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A pathogenetic role for IL-21 in primary Sjögren syndrome

Nature Reviews Rheumatology volume 11, pages 368–374 (2015)Cite this article

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Abstract

Advances in our understanding of the pathogenesis of primary Sjögren syndrome (pSS) characterize it as a highly complex process encompassing both the initiation of innate immunity and subsequent adaptive immune responses. IL-21 is receiving attention as a potential key player in the pathogenesis of pSS owing to its pleiotropic effects on the type I interferon signalling pathway, and newly identified roles in generation of follicular and IL-17-producing subtypes of helper T cells, as well as plasma-cell differentiation and B-cell activation. Taking into consideration the diverse biological functions of IL-21 and its clinical relevance to pSS, we propose that this cytokine has a central role in orchestrating the complex immune response in pSS. This hypothesis might provide new insight into the pathogenesis of pSS and facilitate the development of effective therapeutic strategies.

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Figure 1: IL-21 signalling pathways: a possible link between type I interferons and IL-21.
Figure 2: Actions of IL-21 on target cells.
Figure 3: Hypothetical central role of IL-21 in pSS.

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References

  1. Fox, R. I. Sjögren's syndrome. Lancet 366, 321–331 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Nocturne, G. & Mariette, X. Advances in understanding the pathogenesis of primary Sjögren's syndrome. Nat. Rev. Rheumatol. 9, 544–556 (2013).

    Article  CAS  PubMed  Google Scholar 

  3. Mackay, F. & Schneider, P. Cracking the BAFF code. Nat. Rev. Immunol. 9, 491–502 (2009).

    Article  CAS  PubMed  Google Scholar 

  4. Lai Kwan Lam, Q., King Hung Ko, O., Zheng, B. J. & Lu, L. Local BAFF gene silencing suppresses TH17-cell generation and ameliorates autoimmune arthritis. Proc. Natl Acad. Sci. USA 105, 14993–14998 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Ambrosi, A., Espinosa, A. & Wahren-Herlenius, M. IL-17: a new actor in IFN-driven systemic autoimmune diseases. Eur. J. Immunol. 42, 2274–2284 (2012).

    Article  CAS  PubMed  Google Scholar 

  6. Jin, L. et al. CD4+CXCR5+ follicular helper T cells in salivary gland promote B cells maturation in patients with primary Sjögren's syndrome. Int. J. Clin. Exp. Pathol. 7, 1988–1996 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Mitsdoerffer, M. et al. Proinflammatory T helper type 17 cells are effective B-cell helpers. Proc. Natl Acad. Sci. USA 107, 14292–14297 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Spolski, R. & Leonard, W. J. Interleukin-21: basic biology and implications for cancer and autoimmunity. Annu. Rev. Immunol. 26, 57–79 (2008).

    Article  CAS  PubMed  Google Scholar 

  9. Liao, W., Lin, J. X. & Leonard, W. J. IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation. Curr. Opin. Immunol. 23, 598–604 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. De Paiva, C. S. et al. Age-related T-cell cytokine profile parallels corneal disease severity in Sjögren's syndrome-like keratoconjunctivitis sicca in CD25 KO mice. Rheumatology (Oxford) 49, 246–258 (2010).

    Article  CAS  Google Scholar 

  11. Maiti, A. K. et al. Confirmation of an association between rs6822844 at the IL2–IL21 region and multiple autoimmune diseases: evidence of a general susceptibility locus. Arthritis Rheum. 62, 323–329 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kang, K. Y. et al. Impact of interleukin-21 in the pathogenesis of primary Sjögren's syndrome: increased serum levels of interleukin-21 and its expression in the labial salivary glands. Arthritis Res. Ther. 13, R179 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. McGuire, H. M. et al. A subset of interleukin-21+ chemokine receptor CCR9+ T helper cells target accessory organs of the digestive system in autoimmunity. Immunity 34, 602–615 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Li, X. Y. et al. Role of the frequency of blood CD4+ CXCR5+ CCR6+ T cells in autoimmunity in patients with Sjögren's syndrome. Biochem. Biophys. Res. Commun. 422, 238–244 (2012).

    Article  CAS  PubMed  Google Scholar 

  15. Liu, H., Liu, G., Gong, L., Zhang, Y. & Jiang, G. Local suppression of IL-21 in submandibular glands retards the development of Sjögren's syndrome in non-obese diabetic mice. J. Oral Pathol. Med. 41, 728–735 (2012).

    Article  CAS  PubMed  Google Scholar 

  16. Mavragani, C. P., Schini, M., Gravani, F., Kaltsas, G. & Moutsopoulos, H. M. Brief report: adrenal autoimmunity in primary Sjögren's syndrome. Arthritis Rheum. 64, 4066–4071 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. Jin, L. et al. CD4+CXCR5+ follicular helper T cells in salivary gland promote B cell maturation in patients with primary Sjögren's syndrome. Int. J. Clin. Exp. Pathol. 7, 1988–1996 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Lessard, C. J. et al. Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren's syndrome. Nat. Genet. 45, 1284–1292 (2013).

    Article  CAS  PubMed  Google Scholar 

  19. Li, Y. et al. A genome-wide association study in Han Chinese identifies a susceptibility locus for primary Sjögren's syndrome at 7q11.23. Nat. Genet. 45, 1361–1365 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. Hooks, J. J. et al. Immune interferon in the circulation of patients with autoimmune disease. N. Engl. J. Med. 301, 5–8 (1979).

    Article  CAS  PubMed  Google Scholar 

  21. Bave, U. et al. Activation of the type I interferon system in primary Sjögren's syndrome: a possible etiopathogenic mechanism. Arthritis Rheum. 52, 1185–1195 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Emamian, E. S. et al. Peripheral blood gene expression profiling in Sjögren's syndrome. Genes Immun. 10, 285–296 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Brkic, Z. et al. Prevalence of interferon type I signature in CD14 monocytes of patients with Sjögren's syndrome and association with disease activity and BAFF gene expression. Ann. Rheum. Dis. 72, 728–735 (2013).

    Article  CAS  PubMed  Google Scholar 

  24. Litinskiy, M. B. et al. DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nat. Immunol. 3, 822–829 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lavie, F. et al. B-cell activating factor of the tumour necrosis factor family expression in blood monocytes and T cells from patients with primary Sjögren's syndrome. Scand. J. Immunol. 67, 185–192 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. Sivori, S. et al. IL-21 induces both rapid maturation of human CD34+ cell precursors towards NK cells and acquisition of surface killer Ig-like receptors. Eur. J. Immunol. 33, 3439–3447 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Parrish-Novak, J. et al. Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 408, 57–63 (2000).

    CAS  PubMed  Google Scholar 

  28. Strengell, M. et al. IL-21 in synergy with IL-15 or IL-18 enhances IFN-γ production in human NK and T cells. J. Immunol. 170, 5464–5469 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Katsifis, G. E., Rekka, S., Moutsopoulos, N. M., Pillemer, S. & Wahl, S. M. Systemic and local interleukin-17 and linked cytokines associated with Sjögren's syndrome immunopathogenesis. Am. J. Pathol. 175, 1167–1177 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Fei, Y. et al. Clinical parameter and TH17 related to lymphocytes infiltrating degree of labial salivary gland in primary Sjögren's syndrome. Clin. Rheumatol. 33, 523–529 (2014).

    Article  PubMed  Google Scholar 

  31. Sakai, A., Sugawara, Y., Kuroishi, T., Sasano, T. & Sugawara, S. Identification of IL-18 and TH17 cells in salivary glands of patients with Sjögren's syndrome, and amplification of IL-17-mediated secretion of inflammatory cytokines from salivary gland cells by IL-18. J. Immunol. 181, 2898–2906 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Ciccia, F. et al. Potential involvement of IL-22 and IL-22-producing cells in the inflamed salivary glands of patients with Sjögren's syndrome. Ann. Rheum. Dis. 71, 295–301 (2012).

    Article  CAS  PubMed  Google Scholar 

  33. Kawanami, T. et al. Skewed production of IL-6 and TGFβ by cultured salivary gland epithelial cells from patients with Sjögren's syndrome. PLoS ONE 7, e45689 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lin, X. et al. TH17 cells play a critical role in the development of experimental Sjögren's syndrome. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2013-204584.

  35. Deenick, E. K. & Tangye, S. G. Autoimmunity: IL-21: a new player in TH17-cell differentiation. Immunol. Cell Biol. 85, 503–505 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Attridge, K. et al. IL-21 inhibits T cell IL-2 production and impairs TREG homeostasis. Blood 119, 4656–4664 (2012).

    Article  CAS  PubMed  Google Scholar 

  37. Crotty, S. Follicular helper CD4 T cells (TFH). Annu. Rev. Immunol. 29, 621–663 (2011).

    Article  CAS  PubMed  Google Scholar 

  38. Yu, D. & Vinuesa, C. G. The elusive identity of T follicular helper cells. Trends Immunol. 31, 377–383 (2010).

    Article  CAS  PubMed  Google Scholar 

  39. Szabo, K. et al. Follicular helper T cells may play an important role in the severity of primary Sjögren's syndrome. Clin. Immunol. 147, 95–104 (2013).

    Article  CAS  PubMed  Google Scholar 

  40. Ma, C. S., Deenick, E. K., Batten, M. & Tangye, S. G. The origins, function, and regulation of T follicular helper cells. J. Exp. Med. 209, 1241–1253 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Choi, Y. S. et al. ICOS receptor instructs T follicular helper cell versus effector cell differentiation via induction of the transcriptional repressor Bcl6. Immunity 34, 932–946 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Dong, C., Temann, U. A. & Flavell, R. A. Cutting edge: critical role of inducible costimulator in germinal center reactions. J. Immunol. 166, 3659–3662 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Spolski, R. & Leonard, W. J. IL-21 and T follicular helper cells. Int. Immunol. 22, 7–12 (2010).

    Article  CAS  PubMed  Google Scholar 

  44. Risselada, A. P., Looije, M. F., Kruize, A. A., Bijlsma, J. W. & van Roon, J. A. The role of ectopic germinal centers in the immunopathology of primary Sjögren's syndrome: a systematic review. Semin. Arthritis Rheum. 42, 368–376 (2013).

    Article  CAS  PubMed  Google Scholar 

  45. McHeyzer-Williams, L. J., Pelletier, N., Mark, L., Fazilleau, N. & McHeyzer-Williams, M. G. Follicular helper T cells as cognate regulators of B cell immunity. Curr. Opin. Immunol. 21, 266–273 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Youinou, P. & Pers, J. O. Disturbance of cytokine networks in Sjögren's syndrome. Arthritis Res. Ther. 13, 227 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Maehara, T. et al. Selective localization of T helper subsets in labial salivary glands from primary Sjögren's syndrome patients. Clin. Exp. Immunol. 169, 89–99 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Pene, J. et al. Cutting edge: IL-21 is a switch factor for the production of IgG1 and IgG3 by human B cells. J. Immunol. 172, 5154–5157 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Linterman, M. A. et al. IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J. Exp. Med. 207, 353–363 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Dörner, T., Giesecke, C. & Lipsky, P. E. Mechanisms of B cell autoimmunity in SLE. Arthritis Res. Ther. 13, 243 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Lee, S. K. et al. B cell priming for extrafollicular antibody responses requires Bcl-6 expression by T cells. J. Exp. Med. 208, 1377–1388 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Chang, P. P. et al. Identification of Bcl-6-dependent follicular helper NKT cells that provide cognate help for B cell responses. Nat. Immunol. 13, 35–43 (2012).

    Article  CAS  Google Scholar 

  53. Puga, I. et al. B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen. Nat. Immunol. 13, 170–180 (2012).

    Article  CAS  Google Scholar 

  54. Daridon, C. et al. Identification of transitional type II B cells in the salivary glands of patients with Sjögren's syndrome. Arthritis Rheum. 54, 2280–2288 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Simard, N. et al. Analysis of the role of IL-21 in development of murine B cell progenitors in the bone marrow. J. Immunol. 186, 5244–5253 (2011).

    Article  CAS  PubMed  Google Scholar 

  56. Ettinger, R. et al. IL-21 and BAFF/BLyS synergize in stimulating plasma cell differentiation from a unique population of human splenic memory B cells. J. Immunol. 178, 2872–2882 (2007).

    Article  CAS  PubMed  Google Scholar 

  57. Skopouli, F. N. et al. T cell subpopulations in the labial minor salivary gland histopathologic lesion of Sjögren's syndrome. J. Rheumatol. 18, 210–214 (1991).

    CAS  PubMed  Google Scholar 

  58. Polihronis, M. et al. Modes of epithelial cell death and repair in Sjögren's syndrome (SS). Clin. Exp. Immunol. 114, 485–490 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Zeng, R. et al. Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion and function. J. Exp. Med. 201, 139–148 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Gottenberg, J. E. et al. CD4 CD25high regulatory T cells are not impaired in patients with primary Sjögren's syndrome. J. Autoimmun. 24, 235–242 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Sarigul, M. et al. The numbers of Foxp3+ TREG cells are positively correlated with higher grade of infiltration at the salivary glands in primary Sjögren's syndrome. Lupus 19, 138–145 (2010).

    Article  CAS  PubMed  Google Scholar 

  62. Nordmark, G. et al. Association of EBF1, FAM167A (C8orf13)-BLK and TNFSF4 gene variants with primary Sjögren's syndrome. Genes Immun. 12, 100–109 (2011).

    Article  CAS  PubMed  Google Scholar 

  63. Monteleone, G. et al. Interleukin-21 enhances T-helper cell type I signaling and interferon-γ production in Crohn's disease. Gastroenterology 128, 687–694 (2005).

    Article  CAS  PubMed  Google Scholar 

  64. Flesher, D. L., Sun, X., Behrens, T. W., Graham, R. R. & Criswell, L. A. Recent advances in the genetics of systemic lupus erythematosus. Expert Rev. Clin. Immunol. 6, 461–479 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Gomez, L. M. et al. PTPN22 C1858T polymorphism in Colombian patients with autoimmune diseases. Genes Immun. 6, 1628–1631 (2005).

    Article  Google Scholar 

  66. Nemazee, D. & Weigert, M. Revising B cell receptors. J. Exp. Med. 191, 1813–1817 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Maeda, M. et al. IL-21 enhances dendritic cell ability to induce interferon-γ production by natural killer T cells. Immunobiology 212, 537–547 (2007).

    Article  CAS  PubMed  Google Scholar 

  68. Obermeier, F. et al. OX40/OX40L interaction induces the expression of CXCR5 and contributes to chronic colitis induced by dextran sulfate sodium in mice. Eur. J. Immunol. 33, 3265–3274 (2003).

    Article  CAS  PubMed  Google Scholar 

  69. Nakayamada, S. et al. Early TH1 cell differentiation is marked by a TFH cell-like transition. Immunity 35, 919–931 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Konforte, D., Simard, N. & Paige, C. J. IL-21: an executor of B cell fate. J. Immunol. 182, 1781–1787 (2009).

    Article  CAS  PubMed  Google Scholar 

  71. Gong, Y. Z. et al. Differentiation of follicular helper T cells by salivary gland epithelial cells in primary Sjögren's syndrome. J. Autoimmun. 51, 57–66 (2014).

    Article  CAS  PubMed  Google Scholar 

  72. Vogelzang, A. et al. A fundamental role for interleukin-21 in the generation of T follicular helper cells. Immunity 29, 127–137 (2008).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors' research work is supported by the Basic Science Research Program, through the National Research Foundation of Korea (NRF), funded by the Ministry of Science, ICT & Future Planning (grant 2013R1A1A2059368 to H.-Y.-K.).

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Authors and Affiliations

  1. Division of Rheumatology, Department of Internal Medicine, Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-Gu, Seoul, 137-701, Republic of Korea

    Seung-Ki Kwok, Jennifer Lee, Kwi Young Kang, Ji Hyeon Ju & Sung-Hwan Park

  2. The Rheumatism Research Centre, Catholic Research Institute of Medical Science, The Catholic University of Korea, 222 Banpo-daero, Seocho-Gu, Seoul, 137-701, Republic of Korea

    Mi-La Cho

  3. Laboratory for Molecular Immunomodulation, School of Biomedical Sciences, Monash University, Clayton, 3800, VIC, Australia

    Di Yu

  4. Division of Rheumatology, Department of Internal Medicine, Konkuk University School of Medicine, 120-1 Neungdong-ro, Hwayang-dong, Gwangjin-gu, Seoul, 143-729, South Korea

    Hae-Rim Kim & Sang-Heon Lee

  5. Konkuk University Medical Centre, 120-1 Neungdong-ro, Hwayang-dong, Gwangjin-gu, Seoul, 143-729, South Korea

    Ho-Youn Kim

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Contributions

S.-K.K. and J.L. contributed equally to this article. S.-K.K., J.L., D.Y., H.-R.K. and H.-Y.K. participated in researching the data for the article, discussions of its content, writing the manuscript, and reviewing and/or editing of the manuscript before submission. K.Y.K. M.-L.C., J.H.J., S.-H.L. and S.-H.P. contributed to discussions of the article content and review or editing of the manuscript before submission.

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Correspondence to Ho-Youn Kim.

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Kwok, SK., Lee, J., Yu, D. et al. A pathogenetic role for IL-21 in primary Sjögren syndrome. Nat Rev Rheumatol 11, 368–374 (2015). https://doi.org/10.1038/nrrheum.2014.225

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