Interleukin (IL)-17-producing pathogenic T lymphocytes co-express CD20 and are depleted by rituximab in primary Sjögren's syndrome: a pilot study
A. Alunno
Rheumatology Section, Department of Medicine, University of Perugia, Perugia, Italy
These authors contributed equally to the study.
Search for more papers by this authorF. Carubbi
Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
These authors contributed equally to the study.
Search for more papers by this authorO. Bistoni
Rheumatology Section, Department of Medicine, University of Perugia, Perugia, Italy
Search for more papers by this authorS. Caterbi
Rheumatology Section, Department of Medicine, University of Perugia, Perugia, Italy
Search for more papers by this authorE. Bartoloni
Rheumatology Section, Department of Medicine, University of Perugia, Perugia, Italy
Search for more papers by this authorP. Di Benedetto
Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
Search for more papers by this authorP. Cipriani
Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
Search for more papers by this authorR. Giacomelli
Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
Search for more papers by this authorCorresponding Author
R. Gerli
Rheumatology Section, Department of Medicine, University of Perugia, Perugia, Italy
Correspondence: R. Gerli, Rheumatology Unit, Department of Medicine, University of Perugia, Via Enrico Dal Pozzo, I-06122 Perugia, Italy. E-mail: [email protected]Search for more papers by this authorA. Alunno
Rheumatology Section, Department of Medicine, University of Perugia, Perugia, Italy
These authors contributed equally to the study.
Search for more papers by this authorF. Carubbi
Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
These authors contributed equally to the study.
Search for more papers by this authorO. Bistoni
Rheumatology Section, Department of Medicine, University of Perugia, Perugia, Italy
Search for more papers by this authorS. Caterbi
Rheumatology Section, Department of Medicine, University of Perugia, Perugia, Italy
Search for more papers by this authorE. Bartoloni
Rheumatology Section, Department of Medicine, University of Perugia, Perugia, Italy
Search for more papers by this authorP. Di Benedetto
Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
Search for more papers by this authorP. Cipriani
Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
Search for more papers by this authorR. Giacomelli
Rheumatology Unit, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
Search for more papers by this authorCorresponding Author
R. Gerli
Rheumatology Section, Department of Medicine, University of Perugia, Perugia, Italy
Correspondence: R. Gerli, Rheumatology Unit, Department of Medicine, University of Perugia, Via Enrico Dal Pozzo, I-06122 Perugia, Italy. E-mail: [email protected]Search for more papers by this authorSummary
Compelling evidence suggests that interleukin (IL)-17 and IL-17-producing cells play a pivotal role in the pathogenesis of primary Sjögren's syndrome (pSS). We investigated phenotypical and functional effects of the anti-CD20 antibody rituximab (RTX) on circulating and glandular IL-17-producing T cells in pSS. RTX is able to deplete glandular IL-17+ CD3+CD4–CD8– double-negative (DN) and CD4+ Th17 cells as well as circulating IL-17+ DN T cells. A fraction of glandular and circulating IL-17+ DN cells and CD4+ T helper type 17 (Th17) cells co-expresses CD20 on the cell surface explaining, at least in part, such depletive capacity of RTX. The exposure to RTX does not rescue the in-vitro corticosteroid resistance of IL-17+ DN T cells. Our results support further the therapeutic role in pSS of RTX that, despite its B cell specificity, appears able to also hamper IL-17-producing T cells in this disease.
Supporting Information
Additional Supporting information may be found in the online version of this article at the publisher's web-site:
| Filename | Description |
|---|---|
| cei12771-sup-0001-suppinfo1.tif2.6 MB |
Fig. S1. Representative flow cytometry dot plots of T cells isolated from minor salivary glands of patients with primary Sjögren's syndrome (pSS) (a–d) and isotype controls of tissue immunofluorescence (e–f). (a) CD3+ lymphocytes; (b) CD4+ T helper type 17 (Th17) cells; (c) DN T cells; (d) interleukin (IL)-17 in double-negative (DN) T cells; (e) Alexa Fluor 488 isotype control; (f) Alexa Fluor 555 isotype control. |
| cei12771-sup-0002-suppinfo2.tif4.1 MB |
Fig. S2. Representative flow cytometry dot-plots of co-expression of CD20 and interleukin (IL)-17 in CD4+ T helper type 17 (Th17) and double-negative (DN) T cells. (a) CD3+ lymphocytes; (b) DN T cells, (c) IL-17+ DN T cells, (d) CD20+ IL-17+ DN T cells; (e) CD4+ Th17 cells; (f) CD20+ IL-17+ CD4+ Th17 cells. (g) Mean fluorescence intensity of CD20 before and after treatment with rituximab. Asterisks indicate P-values less than 0·05 with respect to corresponding T0 P-values calculated with one-way analysis of variance for repeated-measures and multiple-comparison post-hoc tests. The plots display mean ± standard error of the mean. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1 Ambrosi A, Wahren-Herlenius M. Update on the immunobiology of Sjogren's syndrome. Curr Opin Rheumatol 2015; 27: 468–75.
- 2 Brito-Zerón P, Ramos-Casals M. Advances in the understanding and treatment of systemic complications in Sjögren syndrome. Curr Opin Rheumatol 2014; 26: 520–7.
- 3 Cornec D, Jamin C, Pers JO. Sjögren's syndrome: where do we stand, and where shall we go? J Autoimmun 2014; 51: 109–14.
- 4 Routsias JG, Goules JD, Charalampakis G, Tzima S, Papageorgiou A, Voulgarelis M. Malignant lymphoma in primary Sjögren's syndrome: an update on the pathogenesis and treatment. Semin Arthritis Rheum 2013; 43: 178–86.
- 5 Lin X, Rui K, Deng J et al. Th17 cells play a critical role in the development of experimental Sjogren's syndrome. Ann Rheum Dis 2015; 74: 1302–10.
- 6 Nguyen CQ, Hu MH, Li Y, Stewart C, Peck AB. Salivary gland tissue expression of interleukin-23 and interleukin-17 in Sjogren's syndrome. Arthritis Rheum 2008; 58: 734–74.
- 7 Nguyen CG, Yin H, Lee BH, Carcamo WC, Chiorini JA, Peck AB. Pathogenic effect of interleukin-17A in induction of Sjögren's syndrome-like disease using adenovirus-mediated gene transfer. Arthritis Res Ther 2010; 12: R220.
- 8 Alunno A, Bistoni O, Bartoloni E et al. IL-17-producing CD4-CD8- T cells are expanded in the peripheral blood, infiltrate salivary glands and are resistant to corticosteroids in patients with primary Sjogren's syndrome. Ann Rheum Dis 2013; 72: 286–92.
- 9 Lin X, Tian J, Rui K et al. The role of T helper 17 cell subsets in Sjögren's syndrome: similarities and differences between mouse model and humans. Ann Rheum Dis 2014; 73: e43.
- 10 Alunno A, Carubbi F, Caterbi S et al. The role of T helper 17 cell subsets in Sjögren's syndrome: similarities and differences between mouse model and humans. Ann Rheum Dis 2014; 73: e42.
- 11 Alunno A, Carubbi F, Bistoni O et al. CD4-CD8- T-cells in primary Sjögren's syndrome: association with the extent of glandular involvement. J Autoimmun 2014; 51: 38–43.
- 12 Alunno A, Montanucci P, Bistoni O et al. In vitro immunomodulatory effects of microencapsulated umbilical cord Wharton jelly-derived mesenchymal stem cells in primary Sjögren's syndrome. Rheumatology (Oxf) 2015; 54: 163–8.
- 13 Ramos-Casals M, Brito-Zerón P, Sisó-Almirall A, Bosch X, Tzioufas AG. Topical and systemic medications for the treatment of primary Sjögren's syndrome. Nat Rev Rheumatol 2012; 8: 399–411.
- 14 Brito-Zerón P, Sisó-Almirall A, Bové A, Kostov BA, Ramos-Casals M. Primary Sjögren syndrome: an update on current pharmacotherapy options and future directions. Expert Opin Pharmacother 2013; 14: 279–89.
- 15 Carubbi F, Alunno A, Cipriani P et al. Rituximab in pSS: a ten-year journey. Lupus 2014; 23: 1337–49.
- 16 Glennie MJ, French RR, Cragg MS, Taylor RP. Mechanisms of killing by anti-CD20 monoclonal antibodies. Mol Immunol 2007; 44: 3823–37.
- 17 Mélet J, Mulleman D, Goupille P, Ribourtout B, Watier H, Thibault G. Rituximab-induced T cell depletion in patients with rheumatoid arthritis: association with clinical response. Arthritis Rheum 2013; 65: 2783–90.
- 18 Eggleton P, Bremer E, Tarr JM et al. Frequency of Th17 CD20+ cells in the peripheral blood of rheumatoid arthritis patients is higher compared to healthy subjects. Arthritis Res Ther 2011; 13: R208.
- 19 van de Veerdonk FL, Lauwerys B, Marijnissen RJ et al. The anti-CD20 antibody rituximab reduces the Th17 cell response. Arthritis Rheum 2011; 63: 1507–16.
- 20 Abdulahad WH, Meijer JM, Kroese FG. B-cell reconstitution and T-helper-cell balance after rituximab treatment of active primary Sjogren's syndrome. Arthritis Rheum 2011; 63: 1116–23.
- 21 Ciccia F, Guggino G, Rizzo A et al. Rituximab modulates IL-17 expression in the salivary glands of patients with primary Sjogren's syndrome. Rheumatology (Oxf) 2014; 53: 1313–20.
- 22 Ciccia F, Giardina A, Rizzo A et al. Rituximab modulates the expression of IL-22 in the salivary glands of patients with primary Sjogren's syndrome. Ann Rheum Dis 2013; 72: 782–3.
- 23 Carubbi F, Cipriani P, Marrelli A et al. Efficacy and safety of rituximab treatment in early primary Sjögren's syndrome: a prospective, multi-center, follow-up study. Arthritis Res Ther 2013; 15: R172.
- 24 Vitali C, Bombardieri S, Jonsson R et al. Classification criteria for Sjogren's syndrome: a revised version of the European criteria proposed by the American–European Consensus Group. Ann Rheum Dis 2002; 61: 554–8.
- 25 Seror R, Ravaud P, Bowman SJ et al. EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI): development of a consensus systemic disease activity index for primary Sjögren's syndrome. Ann Rheum Dis 2010; 69: 1103–9.
- 26 Conti F, Perricone C, Ceccarelli F, Valesini G. Rituximab treatment of systemic lupus erythematosus in controlled trials and in clinical practice: two sides of the same coin. Autoimmun Rev 2010; 9: 716–20.
- 27 Datta SK. Anti-CD20 antibody is an efficient therapeutic tool for the selective removal of autoreactive T cells. Nat Clin Pract Rheumatol 2009; 5: 80–2.
- 28 Wilk E, Witte T, Marquardt N et al. Depletion of functionally active CD20+ T cells by rituximab treatment. Arthritis Rheum 2009; 60: 3563–71.
- 29 Pers JO, Devauchelle V, Daridon C et al. BAFF-modulated repopulation of B lymphocytes in the blood and salivary glands of rituximab-treated patients with Sjögren's syndrome. Arthritis Rheum 2007; 56: 1464–77.
- 30 Alunno A, Bistoni O, Caterbi S, Bartoloni E, Cafaro G, Gerli R. Serum interleukin-17 in primary Sjögren's syndrome: association with disease duration and parotid gland swelling. Clin Exp Rheumatol 2015; 33: 129.
- 31 Hsu HC, Yang P, Wang J et al. Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat Immunol 2008; 9: 166–75.
- 32 Alunno A, Carubbi F, Bistoni O et al. T regulatory and T helper 17 cells in primary Sjögren's syndrome: facts and perspectives. Mediators Inflamm 2015; 2015: 243723.
- 33 Alunno A, Carubbi F, Bartoloni E et al. Unmasking the pathogenic role of IL-17 axis in primary Sjögren's syndrome: a new era for therapeutic targeting? Autoimmun Rev 2014; 13: 1167–73.
