1932

Abstract

Primary Sjögren's syndrome (SS) is a common chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands, mainly salivary and lacrimal, resulting in oral and ocular dryness, although virtually any organ system can be affected. SS-related systemic manifestations are classified as either related to the presence of periepithelial infiltrates in exocrine and parenchymal organs or resulting from immunocomplex deposition due to B cell hyperactivity with increased risk for B cell lymphoma development. Activation of both innate and adaptive immune pathways contributes to disease pathogenesis, with prominent interferon (IFN) signatures identified in both peripheral blood and affected salivary gland tissues. Recently, LINE-1 genomic repeat elements have been proposed as potential triggers of type I IFN pathway activation in SS through activation of Toll-like receptor–dependent and –independent pathways. In view of the increasingly appreciated variability of SS, elucidation of distinct operating pathways in relation to diverse clinical phenotypes and selection of the optimal therapeutic intervention remain major challenges. Inhibition of cathepsin S molecules, blockade of costimulation through administration of abatacept and inhibitors of B7-related molecules and CD40, blockade of B cell function and B cell survival factors, and disruption of the formation of ectopic germinal centers are considered the main therapeutic targets. Well-controlled multicenter clinical trials are ongoing and data are awaited.

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2017-01-14
2024-03-28
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Literature Cited

  1. Mavragani CP, Crow MK. 1.  2010. Activation of the type I interferon pathway in primary Sjogren's syndrome. J. Autoimmun. 35:225–31 [Google Scholar]
  2. Mavragani CP, Moutsopoulos HM. 2.  2014. Sjogren's syndrome. Annu. Rev. Pathol. Mech. Dis. 9:273–85 [Google Scholar]
  3. Mavragani CP, Moutsopoulos HM. 3.  2014. Sjogren syndrome. Can. Med. Assoc. J 186:E579–86 [Google Scholar]
  4. Zintzaras E, Voulgarelis M, Moutsopoulos HM. 4.  2005. The risk of lymphoma development in autoimmune diseases: a meta-analysis. Arch. Intern. Med. 165:2337–44 [Google Scholar]
  5. Skopouli FN, Dafni U, Ioannidis JP, Moutsopoulos HM. 5.  2000. Clinical evolution, and morbidity and mortality of primary Sjogren's syndrome. Semin. Arthritis Rheum 29:296–304 [Google Scholar]
  6. Fragkioudaki S, Mavragani CP, Moutsopoulos HM. 6.  2016. Predicting the risk of lymphoma among patients with Sjogren's syndrome: an easy to use clinical tool. Medicine 95:e3766 [Google Scholar]
  7. Nocturne G, Virone A, Ng WF. 7.  et al. 2016. Rheumatoid factor and disease activity are independent predictors of lymphoma in primary Sjogren's syndrome. Arthritis Rheumatol 68:977–85 [Google Scholar]
  8. Boumba D, Skopouli FN, Moutsopoulos HM. 8.  1995. Cytokine mRNA expression in the labial salivary gland tissues from patients with primary Sjogren's syndrome. Br. J. Rheumatol. 34:326–33 [Google Scholar]
  9. Mariette X, Ravaud P, Steinfeld S. 9.  et al. 2004. Inefficacy of infliximab in primary Sjogren's syndrome: results of the randomized, controlled Trial of Remicade in Primary Sjogren's Syndrome (TRIPSS). Arthritis Rheum 50:1270–76 [Google Scholar]
  10. Sankar V, Brennan MT, Kok MR. 10.  et al. 2004. Etanercept in Sjogren's syndrome: a twelve-week randomized, double-blind, placebo-controlled pilot clinical trial. Arthritis Rheum 50:2240–45 [Google Scholar]
  11. Zandbelt MM, de Wilde P, van Damme P. 11.  et al. 2004. Etanercept in the treatment of patients with primary Sjogren's syndrome: a pilot study. J. Rheumatol. 31:96–101 [Google Scholar]
  12. Mavragani CP, Niewold TB, Moutsopoulos NM. 12.  et al. 2007. Augmented interferon-alpha pathway activation in patients with Sjogren's syndrome treated with etanercept. Arthritis Rheum 56:3995–4004 [Google Scholar]
  13. Dantzer R, O'Connor JC, Freund GG. 13.  et al. 2008. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat. Rev. Neurosci. 9:46–56 [Google Scholar]
  14. Norheim KB, Harboe E, Goransson LG, Omdal R. 14.  2012. Interleukin-1 inhibition and fatigue in primary Sjogren's syndrome—a double blind, randomised clinical trial. PLOS ONE 7:e30123 [Google Scholar]
  15. Awada A, Nicaise C, Ena S. 15.  et al. 2014. Potential involvement of the IL-33-ST2 axis in the pathogenesis of primary Sjogren's syndrome. Ann. Rheum. Dis. 73:1259–63 [Google Scholar]
  16. Roescher N, Tak PP, Illei GG. 16.  2009. Cytokines in Sjogren's syndrome. Oral Dis 15:519–26 [Google Scholar]
  17. Gong YZ, Nititham J, Taylor K. 17.  et al. 2014. Differentiation of follicular helper T cells by salivary gland epithelial cells in primary Sjogren's syndrome. J. Autoimmun. 51:57–66 [Google Scholar]
  18. Maier-Moore JS, Horton CG, Mathews SA. 18.  et al. 2014. Interleukin-6 deficiency corrects nephritis, lymphocyte abnormalities, and secondary Sjogren's syndrome features in lupus-prone Sle1.Yaa mice. Arthritis Rheumatol 66:2521–31 [Google Scholar]
  19. Brkic Z, Maria NI, van Helden-Meeuwsen CG. 19.  et al. 2013. Prevalence of interferon type I signature in CD14 monocytes of patients with Sjogren's syndrome and association with disease activity and BAFF gene expression. Ann. Rheum. Dis. 72:728–35 [Google Scholar]
  20. Hall JC, Casciola-Rosen L, Berger AE. 20.  et al. 2012. Precise probes of type II interferon activity define the origin of interferon signatures in target tissues in rheumatic diseases. PNAS 109:17609–14 [Google Scholar]
  21. Hall JC, Baer AN, Shah AA. 21.  et al. 2015. Molecular subsetting of interferon pathways in Sjogren's syndrome. Arthritis Rheumatol 67:2437–46 [Google Scholar]
  22. Gottenberg JE, Cagnard N, Lucchesi C. 22.  et al. 2006. Activation of IFN pathways and plasmacytoid dendritic cell recruitment in target organs of primary Sjogren's syndrome. PNAS 103:2770–75 [Google Scholar]
  23. Mitsias DI, Tzioufas AG, Veiopoulou C. 23.  et al. 2002. The Th1/Th2 cytokine balance changes with the progress of the immunopathological lesion of Sjogren's syndrome. Clin. Exp. Immunol. 128:562–68 [Google Scholar]
  24. Rusakiewicz S, Nocturne G, Lazure T. 24.  et al. 2013. NCR3/NKp30 contributes to pathogenesis in primary Sjogren's syndrome. Sci. Transl. Med. 5:195ra96 [Google Scholar]
  25. Nezos A, Gravani F, Tassidou A. 25.  et al. 2015. Type I and II interferon signatures in Sjogren's syndrome pathogenesis: contributions in distinct clinical phenotypes and Sjogren's related lymphomagenesis. J. Autoimmun. 63:47–58 [Google Scholar]
  26. Mavragani CP, Sagalovskiy I, Guo Q. 26.  et al. 2016. Long interspersed nuclear element-1 retroelements are expressed in patients with systemic autoimmune disease and induce type I interferon. Arthritis Rheumatol 68:2686–96 [Google Scholar]
  27. Hung T, Pratt GA, Sundararaman B. 27.  et al. 2015. The Ro60 autoantigen binds endogenous retroelements and regulates inflammatory gene expression. Science 350:455–59 [Google Scholar]
  28. Thurmond RL, Sun S, Karlsson L, Edwards JP. 28.  2005. Cathepsin S inhibitors as novel immunomodulators. Curr. Opin. Investig. Drugs 6:473–82 [Google Scholar]
  29. Hamm-Alvarez SF, Janga SR, Edman MC. 29.  et al. 2014. Tear cathepsin S as a candidate biomarker for Sjogren's syndrome. Arthritis Rheumatol 66:1872–81 [Google Scholar]
  30. Tzioufas AG, Kapsogeorgou EK, Moutsopoulos HM. 30.  2012. Pathogenesis of Sjogren's syndrome: what we know and what we should learn. J. Autoimmun. 39:4–8 [Google Scholar]
  31. Saegusa K, Ishimaru N, Yanagi K. 31.  et al. 2000. Treatment with anti-CD86 costimulatory molecule prevents the autoimmune lesions in murine Sjogren's syndrome (SS) through up-regulated Th2 response. Clin. Exp. Immunol. 119:354–60 [Google Scholar]
  32. Yin H, Nguyen CQ, Samuni Y. 32.  et al. 2012. Local delivery of AAV2-CTLA4IgG decreases sialadenitis and improves gland function in the C57BL/6.NOD-Aec1Aec2 mouse model of Sjogren's syndrome. Arthritis Res. Ther. 14:R40 [Google Scholar]
  33. Tsuboi H, Matsumoto I, Hagiwara S. 33.  et al. 2014. Efficacy and safety of abatacept for patients with Sjogren's syndrome associated with rheumatoid arthritis: Rheumatoid arthritis with Orencia trial toward Sjogren's syndrome Endocrinopathy (ROSE) trial—an open-label, one-year, prospective study—interim analysis of 32 patients for 24 weeks. Modern Rheumatol. Jpn. Rheum. Assoc. 25:187–93 [Google Scholar]
  34. Adler S, Korner M, Forger F. 34.  et al. 2013. Evaluation of histologic, serologic, and clinical changes in response to abatacept treatment of primary Sjogren's syndrome: a pilot study. Arthritis Care Res 65:1862–68 [Google Scholar]
  35. Meiners PM, Vissink A, Kroese FG. 35.  et al. 2014. Abatacept treatment reduces disease activity in early primary Sjogren's syndrome (open-label proof of concept ASAP study). Ann. Rheum. Dis. 73:1393–96 [Google Scholar]
  36. Nezos A, Mavragani CP. 36.  2015. Contribution of genetic factors to Sjogren's syndrome and Sjogren's syndrome related lymphomagenesis. J. Immunol. Res 2015:754825 [Google Scholar]
  37. Maier-Moore JS, Koelsch KA, Smith K. 37.  et al. 2014. Antibody-secreting cell specificity in labial salivary glands reflects the clinical presentation and serology in patients with Sjogren's syndrome. Arthritis Rheumatol 66:3445–56 [Google Scholar]
  38. Hamza N, Hershberg U, Kallenberg CG. 38.  et al. 2015. Ig gene analysis reveals altered selective pressures on Ig-producing cells in parotid glands of primary Sjogren's syndrome patients. J. Immunol. 194:514–21 [Google Scholar]
  39. Youinou P, Devauchelle-Pensec V, Pers JO. 39.  2010. Significance of B cells and B cell clonality in Sjogren's syndrome. Arthritis Rheum 62:2605–10 [Google Scholar]
  40. Guggino G, Ciccia F, Raimondo S. 40.  et al. 2016. Invariant NKT cells are expanded in peripheral blood but are undetectable in salivary glands of patients with primary Sjogren's syndrome. Clin. Exp. Rheumatol. 34:25–31 [Google Scholar]
  41. Wermeling F, Lind SM, Jordo ED. 41.  et al. 2010. Invariant NKT cells limit activation of autoreactive CD1d-positive B cells. J. Exp. Med. 207:943–52 [Google Scholar]
  42. Dass S, Bowman SJ, Vital EM. 42.  et al. 2008. Reduction of fatigue in Sjogren syndrome with rituximab: results of a randomised, double-blind, placebo-controlled pilot study. Ann. Rheum. Dis. 67:1541–44 [Google Scholar]
  43. Seror R, Sordet C, Guillevin L. 43.  et al. 2007. Tolerance and efficacy of rituximab and changes in serum B cell biomarkers in patients with systemic complications of primary Sjogren's syndrome. Ann. Rheum. Dis. 66:351–57 [Google Scholar]
  44. Meiners PM, Arends S, Brouwer E. 44.  et al. 2012. Responsiveness of disease activity indices ESSPRI and ESSDAI in patients with primary Sjogren's syndrome treated with rituximab. Ann. Rheum. Dis. 71:1297–302 [Google Scholar]
  45. Mekinian A, Ravaud P, Hatron PY. 45.  et al. 2012. Efficacy of rituximab in primary Sjogren's syndrome with peripheral nervous system involvement: results from the AIR registry. Ann. Rheum. Dis. 71:84–87 [Google Scholar]
  46. Meijer JM, Meiners PM, Vissink A. 46.  et al. 2010. Effectiveness of rituximab treatment in primary Sjogren's syndrome: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 62:960–68 [Google Scholar]
  47. Devauchelle-Pensec V, Mariette X, Jousse-Joulin S. 47.  et al. 2014. Treatment of primary Sjogren syndrome with rituximab: a randomized trial. Ann. Intern. Med. 160:233–42 [Google Scholar]
  48. Meiners PM, Arends S, Meijer JM. 48.  et al. 2015. Efficacy of retreatment with rituximab in patients with primary Sjogren's syndrome. Clin. Exp. Rheumatol. 33:443–44 [Google Scholar]
  49. Alunno A, Carubbi F, Bistoni O. 49.  et al. 2016. Interleukin (IL)-17-producing pathogenic T lymphocytes co-express CD20 and are depleted by rituximab in primary Sjogren's syndrome: a pilot study. Clin. Exp. Immunol. 184:284–92 [Google Scholar]
  50. Gottenberg JE, Cinquetti G, Larroche C. 50.  et al. 2012. Efficacy of rituximab in systemic manifestations of primary Sjogren's syndrome: results in 78 patients of the AutoImmune and Rituximab registry. Ann. Rheum. Dis. 72:1026–31 [Google Scholar]
  51. Bowman S, Everett C, Bombardieri M. 51.  et al. 2015. Preliminary results of a double-blind randomised trial of rituximab anti-B-cell therapy in patients with primary Sjogren's syndrome. Arthritis Rheumatol 67:Suppl. 10 Abstr. [Google Scholar]
  52. Souza FB, Porfirio GJ, Andriolo BN. 52.  et al. 2016. Rituximab effectiveness and safety for treating primary Sjogren's syndrome (pSS): systematic review and meta-analysis. PLOS ONE 11:e0150749 [Google Scholar]
  53. Hamza N, Bootsma H, Yuvaraj S. 53.  et al. 2012. Persistence of immunoglobulin-producing cells in parotid salivary glands of patients with primary Sjogren's syndrome after B cell depletion therapy. Ann. Rheum. Dis. 71:1881–87 [Google Scholar]
  54. Hiepe F, Dorner T, Hauser AE. 54.  et al. 2011. Long-lived autoreactive plasma cells drive persistent autoimmune inflammation. Nat. Rev. Rheumatol. 7:170–78 [Google Scholar]
  55. Ahuja A, Anderson SM, Khalil A, Shlomchik MJ. 55.  2008. Maintenance of the plasma cell pool is independent of memory B cells. PNAS 105:4802–7 [Google Scholar]
  56. Alexander T, Sarfert R, Klotsche J. 56.  et al. 2015. The proteasome inhibitior bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus. Ann. Rheum. Dis. 74:1474–78 [Google Scholar]
  57. Jakez-Ocampo J, Atisha-Fregoso Y, Llorente L. 57.  2015. Refractory primary Sjogren syndrome successfully treated with bortezomib. J. Clin. Rheumatol. 21:31–32 [Google Scholar]
  58. Delli K, Haacke EA, Kroese FG. 58.  et al. 2016. Towards personalised treatment in primary Sjogren's syndrome: baseline parotid histopathology predicts responsiveness to rituximab treatment. Ann. Rheum. Dis. 75:1933–38 [Google Scholar]
  59. Cornec D, Costa S, Devauchelle-Pensec V. 59.  et al. 2016. Blood and salivary-gland BAFF-driven B-cell hyperactivity is associated to rituximab inefficacy in primary Sjogren's syndrome. J. Autoimmun. 67:102–10 [Google Scholar]
  60. Delli K, Haacke EA, Kroese FG. 60.  et al. 2016. In primary Sjogren's syndrome high absolute numbers and proportions of B cells in parotid glands predict responsiveness to rituximab as defined by ESSDAI, but not by SSRI. Ann. Rheum. Dis. 75:e34 [Google Scholar]
  61. Cornec D, Costa S, Devauchelle-Pensec V. 61.  et al. 2016. Do high numbers of salivary gland-infiltrating B cells predict better or worse outcomes after rituximab in patients with primary Sjogren's syndrome?. Ann. Rheum. Dis. 75:e33 [Google Scholar]
  62. Mackay F, Woodcock SA, Lawton P. 62.  et al. 1999. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J. Exp. Med. 190:1697–710 [Google Scholar]
  63. Thompson N, Isenberg DA, Jury EC, Ciurtin C. 63.  2016. Exploring BAFF: its expression, receptors and contribution to the immunopathogenesis of Sjogren's syndrome. Rheumatology 55:1548–55 [Google Scholar]
  64. Sjostrand M, Johansson A, Aqrawi L. 64.  et al. 2016. The expression of BAFF is controlled by IRF transcription factors. J. Immunol. 196:91–96 [Google Scholar]
  65. Mariette X, Seror R, Quartuccio L. 65.  et al. 2015. Efficacy and safety of belimumab in primary Sjogren's syndrome: results of the BELISS open-label phase II study. Ann. Rheum. Dis. 74:526–31 [Google Scholar]
  66. De Vita S, Quartuccio L, Seror R. 66.  et al. 2015. Efficacy and safety of belimumab given for 12 months in primary Sjogren's syndrome: the BELISS open-label phase II study. Rheumatology 54:2249–56 [Google Scholar]
  67. Quartuccio L, Salvin S, Corazza L. 67.  et al. 2016. Efficacy of belimumab and targeting of rheumatoid factor-positive B-cell expansion in Sjogren's syndrome: follow-up after the end of the phase II open-label BELISS study. Clin. Exp. Rheumatol. 34:311–14 [Google Scholar]
  68. Pontarini E, Fabris M, Quartuccio L. 68.  et al. 2015. Treatment with belimumab restores B cell subsets and their expression of B cell activating factor receptor in patients with primary Sjogren's syndrome. Rheumatology 54:1429–34 [Google Scholar]
  69. Quartuccio L, Salvin S, Fabris M. 69.  et al. 2013. BLyS upregulation in Sjogren's syndrome associated with lymphoproliferative disorders, higher ESSDAI score and B-cell clonal expansion in the salivary glands. Rheumatology 52:276–81 [Google Scholar]
  70. Nezos A, Papageorgiou A, Fragoulis G. 70.  et al. 2014. B-cell activating factor genetic variants in lymphomagenesis associated with primary Sjogren's syndrome. J. Autoimmun. 51:89–98 [Google Scholar]
  71. Papageorgiou A, Mavragani CP, Nezos A. 71.  et al. 2015. A BAFF receptor His159Tyr mutation in Sjogren's syndrome-related lymphoproliferation. Arthritis Rheumatol 67:2732–41 [Google Scholar]
  72. Martin T, Weber JC, Levallois H. 72.  et al. 2000. Salivary gland lymphomas in patients with Sjogren's syndrome may frequently develop from rheumatoid factor B cells. Arthritis Rheum 43:908–16 [Google Scholar]
  73. Seror R, Nocturne G, Lazure T. 73.  et al. 2015. Low numbers of blood and salivary natural killer cells are associated with a better response to belimumab in primary Sjogren's syndrome: results of the BELISS study. Arthritis Res. Ther. 17:241 [Google Scholar]
  74. Quartuccio L, Mavragani CP, Nezos A. 74.  2016. Type I interferon predicts biological effect of belimumab on rheumatoid factor positive B-cells in Sjogren's syndrome: results from the BELISS trial. Ann. Rheum. Dis. 75:Suppl. 2294 [Google Scholar]
  75. Gong Q, Ou Q, Ye S. 75.  et al. 2005. Importance of cellular microenvironment and circulatory dynamics in B cell immunotherapy. J. Immunol. 174:817–26 [Google Scholar]
  76. De Vita S, Quartuccio L, Salvin S. 76.  et al. 2014. Sequential therapy with belimumab followed by rituximab in Sjogren's syndrome associated with B-cell lymphoproliferation and overexpression of BAFF: evidence for long-term efficacy. Clin. Exp. Rheumatol. 32:490–94 [Google Scholar]
  77. Wiestner A. 77.  2015. The role of B-cell receptor inhibitors in the treatment of patients with chronic lymphocytic leukemia. Haematologica 100:1495–507 [Google Scholar]
  78. Nayar S, Campos J, Buckley CD. 78.  et al. 2016. Phosphatidylinositol 3–kinase delta pathway a novel therapeutic target for Sjoegren's syndrome. Ann. Rheum. Dis. 75:A58 (Abstr.) [Google Scholar]
  79. Corneth OBJ, Verstappen G, de Bruijn M. 79.  et al. 2015. Bruton's tyrosine kinase levels are increased in B cells from patients with primary Sjögren's syndrome. Arthritis Rheumatol 67:Suppl. 10 [Google Scholar]
  80. Steinfeld SD, Tant L, Burmester GR. 80.  et al. 2006. Epratuzumab (humanised anti-CD22 antibody) in primary Sjogren's syndrome: an open-label phase I/II study. Arthritis Res. Ther. 8:R129 [Google Scholar]
  81. Amft N, Curnow SJ, Scheel-Toellner D. 81.  et al. 2001. Ectopic expression of the B cell-attracting chemokine BCA-1 (CXCL13) on endothelial cells and within lymphoid follicles contributes to the establishment of germinal center-like structures in Sjogren's syndrome. Arthritis Rheum 44:2633–41 [Google Scholar]
  82. Risselada AP, Looije MF, Kruize AA. 82.  et al. 2013. The role of ectopic germinal centers in the immunopathology of primary Sjogren's syndrome: a systematic review. Semin. Arthritis Rheum. 42:368–76 [Google Scholar]
  83. Theander E, Vasaitis L, Baecklund E. 83.  et al. 2011. Lymphoid organisation in labial salivary gland biopsies is a possible predictor for the development of malignant lymphoma in primary Sjogren's syndrome. Ann. Rheum. Dis. 70:1363–68 [Google Scholar]
  84. Szabo K, Papp G, Barath S. 84.  et al. 2013. Follicular helper T cells may play an important role in the severity of primary Sjogren's syndrome. Clin. Immunol. 147:95–104 [Google Scholar]
  85. Bombardieri M, Barone F, Humby F. 85.  et al. 2007. Activation-induced cytidine deaminase expression in follicular dendritic cell networks and interfollicular large B cells supports functionality of ectopic lymphoid neogenesis in autoimmune sialoadenitis and MALT lymphoma in Sjogren's syndrome. J. Immunol. 179:4929–38 [Google Scholar]
  86. Pitzalis C, Jones GW, Bombardieri M, Jones SA. 86.  2014. Ectopic lymphoid-like structures in infection, cancer and autoimmunity. Nat. Rev. Immunol. 14:447–62 [Google Scholar]
  87. Barone F, Nayar S, Campos J. 87.  et al. 2015. IL-22 regulates lymphoid chemokine production and assembly of tertiary lymphoid organs. PNAS 112:11024–29 [Google Scholar]
  88. Alunno A, Carubbi F, Bistoni O. 88.  et al. 2015. T regulatory and T helper 17 cells in primary Sjogren's syndrome: facts and perspectives. Mediators Inflamm 2015:243723 [Google Scholar]
  89. Fava RA, Kennedy SM, Wood SG. 89.  et al. 2011. Lymphotoxin-beta receptor blockade reduces CXCL13 in lacrimal glands and improves corneal integrity in the NOD model of Sjogren's syndrome. Arthritis Res. Ther. 13:R182 [Google Scholar]
  90. St. Clair EW, Baer AN, Noaiseh G. 90.  et al. 2015. The clinical efficacy and safety of baminercept, a lymphotoxin-beta receptor fusion protein, in primary Sjögren's syndrome: results from a randomized, double-blind, placebo-controlled phase II trial. Arthritis Rheumatol 67:Suppl. 10 [Google Scholar]
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