mediating collagen-induced arthritis. Cell Immunol. 1996;172(1):21–8.CrossRefPubMed
25.
Trentham DE, Dynesius-Trentham RA, Orav EJ, Combitchi D, Lorenzo C, Sewell KL, et al. Effects of oral administration of type II collagen on rheumatoid arthritis. Science. 1993;261(5129):1727–30.CrossRefPubMed
26.
Corthay A, Backlund J, Broddefalk J, Michaelsson E, Goldschmidt TJ, Kihlberg J, et al. Epitope glycosylation plays a critical role for T cell recognition of type II collagen in collagen-induced arthritis. Eur J Immunol. 1998;28(8):2580–90.CrossRefPubMed
27.
Stuart JM, Cremer MA, Townes AS, Kang AH. Type II collagen-induced arthritis in rats. Passive transfer with serum and evidence that IgG anticollagen antibodies can cause arthritis. J Exp Med. 1982;155(1):1–16.CrossRefPubMed
28.
Holmdahl R, Rubin K, Klareskog L, Larsson E, Wigzell H. Characterization of the antibody response in mice with type II collagen–induced arthritis, using monoclonal anti–type II collagen antibodies. Arthritis Rheum. 1986;29(3):400–10.CrossRefPubMed
29.
Bajtner E, Nandakumar KS, Engstrom A, Holmdahl R. Chronic development of collagen-induced arthritis is associated with arthritogenic antibodies against specific epitopes on type II collagen. Arthritis Res Ther. 2005;7(5):R1148–57.CrossRefPubMedPubMedCentral
30.
Burkhardt H, Koller T, Engstrom A, Nandakumar KS, Turnay J, Kraetsch HG, et al. Epitope-specific recognition of type II collagen by rheumatoid arthritis antibodies is shared with recognition by antibodies that are arthritogenic in collagen-induced arthritis in the mouse. Arthritis Rheum. 2002;46(9):2339–48.CrossRefPubMed
31.
Morgan ME, Flierman R, van Duivenvoorde LM, Witteveen HJ, van Ewijk W, van Laar JM, et al. Effective treatment of collagen-induced arthritis by adoptive transfer of CD25+ regulatory T cells. Arthritis Rheum. 2005;52(7):2212–21.CrossRefPubMed
32.
Fuchs EJ, Matzinger P. B cells turn off virgin but not memory T cells. Science. 1992;258(5085):1156–9.CrossRefPubMed
33.
Eynon EE. Small B, cells as antigen-presenting cells in the induction of tolerance to soluble protein antigens. J Exp Med. 1992;175(1):131–8.CrossRefPubMed
34.
Calderón-Gómez E, Fillatreau S. Utilization of a Lentiviral System for the Generation of B Cells with Regulatory Properties. In: Vitale G, Mion F, editors. Regulatory B Cells: Methods and Protocols. New York, NY: Springer New York; 2014. p. 105–13.
35.
Pala F, Morbach H, Castiello MC, Schickel JN, Scaramuzza S, Chamberlain N, et al. Lentiviral-mediated gene therapy restores B cell tolerance in Wiskott-Aldrich syndrome patients. J Clin Invest. 2015;125(10):3941–51.CrossRefPubMedPubMedCentral
36.
Corthay A. Collagen-induced arthritis development requires alphabeta T cells but not gammadelta T cells: studies with T cell-deficient (TCR mutant) mice. Int Immunol. 1999;11(7):1065–73.CrossRefPubMed
37.
Svensson, Jirholt, Holmdahl, Jansson. B cell-deficient mice do not develop type II collagen-induced arthritis (CIA). Clin Exp Immunol. 1998;111(3):521–6.CrossRefPubMedPubMedCentral
38.
Carnrot C, Prokopec KE, Rasbo K, Karlsson MC, Kleinau S. Marginal zone B cells are naturally reactive to collagen type II and are involved in the initiation of the immune response in collagen-induced arthritis. Cell Mol Immunol. 2011;8(4):296–304.CrossRefPubMedPubMedCentral
39.
Raposo B, Dobritzsch D, Ge C, Ekman D, Xu B, Lindh I, et al. Epitope-specific antibody response is controlled by immunoglobulin V(H) polymorphisms. J Exp Med. 2014;211(3):405–11.CrossRefPubMedPubMedCentral
40.
Ljungqvist L, Worsaae A, Heron I. Antibody responses against Mycobacterium tuberculosis in 11 strains of inbred mice: novel monoclonal antibody specificities generated by fusions, using spleens from BALB. B10 and CBA/J mice. Infect Immun. 1988;56(8):1994–8.PubMedPubMedCentral
41.
McHeyzer-Williams LJ, Milpied PJ, Okitsu SL, McHeyzer-Williams MG. Class-switched memory B cells remodel BCRs within secondary germinal centers. Nat Immunol. 2015;16(3):296–305.CrossRefPubMedPubMedCentral
42.
Rosser EC, Mauri C. Regulatory B cells: origin, phenotype, and function. Immunity. 2015;42(4):607–12.CrossRefPubMed
43.
Zhong G, Sousa CR, Germain RN. Antigen-unspecific B Cells and Lymphoid Dendritic Cells Both Show Extensive Surface Expression of Processed Antigen–Major Histocompatibility Complex Class II Complexes after Soluble Protein Exposure In Vivo or In Vitro. J Exp Med. 1997;186(5):673–82.CrossRefPubMedPubMedCentral
44.
Sun JB, Flach CF, Czerkinsky C, Holmgren J. B lymphocytes promote expansion of regulatory T cells in oral tolerance: powerful induction by antigen coupled to cholera toxin B subunit. J Immunol. 2008;181(12):8278–87.CrossRefPubMed
45.
Holmdahl M, Vestberg M, Holmdahl R. Primed B cells present type-II collagen to T cells. Scand J Immunol. 2002;55(4):382–9.CrossRefPubMed
46.
Carter NA, Rosser EC, Mauri C. Interleukin-10 produced by B cells is crucial for the suppression of Th17/Th1 responses, induction of T regulatory type 1 cells and reduction of collagen-induced arthritis. Arthritis Res Ther. 2012;14(1):R32.CrossRefPubMedPubMedCentral
47.
Reichardt P, Dornbach B, Rong S, Beissert S, Gueler F, Loser K, et al. Naive B cells generate regulatory T cells in the presence of a mature immunologic synapse. Blood. 2007;110(5):1519–29.CrossRefPubMed
48.
Aloulou M, Carr EJ, Gador M, Bignon A, Liblau RS, Fazilleau N, et al. Follicular regulatory T cells can be specific for the immunizing antigen and derive from naive T cells. Nat Commun. 2016;7:10579.CrossRefPubMedPubMedCentral
Metadata
Title
Collagen epitope expression on B cells is sufficient to confer tolerance to collagen-induced arthritis
Authors
Sofia E. M. Andersson
Tove Eneljung
Sara Tengvall
Pernilla Jirholt
Anna Stern
Louise Henningsson
Bibo Liang
Katrin Thorarinsdottir
Jan Kihlberg
Rikard Holmdahl
Inga-Lill Mårtensson
Kenth Gustafsson
Inger Gjertsson
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Arthritis Research & Therapy / Issue 1/2016
Electronic ISSN: 1478-6362
DOI
https://doi.org/10.1186/s13075-016-1037-7

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