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Arthritis Research & Therapy

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Open Access 01-12-2017 | Research article

TIM-1 defines a human regulatory B cell population that is altered in frequency and function in systemic sclerosis patients

Authors: Octavio Aravena, Ashley Ferrier, Madhvi Menon, Claudia Mauri, Juan Carlos Aguillón, Lilian Soto, Diego Catalán

Published in: Arthritis Research & Therapy | Issue 1/2017

Abstract

Background

Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by excessive production of extracellular matrix by fibroblasts on skin and internal organs. Although Th2 cells have been involved in fibroblast stimulation, hyperactivated B cells may also play an important role. Regulatory B cells (Bregs) are cells capable of inhibiting inflammatory responses and controlling autoimmune diseases. Although many Breg populations have in common the ability to produce high amounts of IL-10, a unique surface marker defining most human Bregs is lacking. It has been described in mice that T cell Ig and mucin domain protein 1 (TIM-1) is an inclusive marker for Bregs, and that TIM-1+ B cells are able to prevent the development of autoimmunity. The aim of this work was to evaluate TIM-1 as a marker for human IL-10⁺ Bregs, and to determine whether TIM-1+ B cells are defective in SSc patients.

Methods

SSc patients (n = 39) and 53 healthy subjects were recruited. TIM-1 and IL-10 expression was assessed in resting or activated peripheral blood CD19⁺ B cells by flow cytometry. The regulatory function of TIM-1⁺ or activated B cells from SSc patients and healthy subjects was assessed in autologous and allogenic co-cultures with CD4⁺ T cells, where T cell proliferation and IFN-γ, IL-17, TNF-α and IL-4 production by T cells was measured by flow cytometry.

Results

TIM-1 and IL-10 were preferentially expressed in transitional B cells, but were upregulated in naïve and memory B cells upon stimulation. The frequency of transitional TIM-1⁺ IL-10⁺ B cells was significantly decreased in SSc patients compared to healthy controls. In addition, activated B cells from SSc patients induced stronger allogenic Th1 and Th2 responses than activated B cells from healthy controls. Finally, TIM-1⁺ B cells, including transitional and non-transitional cells, exhibited a higher CD4⁺ T cell suppressive ability than TIM-1⁻ B cells in healthy controls, but not in SSc patients.

Conclusions

TIM-1 is a unique marker for the identification of a human IL-10⁺ Breg subpopulation which is partially superimposed with transitional B cells. Alterations in TIM-1⁺ B cells could contribute to the development of autoimmune diseases such as SSc.

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Mauri C, Bosma A. Immune regulatory function of B cells. Annu Rev Immunol. 2012;30:221–41.CrossRefPubMed

Mauri C, Menon M. The expanding family of regulatory B cells. Int Immunol. 2015;27(10):479–86.CrossRefPubMedPubMedCentral

Evans JG, Chavez-Rueda KA, Eddaoudi A, Meyer-Bahlburg A, Rawlings DJ, Ehrenstein MR, Mauri C. Novel suppressive function of transitional 2 B cells in experimental arthritis. J Immunol. 2007;178(12):7868–78.CrossRefPubMed

Yanaba K, Bouaziz JD, Haas KM, Poe JC, Fujimoto M, Tedder TF. A regulatory B cell subset with a unique CD1dhiCD5+ phenotype controls T cell-dependent inflammatory responses. Immunity. 2008;28(5):639–50.CrossRefPubMed

Matsumoto M, Baba A, Yokota T, Nishikawa H, Ohkawa Y, Kayama H, Kallies A, Nutt SL, Sakaguchi S, Takeda K, et al. Interleukin-10-producing plasmablasts exert regulatory function in autoimmune inflammation. Immunity. 2014;41(6):1040–51.CrossRefPubMed

Shen P, Roch T, Lampropoulou V, O'Connor RA, Stervbo U, Hilgenberg E, Ries S, Dang VD, Jaimes Y, Daridon C, et al. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature. 2014;507(7492):366–70.CrossRefPubMedPubMedCentral

Blair PA, Norena LY, Flores-Borja F, Rawlings DJ, Isenberg DA, Ehrenstein MR, Mauri C. CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients. Immunity. 2010;32(1):129–40.CrossRefPubMed

Iwata Y, Matsushita T, Horikawa M, Dilillo DJ, Yanaba K, Venturi GM, Szabolcs PM, Bernstein SH, Magro CM, Williams AD, et al. Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. Blood. 2011;117(2):530–41.CrossRefPubMedPubMedCentral

Kessel A, Haj T, Peri R, Snir A, Melamed D, Sabo E, Toubi E. Human CD19(+)CD25(high) B regulatory cells suppress proliferation of CD4(+) T cells and enhance Foxp3 and CTLA-4 expression in T-regulatory cells. Autoimmun Rev. 2012;11(9):670–7.CrossRefPubMed

10.

Rosser EC, Mauri C. Regulatory B cells: origin, phenotype, and function. Immunity. 2015;42(4):607–12.CrossRefPubMed

11.

Xiao S, Brooks CR, Sobel RA, Kuchroo VK. Tim-1 is essential for induction and maintenance of IL-10 in regulatory B cells and their regulation of tissue inflammation. J Immunol. 2015;194(4):1602–8.CrossRefPubMedPubMedCentral

12.

Ding Q, Yeung M, Camirand G, Zeng Q, Akiba H, Yagita H, Chalasani G, Sayegh MH, Najafian N, Rothstein DM. Regulatory B cells are identified by expression of TIM-1 and can be induced through TIM-1 ligation to promote tolerance in mice. J Clin Invest. 2011;121(9):3645–56.CrossRefPubMedPubMedCentral

13.

Xiao S, Brooks CR, Zhu C, Wu C, Sweere JM, Petecka S, Yeste A, Quintana FJ, Ichimura T, Sobel RA, et al. Defect in regulatory B-cell function and development of systemic autoimmunity in T-cell Ig mucin 1 (Tim-1) mucin domain-mutant mice. Proc Natl Acad Sci U S A. 2012;109(30):12105–10.CrossRefPubMedPubMedCentral

14.

Yeung MY, Ding Q, Brooks CR, Xiao S, Workman CJ, Vignali DA, Ueno T, Padera RF, Kuchroo VK, Najafian N, et al. TIM-1 signaling is required for maintenance and induction of regulatory B cells. Am J Transplant. 2015;15(4):942–53.CrossRefPubMedPubMedCentral

15.

Liu J, Zhan W, Kim CJ, Clayton K, Zhao H, Lee E, Cao JC, Ziegler B, Gregor A, Yue FY, et al. IL-10-producing B cells are induced early in HIV-1 infection and suppress HIV-1-specific T cell responses. PLoS One. 2014;9(2):e89236.CrossRefPubMedPubMedCentral

16.

Kristensen B, Hegedus L, Lundy SK, Brimnes MK, Smith TJ, Nielsen CH. Characterization of regulatory B cells in Graves' disease and Hashimoto's thyroiditis. PLoS One. 2015;10(5):e0127949.CrossRefPubMedPubMedCentral

17.

Xue H, Lin F, Tan H, Zhu ZQ, Zhang ZY, Zhao L. Overrepresentation of IL-10-expressing B cells suppresses cytotoxic CD4+ T cell activity in HBV-induced hepatocellular carcinoma. PLoS One. 2016;11(5):e0154815.CrossRefPubMedPubMedCentral

18.

Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med. 2009;360(19):1989–2003.CrossRefPubMed

19.

Parel Y, Aurrand-Lions M, Scheja A, Dayer JM, Roosnek E, Chizzolini C. Presence of CD4 + CD8+ double-positive T cells with very high interleukin-4 production potential in lesional skin of patients with systemic sclerosis. Arthritis Rheum. 2007;56(10):3459–67.CrossRefPubMed

20.

Chizzolini C, Parel Y, De Luca C, Tyndall A, Akesson A, Scheja A, Dayer JM. Systemic sclerosis Th2 cells inhibit collagen production by dermal fibroblasts via membrane-associated tumor necrosis factor alpha. Arthritis Rheum. 2003;48(9):2593–604.CrossRefPubMed

21.

Truchetet ME, Brembilla NC, Montanari E, Allanore Y, Chizzolini C. Increased frequency of circulating Th22 in addition to Th17 and Th2 lymphocytes in systemic sclerosis: association with interstitial lung disease. Arthritis Res Ther. 2011;13(5):R166.CrossRefPubMedPubMedCentral

22.

Liu M, Yang J, Xing X, Cui X, Li M. Interleukin-17A promotes functional activation of systemic sclerosis patient-derived dermal vascular smooth muscle cells by extracellular-regulated protein kinases signalling pathway. Arthritis Res Ther. 2014;16(6):4223.CrossRefPubMedPubMedCentral

23.

Radstake TR, van Bon L, Broen J, Wenink M, Santegoets K, Deng Y, Hussaini A, Simms R, Cruikshank WW, Lafyatis R. Increased frequency and compromised function of T regulatory cells in systemic sclerosis (SSc) is related to a diminished CD69 and TGFbeta expression. PLoS One. 2009;4(6):e5981.CrossRefPubMedPubMedCentral

24.

Sato S, Fujimoto M, Hasegawa M, Takehara K. Altered blood B lymphocyte homeostasis in systemic sclerosis: expanded naive B cells and diminished but activated memory B cells. Arthritis Rheum. 2004;50(6):1918–27.CrossRefPubMed

25.

Matsushita T, Hasegawa M, Yanaba K, Kodera M, Takehara K, Sato S. Elevated serum BAFF levels in patients with systemic sclerosis: enhanced BAFF signaling in systemic sclerosis B lymphocytes. Arthritis Rheum. 2006;54(1):192–201.CrossRefPubMed

26.

Matsushita T, Hamaguchi Y, Hasegawa M, Takehara K, Fujimoto M. Decreased levels of regulatory B cells in patients with systemic sclerosis: association with autoantibody production and disease activity. Rheumatology (Oxford). 2015;55(2):263–7.CrossRef

27.

Mavropoulos A, Simopoulou T, Varna A, Liaskos C, Katsiari CG, Bogdanos DP, Sakkas LI. Breg cells are numerically decreased and functionally impaired in patients with systemic sclerosis. Arthritis Rheumatol. 2016;68(2):494–504.CrossRefPubMed

28.

Soto L, Ferrier A, Aravena O, Fonseca E, Berendsen J, Biere A, Bueno D, Ramos V, Aguillon JC, Catalan D. Systemic sclerosis patients present alterations in the expression of molecules involved in B-cell regulation. Front Immunol. 2015;6:496.CrossRefPubMedPubMedCentral

29.

Sakkas LI, Bogdanos DP. Systemic sclerosis: New evidence re-enforces the role of B cells. Autoimmun Rev. 2016;15(2):155–61.CrossRefPubMed

30.

van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, Matucci-Cerinic M, Naden RP, Medsger Jr TA, Carreira PE, et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum. 2013;65(11):2737–47.CrossRefPubMedPubMedCentral

31.

Sims GP, Ettinger R, Shirota Y, Yarboro CH, Illei GG, Lipsky PE. Identification and characterization of circulating human transitional B cells. Blood. 2005;105(11):4390–8.CrossRefPubMedPubMedCentral

32.

Flores-Borja F, Bosma A, Ng D, Reddy V, Ehrenstein MR, Isenberg DA, Mauri C. CD19 + CD24hiCD38hi B cells maintain regulatory T cells while limiting TH1 and TH17 differentiation. Sci Transl Med. 2013;5(173):173ra123.CrossRef

33.

Sato S, Hasegawa M, Fujimoto M, Tedder TF, Takehara K. Quantitative genetic variation in CD19 expression correlates with autoimmunity. J Immunol. 2000;165(11):6635–43.CrossRefPubMed

34.

Saito E, Fujimoto M, Hasegawa M, Komura K, Hamaguchi Y, Kaburagi Y, Nagaoka T, Takehara K, Tedder TF, Sato S. CD19-dependent B lymphocyte signaling thresholds influence skin fibrosis and autoimmunity in the tight-skin mouse. J Clin Invest. 2002;109(11):1453–62.CrossRefPubMedPubMedCentral

35.

Liu BS, Cao Y, Huizinga TW, Hafler DA, Toes RE. TLR-mediated STAT3 and ERK activation controls IL-10 secretion by human B cells. Eur J Immunol. 2014;44(7):2121–9.CrossRefPubMed

36.

Yoshizaki A, Iwata Y, Komura K, Ogawa F, Hara T, Muroi E, Takenaka M, Shimizu K, Hasegawa M, Fujimoto M, et al. CD19 regulates skin and lung fibrosis via Toll-like receptor signaling in a model of bleomycin-induced scleroderma. Am J Pathol. 2008;172(6):1650–63.CrossRefPubMedPubMedCentral

37.

Lafyatis R, O'Hara C, Feghali-Bostwick CA, Matteson E. B cell infiltration in systemic sclerosis-associated interstitial lung disease. Arthritis Rheum. 2007;56(9):3167–8.CrossRefPubMed

38.

Whitfield ML, Finlay DR, Murray JI, Troyanskaya OG, Chi JT, Pergamenschikov A, McCalmont TH, Brown PO, Botstein D, Connolly MK. Systemic and cell type-specific gene expression patterns in scleroderma skin. Proc Natl Acad Sci U S A. 2003;100(21):12319–24.CrossRefPubMedPubMedCentral

39.

Daoussis D, Melissaropoulos K, Sakellaropoulos G, Antonopoulos I, Markatseli TE, Simopoulou T, Georgiou P, Andonopoulos AP, Drosos AA, Sakkas L, et al. A multicenter, open-label, comparative study of B-cell depletion therapy with Rituximab for systemic sclerosis-associated interstitial lung disease. Semin Arthritis Rheum. 2016. doi:10.1016/j.semarthrit.2016.10.003 [Epub ahead of print].

40.

Bouaziz JD, Calbo S, Maho-Vaillant M, Saussine A, Bagot M, Bensussan A, Musette P. IL-10 produced by activated human B cells regulates CD4(+) T-cell activation in vitro. Eur J Immunol. 2010;40(10):2686–91.CrossRefPubMed

41.

Tretter T, Venigalla RK, Eckstein V, Saffrich R, Sertel S, Ho AD, Lorenz HM. Induction of CD4+ T-cell anergy and apoptosis by activated human B cells. Blood. 2008;112(12):4555–64.CrossRefPubMed

42.

Wong SH, Barlow JL, Nabarro S, Fallon PG, McKenzie AN. Tim-1 is induced on germinal centre B cells through B-cell receptor signalling but is not essential for the germinal centre response. Immunology. 2010;131(1):77–88.PubMedPubMedCentral

43.

Munoz LE, Lauber K, Schiller M, Manfredi AA, Herrmann M. The role of defective clearance of apoptotic cells in systemic autoimmunity. Nat Rev Rheumatol. 2010;6(5):280–9.CrossRefPubMed

44.

Zhang Y, Zhang X, Xia Y, Jia X, Li H, Zhang Y, Shao Z, Xin N, Guo M, Chen J, et al. CD19+ Tim-1+ B cells are decreased and negatively correlated with disease severity in Myasthenia Gravis patients. Immunol Res. 2016.

45.

Rosser EC, Oleinika K, Tonon S, Doyle R, Bosma A, Carter NA, Harris KA, Jones SA, Klein N, Mauri C. Regulatory B cells are induced by gut microbiota-driven interleukin-1beta and interleukin-6 production. Nat Med. 2014;20(11):1334–9.CrossRefPubMed

Title: TIM-1 defines a human regulatory B cell population that is altered in frequency and function in systemic sclerosis patients
Authors: Octavio Aravena
Ashley Ferrier
Madhvi Menon
Claudia Mauri
Juan Carlos Aguillón
Lilian Soto
Diego Catalán
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Arthritis Research & Therapy / Issue 1/2017
Electronic ISSN: 1478-6362
DOI: https://doi.org/10.1186/s13075-016-1213-9

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Abstract

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Results

Conclusions

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