ИНТЕРФЕРОНОПАТИИ ТИПА I КАК ОДИН ИЗ МЕХАНИЗМОВ РАЗВИТИЯ ИММУНОВОСПАЛИТЕЛЬНЫХ РЕВМАТИЧЕСКИХ ЗАБОЛЕВАНИЙ (ОБЗОР ЛИТЕРАТУРЫ)

Аннотация

Иммуновоспалительные ревматические заболевания (ИВРЗ) — это широкая группа патологических состояний, в основе которых лежит нарушение иммунологической толерантности к собственным тканям, ведущее к воспалению и необратимым органным повреждениям. В последние годы в патогенезе ИВРЗ большое внимание уделяется так называемым «интерферонопатиям», т.е. нарушениям регуляции продукции интерферонов (ИФН) 1 типа. ИФН представляют собой группу молекул, обладающих плейотропным действием на иммунную систему и осуществляющими связь между врожденными и адаптивными иммунными реакциями. Важная роль гиперпродукции ИФН типа 1 в патогенезе ИВРЗ подтверждается как на моделях ревматических заболеваний у лабораторных животных, так и у пациентов с наследственными моногенными заболеваниями со специфическим воспалительным фенотипом, которые в 2011 году было предложено объединить в группу врожденных интерферонопатий I типа. Взаимосвязь гиперпродукции ИФН-типа I с развитием аутоиммунной патологии также подтверждается фактом развития симптомов аутоиммунного заболевания у пациентов, получающих терапию ИФН 1 типа по поводу вирусной инфекции или злокачественных новообразований. Повышенная экспрессия ИФН стимулированных генов была названа ИФН «автографом». Оценка нарушений в регуляции продукции ИФН I типа может позволить выделить клинические фенотипы заболеваний, характеризующиеся гиперпродукцией ИФН I типа, а также разработать персонифицированные подходы к терапии. Следует отметить, что схожие нарушения наблюдаются при обширном круге ИВРЗ, что создает предпосылки для широкого использования препаратов, блокирующих эффекты ИФН 1 типа. Целью публикации является обобщение и анализ наиболее важных исследований, касающихся роли ИФН типа I в патогенезе ИВРЗ, а также обсуждение методов оценки ИФН «автографа».

Annotation

Systemic autoimmune rheumatic diseases (SARDs) are a broad group of pathological conditions based on impaired immunological tolerance to one’s own tissues leading to inflammation and irreversible organ damage. In recent years, much attention has been paid to the so-called “interferonopathies” in the pathogenesis of SARDs, i.e. dysregulation of the production of interferons (IFN) type 1. Evaluation of these disorders can make it possible to identify the clinical phenotypes of diseases, as well as to predict the results of therapy. Similar disorders are observed in a wide range of pathological conditions, which creates the prerequisites for the widespread use of drugs that block the effects of type 1 IFN. The purpose of the publication is to summarize and analyze the most important studies on the role of type I IFN in the pathogenesis of SARDs.

Об авторах

Список литературы

1. Nasonov E.L., Karateev D.E., Balabanova R.M. Rheumatoid arthritis. In: Nasonov E.L., Nasonova V.A., eds. Rheumatology. National guidance [Revmatologiya. Natsional’noe rukovodstvo]. Moscow: GEOTAR-Media; 2008: 290-331. (in Russian)
2. Hall J.C., Rosen A. Type I interferons: crucial participants in disease amplification in autoimmunity. Nat. Rev. Rheumatol. 2010; 6:40-9. DOI: 10.1038/nrrheum.2009.237.
3. Honda K., Takaoka A., Taniguchi T. Type I interferon gene induction by the interferon regulatory factor family of transcription factors. Immunity. 2006; 25:349-60. DOI: 10.1016/j.immuni.2006.08.009.
4. Longhi M.P., Trumpfheller C., Idoyaga J., Caskey M., Matos I., Kluger C. et al. Dendritic cells require a systemic type I interferon response to mature and induce CD4+ Th1 immunity with poly IC as adjuvant. J. Exp. Med. 2009; 206:1589-602. DOI: 10.1084/jem.20090247.
5. Le Bon A., Thompson C., Kamphuis E., Durand V., Rossmann C., Kalinkeet U. et al. Cutting edge: enhancement of antibody responses through direct stimulation of B and T cells by type I IFN. J. Immunol 2006; 176:2074-8. DOI: 10.4049/jimmunol.176.4.2074.
6. Green D.S., Young H.A., Valencia J.C. Current prospects of type II interferon γ signaling and autoimmunity. J. Biol. Chem. 2017; 292(34):13925-33. DOI: 10.1074/jbc.R116.774745.
7. Psarras A., Emery P., Vital E.M. Type I interferon-mediated autoimmune diseases: pathogenesis, diagnosis and targeted therapy. Rheumatology (Oxford). 2017; 56(10):1662-75. DOI: 10.1093/rheumatology/kew431.
8. Nan Y., Wu C., Zhang Y.J. Interplay between Janus Kinase/Signal Transducer and Activator of Transcription Signaling Activated by Type I Interferons and Viral Antagonism. Front. Immunol. 2017; 8:1758. DOI: 10.3389/fimu.2017.01758.
9. Schwartz D.M, Kanno Y., Villarino A., Ward M., Gadina M., O’Shea J. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat. Rev. Drug Discov. 2017; 16(12):843-62. DOI: 10.1038/nrd.2017.201.
10. Hammarén H.M., Virtanen A.T., Raivola J., Silvennoinen O. The regulation of JAKs in cytokine signaling and its breakdown in disease. Cytokine. 2018; 20. pii: S1043-4666(18)30127-3. DOI: 10.1016/j.cyto.2018.03.041.
11. Gadina M., Johnson C., Schwartz D., Bonelli M., Hasni S., Kannoet Y. Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs. J. Leukoc. Biol. 2018; 104(3):499-514. DOI: 10.1002/JLB.5RI0218-084R.
12. de Weerd, N.A., Vivian J.P., Nguyen T.K., Mangan N.E., Gould J.A., Braniff S.J. Structural basis of a unique interferon-beta signaling axis mediated via the receptor IFNAR1. Nat. Immunol. 2013; 14:901–7. DOI: 10.1038/ni.2667.
13. Ivashkiv L.B., Donlin L.T. Regulation of type I interferon responses. Nat. Rev. Immunol. 2014; 14:36–49. DOI: 10.1038/nri3581.
14. Muskardin T.L., Niewold T.B. Type I interferon in rheumatic diseases. Nat. Rev. Rheumatol. 2018; 14(4):214-28. DOI: 10.1038/nrrheum.2018.31.
15. Fink K., Martin L., Mukawera E., Chartier S., De Deken X., Brochiero E., et al. IFNβ/TNFα synergism induces a noncanonical STAT2/IRF9-dependent pathway triggering a novel DUOX2 NADPH oxidase-mediated airway antiviral response. Cell Res. 2013; 23:673–90. DOI: 10.1038/cr.2013.47.
16. Crow Y.J. Type I interferonopathies: a novel set of inborn errors of immunity: type I interferonopathies. Ann. N. Y. Acad. Sci. 2011; 1238:91-8. DOI: 10.1111/j.1749-6632.2011.06220.x.
17. Fazzi E., Cattalini M., Orcesi S., Tincani A., Andreoli L., Balottin U. et al. Aicardi-Goutieres syndrome, a rare neurological disease in children: a new autoimmune disorder? Autoimmun. Rev. 2013; 12:506-9. DOI: 10.1016/j.autrev.2012.08.012.
18. König N., Fiehn C., Wolf C., Schuster M., Cura Costa E., Tüngler V. et al. Familial chilblain lupus due to a gain-of-function mutation in STING. Ann. Rheum. Dis. 2016; 76:468-72. DOI: 10.1136/annrheumdis-2016-209841.
19. Munoz J., Marque M., Dandurand M., Meunier L., Crow Y.J., Bessis D. Type I interferonopathies. Ann. Dermatol. Venereol. 2015; 142:653-63. DOI: 10.1016/j.annder.2015.06.018.
20. Munoz J., Rodière M., Jeremiah N., Rieux-Laucat F., Oojageer A., Rice G.I. et al. Stimulator of interferon genes-associated vasculopathy with onset in infancy: a mimic of childhood granulomatosis with polyangiitis. JAMA Dermatol. 2015; 151:872-7. DOI: 10.1001/jamadermatol.2015.0251.
21. Günther C., Kind B., Reijns M.A. Berndt N., Martinez-Bueno M., Wolf C. et al. Defective removal of ribonucleotides from DNA promotes systemic autoimmunity. J. Clin. Invest. 2015; 125:413-24. DOI: 10.1172/JCI78001.
22. Lee-Kirsch M.A., Gong M., Chowdhury D. Senenko L., Engel K., Lee Y.A. et al. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat. Genet. 2007; 39:1065-7. DOI: 10.1038/ng2091.
23. An J., Briggs T.A., Dumax-Vorzet A. Alarcón-Riquelme M., Belot A., Beresford M. et al. Tartrate-resistant acid phosphatase deficiency in the predisposition to systemic lupus erythematosus. Arthritis Rheumatol. 2017; 69:131-42. DOI: 10.1002/art.39810.
24. Liu Y., Jesus A.A., Marrero B., Yang D., Ramsey S.E., Montealegre Sanchez G.A. et al. Activated STING in a vascular and pulmonary syndrome. N. Engl. J. Med. 2014; 371:507-18. DOI: 10.1056/NEJMoa1312625.
25. Crow Y.J., Casanova J.L.STING-associated vasculopathy with onset in infancy — a new interferonopathy. N. Engl. J. Med. 2014; 371:568-71. DOI: 10.1056/NEJMe1407246.
26. Picard C., Thouvenin G., Kannengiesser C. Dubus J., Jeremiah N., Rieux-Laucat F. et al. Severe pulmonary fibrosis as the first manifestation of interferonopathy (TMEM173 mutation). Chest. 2016; 150:e65-e71. DOI: 10.1016/j.chest.2016.02.682.
27. Clarke S.L., Pellowe E.J., de Jesus A.A. Goldbach-Mansky R., Hilliard T., Ramanan A.V. Interstitial lung disease caused by STING-associated vasculopathy with onset in infancy. Am. J. Respir. Crit. Care Med. 2016; 194:639-42. DOI: 10.1164/rccm.201510-2102LE.
28. Ioannou Y., Isenberg D.A. Current evidence for the induction of autoimmune rheumatic manifestations by cytokine therapy. Arthritis Rheum. 2000; 43:1431-42. DOI: 10.1002/1529-0131(200007)43:7<1431:AID-ANR3>3.0.CO;2-E.
29. Okanoue T., Sakamoto S., Itoh Y., Minami M., Yasui K., Sakamoto M. et al. Side effects of high dose interferon therapy for chronic hepatitis C. J. Hepatol. 1996; 25:283-91. DOI: 10.1016/s0168-8278(96)80113-9.
30. Munroe M.E. Lu R., Zhao Y.D., Fife D.A., Robertson J., Guthridge J.M. et al. Altered type II interferon precedes autoantibody accrual and elevated type I interferon activity prior to systemic lupus erythematosus classification. Ann. Rheum. Dis. 2016; 75:2014–2202. DOI: 10.1136/annrheumdis-2015-208140.
31. Kariuki S.N. Franek B.S., Kumar A.A., Arrington J., Mikolaitis R.A., Utset T.O. et al. Trait-stratified genome-wide association study identifies novel and diverse genetic associations with serologic and cytokine phenotypes in systemic lupus erythematosus. Arthritis Res. Ther. 2010; 12:R15. DOI: 10.1186/ar3101.
32. Ghodke-Puranik Y., Niewold T.B. Genetics of the type I interferon pathway in systemic lupus erythematosus. Int. J. Clin. Rheumtol. 2013; 8(6):10.2217/ijr.13.58. DOI.10.2217/ijr.13.58.
33. Yasuda K., Watkins A.A., Kochar G.S., Wilson G.E., Laskow B., Richez C. et al. Interferon regulatory factor-5 deficiency ameliorates disease severity in the MRL/lpr mouse model of lupus in the absence of a mutation in DOCK2. PLoS ONE. 2014; 9: e103478. DOI: 10.1371/journal.pone.0103478.
34. Lessard C.J. Li H., Adrianto I., Ice J.A., Rasmussen A., Grundahl K.M. et al. Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren’s syndrome. Nat. Genet. 2013; 45: 1284–92. DOI: 10.1038/ng.2792.
35. Radstake T.R. Gorlova O., Rueda B., Martin J., Alizadeh B., Palomino-Morales R. et al. Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nat. Genet. 2010; 42: 426–9. DOI: 10.1038/ng.565.
36. Nordang G.B., Viken M.K., Amundsen S.S., Sanchez E.S., Flatø B., Førre O. et al. Interferon regulatory factor 5 gene polymorphism confers risk to several rheumatic diseases and correlates with expression of alternative thymic transcripts. Rheumatology (Oxford).2012; 51:619–26. DOI:10.1093/rheumatology/ker364.
37. Niewold T.B. Kelly J.A., Kariuki S.N., Franek B.S., Kumar A.A., Kaufman K.M. et al. IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus. Ann. Rheum. Dis. 2012; 71:463–8. DOI: 10.1136/annrheumdis-2011-200463.
38. Salloum R., Franek B.S., Kariuki S.N., Rhee L., Mikolaitis R.A., Jolly M. et al. Genetic variation at the IRF7/PHRF1 locus is associated with autoantibody profile and serum interferon-α activity in lupus patients. Arthritis Rheum. 2010; 62: 553–61. DOI: 10.1002/art.27182.
39. Chrabot B.S. Kariuki S.N., Zervou M.I., Feng X., Arrington J., Jolly M. et al. Genetic variation near IRF8 is associated with serologic and cytokine profiles in systemic lupus erythematosus and multiple sclerosis. Genes Immun. 2013; 14: 471–8. DOI: 10.1038/gene.2013.42.
40. Pothlichet J. Niewold T.B., Vitour D., Solhonne B., Crow M.K., Si-Tahar M. et al. A loss‑of‑function variant of the antiviral molecule MAVS is associated with a subset of systemic lupus patients. EMBO Mol. Med. 2011; 3:142–52. DOI: 10.1002/emmm.201000120.
41. Wang Y. Shaked I., Stanford S., Zhou W., Curtsinger J., Mikulski Z. et al. The autoimmunity-associated gene PTPN22 potentiates toll-like receptor-driven, type I interferon-dependent immunity. Immunity. 2013; 39:111–22. DOI: 10.1016/j.immuni.2013.06.013.
42. Gestermann N., Mekinian A., Comets E., Loiseau P., Puechal X., Hachulla E. et al. STAT4 is a confirmed genetic risk factor for Sjögren’s syndrome and could be involved in type I interferon pathway signaling. Genes Immun. 2010; 11:432–8. DOI: 10.1038/gene.2010.29.
43. Dieude P. Guedj M., Wipff J., Ruiz B., Hachulla E., Diot E. et al. STAT4 is a genetic risk factor for systemic sclerosis having additive effects with IRF5 on disease susceptibility and related pulmonary fibrosis. Arthritis Rheum. 2009; 60: 2472–9. DOI: 10.1002/art.24688.
44. Remmers E.F. Plenge R.M., Lee A.T., Graham R.R., Hom G., Behrens T.W. et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N. Engl. J. Med. 2007; 357:977–86. DOI: 10.1056/NEJMoa073003.
45. Zervou M.I., Goulielmos G. N., Castro-Giner F. Tosca A.D., Krueger-Krasagakis S. et al. STAT4 gene polymorphism is associated with psoriasis in the genetically homogeneous population of Crete, Greece. Hum. Immunol. 2009; 70:738–41. DOI: 10.1016/j.humimm.2009.05.008.
46. Liang Y.L. Wu H., Shen X., Li P., Yang X., Liang L.et al. Association of STAT4 rs7574865 polymorphism with autoimmune diseases: a metaanalysis. Mol. Biol. Rep. 2012; 39:8873–82. DOI: 10.1007/s11033-012-1754-1.
47. Hebert H.L. Bowes J., Smith R.L., Flynn E., Parslew R., Alsharqi A. et al. Identification of loci associated with late-onset psoriasis using dense genotyping of immunerelated regions. Br. J. Dermatol. 2015; 172:933–9. DOI: 10.1111/bjd.13340.
48. Lee Y.H. Rho Y.H., Choi S.J., Ji J.D., Song G.G., Nath S.K. et al. The PTPN22 C1858T functional polymorphism and autoimmune diseases — a metaanalysis. Rheumatology (Oxford) 2007; 46:49–56. DOI: 10.1093/rheumatology/kel170.
49. Weckerle C.E. Franek B.S., Kelly J.A., Kumabe M., Mikolaitis R.A., Green S.L. et al. Network analysis of associations between serum interferon-α activity, autoantibodies, and clinical features in systemic lupus erythematosus. Arthritis Rheum. 2011; 63:1044–53. DOI: 10.1002/art.30187.
50. Baechler E.C. Batliwalla F.M., Karypis G., Gaffney P.M., Ortmann W.A., Espe K.J. et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc. Natl Acad. Sci. 2003; 100:2610–5. DOI: 10.1073/pnas.0337679100.
51. Landolt-Marticorena C. Bonventi G., Lubovich A., Ferguson C., Unnithan T., Su J. et al. Lack of association between the interferon-α signature and longitudinal changes in disease activity in systemic lupus erythematosus. Ann. Rheum. Dis. 2009; 68:1440–6. DOI: 10.1136/ard.2008.093146.
52. Bauer J.W., Petri M., Batliwalla F.M., Koeuth T., Wilson J., Slattery C. et al. Interferon-regulated chemokines as biomarkers of systemic lupus erythematosus disease activity: a validation study. Arthritis Rheum. 2009; 60: 3098–3107. DOI: 10.1002/art.24803
53. Fuchs T.A., Abed U., Goosmann C., Hurwitz R., Schulze I., Wahn V. et al. Novel cell death program leads to neutrophil extracellular traps. J. Cell Biol. 2007; 176:231-41. DOI: 10.1083/jcb.200606027.
54. Martinelli S., Urosevic M., Daryadel A., Oberholzer P., Baumann C., Fey M. et al. Induction of genes mediating interferon-dependent extracellular trap formation during neutrophil differentiation. J. Biol. Chem. 2004; 279:44123-32. DOI: 10.1074/jbc.M405883200.
55. Lubbers J. M. Brink, van de Stadt L., Vosslamber S., Wesseling J.G., van Schaardenburg D. et al. The type I IFN signature as a biomarker of preclinical rheumatoid arthritis. Ann. Rheum. Dis. 2013; 72:776–80. DOI: 10.1136/annrheumdis-2012-02753.
56. Higgs B.W., Liu Z., White B., Zhu W., White W., Morehouse C. et al. Patients with systemic lupus erythematosus, myositis, rheumatoid arthritis and scleroderma share activation of a common type I interferon pathway. Ann. Rheum. Dis. 2011; 70:2029–36. DOI: 10.1136/ard.2011.150326.
57. Orozco G. Sánchez E., González-Gay M., López-Nevot M., Torres B., Cáliz R. et al. Association of a functional singlenucleotide polymorphism of PTPN22, encoding lymphoid protein phosphatase, with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Rheum.2005; 52:219–24. DOI: 10.1002/art.20771.
58. Roelofs M.F. Wenink M.H., Brentano F., Abdollahi-Roodsaz S., Oppers-Walgreen B., Barrera P. et al. Type I interferons might form the link between Toll-like receptor (TLR) 3/7 and TLR4‑mediated synovial inflammation in rheumatoid arthritis (RA). Ann. Rheum. Dis. 2009; 68:1486–93. DOI: 10.1136/ard.2007.086421.
59. Palmer G. Mezin F., Juge-Aubry C.E., Plater-Zyberk C., Gabay C., Guerne P.A. Interferon β stimulates interleukin 1 receptor antagonist production in human articular chondrocytes and synovial fibroblasts. Ann. Rheum. Dis. 2004; 63:43–9. DOI: 10.1136/ard.2002.005546.
60. van Holten J. Reedquist K., Sattonet-Roche P., Smeets T., Plater-Zyberk C., Vervoordeldonk M. et al. Treatment with recombinant interferon-β reduces inflammation and slows cartilage destruction in the collagen-induced arthritis model of rheumatoid arthritis. Arthritis Res. Ther. 2004; 6:R239–R249. DOI: 10.1186/ar1165.
61. van Holten J. Pavelka K., Vencovsky J., Stahl H., Rozman B., Genovese M. et al. A multicentre, randomised, double blind, placebo controlled phase II study of subcutaneous interferon β‑1a in the treatment of patients with active rheumatoid arthritis. Ann. Rheum. Dis. 2005; 64:64–9. DOI: 10.1136/ard.2003.020347.
62. van der Pouw Kraan T.C., Wijbrandts C.A., van Baarsen L.G., Voskuyl A.E., Rustenburg F., Baggen J.M. et al. Rheumatoid arthritis subtypes identified by genomic profiling of peripheral blood cells: assignment of a type I interferon signature in a subpopulation of patients. Ann. Rheum. Dis. 2007; 66:1008–14. DOI: 10.1136/ard.2006.063412.
63. Thurlings R.M., Boumans M., Tekstra J., van Roon J., Vos K., van Westing D. et al. Relationship between the type I interferon signature and the response to rituximab in rheumatoid arthritis patients. Arthritis Rheum. 2010; 62:3607–14. DOI: 10.1002/art.27702.
64. Raterman H.G., Vosslamber S., De RS. Nurmohamed M.T., Lems W., Boers M., et al. The interferon type I signature towards prediction of non-response to rituximab in rheumatoid arthritis patients. Arthritis Res. Ther. 2012; 14:R95. DOI: 10.1186/ar3819.
65. Avdeeva A.S., Chetina E.V., Markova G.A., Nasonov E.L. Expression of interferon-stimulated genes in patients with rheumatoid arthritis on anti-B-cell therapy (preliminary results). Sovremennaya Revmatologiya. 2021; 15(5):12–7. DOI: 10.14412/1996-7012-2021-5-12-17. (in Russian)
66. Wampler Muskardin T. Vashisht P., Dorschner J.M., Jensen M.A., Chrabot B.S., Kern M. et al. Increased pretreatment serum IFN-β/α ratio predicts non-response to tumour necrosis factor α inhibition in rheumatoid arthritis. Ann. Rheum. Dis. 2016; 75:1757–62. DOI: 10.1136/annrheumdis-2015-208001.
67. Davison L.M., Jorgensen T.N. New Treatments for Systemic Lupus Erythematosus on the Horizon: Targeting Plasmacytoid Dendritic Cells to Inhibit Cytokine Production. J. Clin. Cell Immunol. 2017; 8(6). pii: 534. DOI: 10.4172/2155-9899.1000534.
68. Crow M/K. Type I interferon in the pathogenesis of lupus. J. Immunol. 2014; 192:5459-68. DOI: 10.4049/jimmunol.1002795.
69. Chiche L., Jourde-Chiche N., Whalen E., Presnell S., Gersuk V., Dang K. et al. Modular transcriptional repertoire analyses of adults with systemic lupus erythematosus reveal distinct type I and type II interferon signatures. Arthritis Rheumatol. 2014; 66:1583-95. DOI: 10.1002/art.38628.
70. Feng X., Wu H., Grossman J.M., Hanvivadhanakul P., FitzGerald J.D., Park G.S. et al. Association of increased interferon-inducible gene expression with disease activity and lupus nephritis in patients with systemic lupus erythematosus. Arthritis Rheum. 2006; 54:2951-62. DOI: 10.1002/art.22044.
71. Becker A.M., Dao K.H., Han B.K., Kornu R., Lakhanpal S., Mobley A.B. et al. SLE peripheral blood B cell, T cell and myeloid cell transcriptomes display unique profiles and each subset contributes to the interferon signature. PLoS One. 2013; 8:e67003. DOI: 10.1371/journal.pone.0067003.
72. van den Hoogen L.L., van Roon J.A., Mertens J.S., Wienke J., Lopes A.P., de Jager W. et al. Ann. Rheum. Dis. 2018; 77:1810–4. DOI: 10.1136/annrheumdis-2018-213497.

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