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Volumn 125, Issue 6, 2015, Pages 2228-2233

Mechanisms of human autoimmunity

Author keywords

[No Author keywords available]

Indexed keywords

CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; PROGRAMMED DEATH 1 RECEPTOR; TRANSCRIPTION FACTOR FOXP3;

EID: 84930408029     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI78088     Document Type: Article
Times cited : (337)

References (57)
  • 1
    • 77949262985 scopus 로고    scopus 로고
    • Tumor necrosis factor blockade and the risk of viral infection
    • Kim SY, Solomon DH. Tumor necrosis factor blockade and the risk of viral infection. Nat Rev Rheumatol. 2010;6(3): 165-174.
    • (2010) Nat Rev Rheumatol , vol.6 , Issue.3 , pp. 165-174
    • Kim, S.Y.1    Solomon, D.H.2
  • 2
    • 84889673425 scopus 로고    scopus 로고
    • Infectious and malignant complications of TNF inhibitor therapy in IBD
    • Targownik LE, Bernstein CN. Infectious and malignant complications of TNF inhibitor therapy in IBD. Am J Gastroenterol. 2013;108(12): 1835-1842.
    • (2013) Am J Gastroenterol , vol.108 , Issue.12 , pp. 1835-1842
    • Targownik, L.E.1    Bernstein, C.N.2
  • 3
    • 77950355043 scopus 로고    scopus 로고
    • Unraveling the genetics of autoimmunity
    • Zenewicz LA, Abraham C, Flavell RA, Cho JH. Unraveling the genetics of autoimmunity. Cell. 2010;140(6): 791-797.
    • (2010) Cell , vol.140 , Issue.6 , pp. 791-797
    • Zenewicz, L.A.1    Abraham, C.2    Flavell, R.A.3    Cho, J.H.4
  • 4
  • 5
    • 84862682781 scopus 로고    scopus 로고
    • The immunogenetic architecture of autoimmune disease
    • Goris A, Liston A. The immunogenetic architecture of autoimmune disease. Cold Spring Harb Perspect Biol. 2012;4(3): A007260.
    • (2012) Cold Spring Harb Perspect Biol , vol.4 , Issue.3 , pp. a007260
    • Goris, A.1    Liston, A.2
  • 6
    • 0025780344 scopus 로고
    • T cell response to myelin basic protein epitopes in multiple sclerosis patients and healthy subjects
    • Liblau R, et al. T cell response to myelin basic protein epitopes in multiple sclerosis patients and healthy subjects. Eur J Immunol. 1991;21(6): 1391-1395.
    • (1991) Eur J Immunol , vol.21 , Issue.6 , pp. 1391-1395
    • Liblau, R.1
  • 7
    • 0025370870 scopus 로고
    • T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis
    • Ota K, Matsui M, Milford EL, Mackin GA, Weiner HL, Hafler DA. T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis. Nature. 1990;346(6280): 183-187.
    • (1990) Nature , vol.346 , Issue.6280 , pp. 183-187
    • Ota, K.1    Matsui, M.2    Milford, E.L.3    Mackin, G.A.4    Weiner, H.L.5    Hafler, D.A.6
  • 8
    • 77958584113 scopus 로고    scopus 로고
    • Generation of pathogenic T(H)17 cells in the absence of TGF-β signalling
    • Ghoreschi K, et al. Generation of pathogenic T(H)17 cells in the absence of TGF-β signalling. Nature. 2010;467(7318): 967-971.
    • (2010) Nature , vol.467 , Issue.7318 , pp. 967-971
    • Ghoreschi, K.1
  • 9
    • 84859543711 scopus 로고    scopus 로고
    • Cytokine gene polymorphisms and human autoimmune disease in the era of genome-wide association studies
    • Vandenbroeck K. Cytokine gene polymorphisms and human autoimmune disease in the era of genome-wide association studies. J Interferon Cytokine Res. 2012;32(4): 139-151.
    • (2012) J Interferon Cytokine Res , vol.32 , Issue.4 , pp. 139-151
    • Vandenbroeck, K.1
  • 10
    • 73849124607 scopus 로고    scopus 로고
    • Ustekinumab: Lessons learned from targeting interleukin-12/23p40 in immune-mediated diseases
    • Elliott M, et al. Ustekinumab: Lessons learned from targeting interleukin-12/23p40 in immune-mediated diseases. Ann N Y Acad Sci. 2009;1182: 97-110.
    • (2009) Ann N Y Acad Sci , vol.1182 , pp. 97-110
    • Elliott, M.1
  • 11
    • 84859017988 scopus 로고    scopus 로고
    • Brodalumab, an anti-interleukin- 17-receptor antibody for psoriasis
    • Papp KA, et al. Brodalumab, an anti-interleukin- 17-receptor antibody for psoriasis. N Engl J Med. 2012;366(13): 1181-1189.
    • (2012) N Engl J Med , vol.366 , Issue.13 , pp. 1181-1189
    • Papp, K.A.1
  • 12
    • 0035167967 scopus 로고    scopus 로고
    • The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3
    • Bennett CL, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001; 27(1): 20-21.
    • (2001) Nat Genet , vol.27 , Issue.1 , pp. 20-21
    • Bennett, C.L.1
  • 13
    • 0346599403 scopus 로고    scopus 로고
    • An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zincfinger domains
    • Finnish-German APECED Consortium. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zincfinger domains. Nat Genet. 1997;17(4): 399-403.
    • (1997) Nat Genet , vol.17 , Issue.4 , pp. 399-403
  • 14
    • 0029025441 scopus 로고
    • Dominant interfering fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome
    • Fisher GH, et al. Dominant interfering fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell. 1995;81(6): 935-946.
    • (1995) Cell , vol.81 , Issue.6 , pp. 935-946
    • Fisher, G.H.1
  • 15
    • 82255191977 scopus 로고    scopus 로고
    • TLR-dependent T cell activation in autoimmunity
    • Mills KH. TLR-dependent T cell activation in autoimmunity. Nat Rev Immunol. 2011;11(12): 807-822.
    • (2011) Nat Rev Immunol , vol.11 , Issue.12 , pp. 807-822
    • Mills, K.H.1
  • 16
    • 84891818955 scopus 로고    scopus 로고
    • Complexities in the relationship between infection and autoimmunity
    • Root-Bernstein R, Fairweather D. Complexities in the relationship between infection and autoimmunity. Curr Allergy Asthma Rep. 2014;14(1): 407.
    • (2014) Curr Allergy Asthma Rep , vol.14 , Issue.1 , pp. 407
    • Root-Bernstein, R.1    Fairweather, D.2
  • 17
    • 36549034729 scopus 로고    scopus 로고
    • Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain
    • Serafini B, et al. Dysregulated Epstein-Barr virus infection in the multiple sclerosis brain. J Exp Med. 2007;204(12): 2899-2912.
    • (2007) J Exp Med , vol.204 , Issue.12 , pp. 2899-2912
    • Serafini, B.1
  • 18
    • 84899705732 scopus 로고    scopus 로고
    • Periodontitis and porphyromonas gingivalis in patients with rheumatoid arthritis
    • Mikuls TR, et al. Periodontitis and porphyromonas gingivalis in patients with rheumatoid arthritis. Arthritis Rheumatol. 2014;66(5): 1090-1100.
    • (2014) Arthritis Rheumatol , vol.66 , Issue.5 , pp. 1090-1100
    • Mikuls, T.R.1
  • 19
    • 77958119730 scopus 로고    scopus 로고
    • Central nervous system demyelinating disease protection by the human commensal Bacteroides fragilis depends on polysaccharide A expression
    • Ochoa-Repáraz J, et al. Central nervous system demyelinating disease protection by the human commensal Bacteroides fragilis depends on polysaccharide A expression. J Immunol. 2010;185(7): 4101-4108.
    • (2010) J Immunol , vol.185 , Issue.7 , pp. 4101-4108
    • Ochoa-Repáraz, J.1
  • 20
    • 84897138296 scopus 로고    scopus 로고
    • Role of the microbiota in immunity and inflammation
    • Belkaid Y, Hand TW. Role of the microbiota in immunity and inflammation. Cell. 2014;157(1): 121-141.
    • (2014) Cell , vol.157 , Issue.1 , pp. 121-141
    • Belkaid, Y.1    Hand, T.W.2
  • 21
    • 80054927213 scopus 로고    scopus 로고
    • Microbiota and autoimmune disease: The hosted self
    • Mathis D, Benoist C. Microbiota and autoimmune disease: The hosted self. Cell Host Microbe. 2011;10(4): 297-301.
    • (2011) Cell Host Microbe , vol.10 , Issue.4 , pp. 297-301
    • Mathis, D.1    Benoist, C.2
  • 22
    • 84891776162 scopus 로고    scopus 로고
    • Photosensitivity, apoptosis, and cytokines in the pathogenesis of lupus erythematosus: A critical review
    • Kuhn A, Wenzel J, Weyd H. Photosensitivity, apoptosis, and cytokines in the pathogenesis of lupus erythematosus: A critical review. Clin Rev Allergy Immunol. 2014;47(2): 148-162.
    • (2014) Clin Rev Allergy Immunol , vol.47 , Issue.2 , pp. 148-162
    • Kuhn, A.1    Wenzel, J.2    Weyd, H.3
  • 23
    • 0034614886 scopus 로고    scopus 로고
    • The induction of tolerance by dendritic cells that have captured apoptotic cells
    • Steinman RM, Turley S, Mellman I, Inaba K. The induction of tolerance by dendritic cells that have captured apoptotic cells. J Exp Med. 2000;191(3): 411-416.
    • (2000) J Exp Med , vol.191 , Issue.3 , pp. 411-416
    • Steinman, R.M.1    Turley, S.2    Mellman, I.3    Inaba, K.4
  • 24
    • 15444365480 scopus 로고    scopus 로고
    • Defective B cell tolerance checkpoints in systemic lupus erythematosus
    • Yurasov S, et al. Defective B cell tolerance checkpoints in systemic lupus erythematosus. J Exp Med. 2005;201(5): 703-711.
    • (2005) J Exp Med , vol.201 , Issue.5 , pp. 703-711
    • Yurasov, S.1
  • 25
    • 56649095905 scopus 로고    scopus 로고
    • T regulatory cells in autoimmune diabetes: Past challenges, future prospects
    • Bluestone JA, Tang Q, Sedwick CE. T regulatory cells in autoimmune diabetes: Past challenges, future prospects. J Clin Immunol. 2008;28(6): 677-684.
    • (2008) J Clin Immunol , vol.28 , Issue.6 , pp. 677-684
    • Bluestone, J.A.1    Tang, Q.2    Sedwick, C.E.3
  • 26
    • 84866740799 scopus 로고    scopus 로고
    • Unconventional recognition of peptides by T cells and the implications for autoimmunity
    • Mohan JF, Unanue ER. Unconventional recognition of peptides by T cells and the implications for autoimmunity. Nat Rev Immunol. 2012;12(10): 721-728.
    • (2012) Nat Rev Immunol , vol.12 , Issue.10 , pp. 721-728
    • Mohan, J.F.1    Unanue, E.R.2
  • 27
    • 84855476371 scopus 로고    scopus 로고
    • Register shifting of an insulin peptide-MHC complex allows diabetogenic T cells to escape thymic deletion
    • Mohan JF, Petzold SJ, Unanue ER. Register shifting of an insulin peptide-MHC complex allows diabetogenic T cells to escape thymic deletion. J Exp Med. 2011;208(12): 2375-2383.
    • (2011) J Exp Med , vol.208 , Issue.12 , pp. 2375-2383
    • Mohan, J.F.1    Petzold, S.J.2    Unanue, E.R.3
  • 28
    • 77949872804 scopus 로고    scopus 로고
    • Unique autoreactive T cells recognize insulin peptides generated within the islets of Langerhans in autoimmune diabetes
    • Mohan JF, Levisetti MG, Calderon B, Herzog JW, Petzold SJ, Unanue ER. Unique autoreactive T cells recognize insulin peptides generated within the islets of Langerhans in autoimmune diabetes. Nat Immunol. 2010;11(4): 350-354.
    • (2010) Nat Immunol , vol.11 , Issue.4 , pp. 350-354
    • Mohan, J.F.1    Levisetti, M.G.2    Calderon, B.3    Herzog, J.W.4    Petzold, S.J.5    Unanue, E.R.6
  • 29
    • 80052184362 scopus 로고    scopus 로고
    • Recognition of nucleic acids by pattern-recognition receptors and its relevance in autoimmunity
    • Kawasaki T, Kawai T, Akira S. Recognition of nucleic acids by pattern-recognition receptors and its relevance in autoimmunity. Immunol Rev. 2011;243(1): 61-73.
    • (2011) Immunol Rev , vol.243 , Issue.1 , pp. 61-73
    • Kawasaki, T.1    Kawai, T.2    Akira, S.3
  • 30
    • 39549107115 scopus 로고    scopus 로고
    • Homeostatic MyD88-dependent signals cause lethal inflamMation in the absence of A20
    • Turer EE, et al. Homeostatic MyD88-dependent signals cause lethal inflamMation in the absence of A20. J Exp Med. 2008;205(2): 451-464.
    • (2008) J Exp Med , vol.205 , Issue.2 , pp. 451-464
    • Turer, E.E.1
  • 32
    • 1542313881 scopus 로고    scopus 로고
    • Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor-A
    • Boyman O, Hefti HP, Conrad C, Nickoloff BJ, Suter M, Nestle FO. Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor-A. J Exp Med. 2004;199(5): 731-736.
    • (2004) J Exp Med , vol.199 , Issue.5 , pp. 731-736
    • Boyman, O.1    Hefti, H.P.2    Conrad, C.3    Nickoloff, B.J.4    Suter, M.5    Nestle, F.O.6
  • 33
    • 33748447541 scopus 로고    scopus 로고
    • Type I interferon in systemic lupus erythematosus and other autoimmune diseases
    • Banchereau J, Pascual V. Type I interferon in systemic lupus erythematosus and other autoimmune diseases. Immunity. 2006;25(3): 383-392.
    • (2006) Immunity , vol.25 , Issue.3 , pp. 383-392
    • Banchereau, J.1    Pascual, V.2
  • 34
    • 84892707974 scopus 로고    scopus 로고
    • Treatment of psoriasis and psoriatic arthritis
    • Papoutsaki M, Costanzo A. Treatment of psoriasis and psoriatic arthritis. BioDrugs. 2013;27(suppl 1): 3-12.
    • (2013) BioDrugs , vol.27 , pp. 3-12
    • Papoutsaki, M.1    Costanzo, A.2
  • 35
    • 70349967965 scopus 로고    scopus 로고
    • Anti-TNF biologic agents: Still the therapy of choice for rheumatoid arthritis
    • Taylor PC, Feldmann M. Anti-TNF biologic agents: Still the therapy of choice for rheumatoid arthritis. Nat Rev Rheumatol. 2009;5(10): 578-582.
    • (2009) Nat Rev Rheumatol , vol.5 , Issue.10 , pp. 578-582
    • Taylor, P.C.1    Feldmann, M.2
  • 37
    • 84887992906 scopus 로고    scopus 로고
    • Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: A randomised, double-blind, placebo-controlled trial
    • Baeten D, et al. Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: A randomised, double-blind, placebo-controlled trial. Lancet. 2013;382(9906): 1705-1713.
    • (2013) Lancet , vol.382 , Issue.9906 , pp. 1705-1713
    • Baeten, D.1
  • 38
    • 84876292569 scopus 로고    scopus 로고
    • Effect of IL-17A blockade with secukinumab in autoimmune diseases
    • Patel DD, Lee DM, Kolbinger F, Antoni C. Effect of IL-17A blockade with secukinumab in autoimmune diseases. Ann Rheum Dis. 2013;72(suppl 2): Ii116-ii123.
    • (2013) Ann Rheum Dis , vol.72 , pp. ii116-ii123
    • Patel, D.D.1    Lee, D.M.2    Kolbinger, F.3    Antoni, C.4
  • 39
    • 78649526238 scopus 로고    scopus 로고
    • Mechanisms of impaired regulation by CD4(+)CD25(+)FOXP3(+) regulatory T cells in human autoimmune diseases
    • Buckner JH. Mechanisms of impaired regulation by CD4(+)CD25(+)FOXP3(+) regulatory T cells in human autoimmune diseases. Nat Rev Immunol. 2010;10(12): 849-859.
    • (2010) Nat Rev Immunol , vol.10 , Issue.12 , pp. 849-859
    • Buckner, J.H.1
  • 40
    • 29144516273 scopus 로고    scopus 로고
    • Global natural regulatory T cell depletion in active systemic lupus erythematosus
    • Miyara M, et al. Global natural regulatory T cell depletion in active systemic lupus erythematosus. J Immunol. 2005;175(12): 8392-8400.
    • (2005) J Immunol , vol.175 , Issue.12 , pp. 8392-8400
    • Miyara, M.1
  • 41
    • 0036141438 scopus 로고    scopus 로고
    • Multiple immuno-regulatory defects in type-1 diabetes
    • Kukreja A, et al. Multiple immuno-regulatory defects in type-1 diabetes. J Clin Invest. 2002;109(1): 131-140.
    • (2002) J Clin Invest , vol.109 , Issue.1 , pp. 131-140
    • Kukreja, A.1
  • 42
    • 80051801522 scopus 로고    scopus 로고
    • Foxp3+ regulatory T cells of psoriasis patients easily differentiate into IL-17A-producing cells and are found in lesional skin
    • Bovenschen HJ, van de Kerkhof PC, van Erp PE, Woestenenk R, Joosten I, Koenen HJ. Foxp3+ regulatory T cells of psoriasis patients easily differentiate into IL-17A-producing cells and are found in lesional skin. J Invest Dermatol. 2011;131(9): 1853-1860.
    • (2011) J Invest Dermatol , vol.131 , Issue.9 , pp. 1853-1860
    • Bovenschen, H.J.1    Van De Kerkhof, P.C.2    Van Erp, P.E.3    Woestenenk, R.4    Joosten, I.5    Koenen, H.J.6
  • 43
    • 84896786878 scopus 로고    scopus 로고
    • Memory regulatory T cells reside in human skin
    • Sanchez Rodriguez R, et al. Memory regulatory T cells reside in human skin. J Clin Invest. 2014;124(3): 1027-1036.
    • (2014) J Clin Invest , vol.124 , Issue.3 , pp. 1027-1036
    • Sanchez Rodriguez, R.1
  • 44
    • 43049174722 scopus 로고    scopus 로고
    • Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction
    • Tang Q, et al. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity. 2008;28(5): 687-697.
    • (2008) Immunity , vol.28 , Issue.5 , pp. 687-697
    • Tang, Q.1
  • 45
    • 1042269477 scopus 로고    scopus 로고
    • IL-10 is involved in the suppression of experimental autoimmune encephalomyelitis by CD25+CD4+ regulatory T cells
    • Zhang X. IL-10 is involved in the suppression of experimental autoimmune encephalomyelitis by CD25+CD4+ regulatory T cells. Int Immunol. 2004;16(2): 249-256.
    • (2004) Int Immunol , vol.16 , Issue.2 , pp. 249-256
    • Zhang, X.1
  • 47
    • 82555196118 scopus 로고    scopus 로고
    • Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis
    • Saadoun D, et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med. 2011;365(22): 2067-2077.
    • (2011) N Engl J Med , vol.365 , Issue.22 , pp. 2067-2077
    • Saadoun, D.1
  • 48
    • 84904130542 scopus 로고    scopus 로고
    • Effects of low-dose recombinant interleukin 2 to promote T-regulatory cells in alopecia areata
    • Castela E, et al. Effects of low-dose recombinant interleukin 2 to promote T-regulatory cells in alopecia areata. JAMA Dermatol. 2014;150(7): 748-751.
    • (2014) JAMA Dermatol , vol.150 , Issue.7 , pp. 748-751
    • Castela, E.1
  • 49
    • 82555168440 scopus 로고    scopus 로고
    • Interleukin-2 and regulatory T cells in graft-versus-host disease
    • Koreth J, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med. 2011;365(22): 2055-2066.
    • (2011) N Engl J Med , vol.365 , Issue.22 , pp. 2055-2066
    • Koreth, J.1
  • 50
    • 79953809817 scopus 로고    scopus 로고
    • Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation
    • Di Ianni M, et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood. 2011;117(14): 3921-3928.
    • (2011) Blood , vol.117 , Issue.14 , pp. 3921-3928
    • Di Ianni, M.1
  • 51
    • 84892502529 scopus 로고    scopus 로고
    • CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets
    • Smigiel KS, et al. CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets. J Exp Med. 2014;211(1): 121-136.
    • (2014) J Exp Med , vol.211 , Issue.1 , pp. 121-136
    • Smigiel, K.S.1
  • 52
    • 84897932501 scopus 로고    scopus 로고
    • Regulatory T-cell homeostasis: Steady-state maintenance and modulation during inflammation
    • Smigiel KS, Srivastava S, Stolley JM, Campbell DJ. Regulatory T-cell homeostasis: Steady-state maintenance and modulation during inflammation. Immunol Rev. 2014;259(1): 40-59.
    • (2014) Immunol Rev , vol.259 , Issue.1 , pp. 40-59
    • Smigiel, K.S.1    Srivastava, S.2    Stolley, J.M.3    Campbell, D.J.4
  • 53
    • 27944455288 scopus 로고    scopus 로고
    • Sequential development of interleukin 2-dependent effector and regulatory T cells in response to endogenous systemic antigen
    • Knoechel B, Lohr J, Kahn E, Bluestone JA, Abbas AK. Sequential development of interleukin 2-dependent effector and regulatory T cells in response to endogenous systemic antigen. J Exp Med. 2005;202(10): 1375-1386.
    • (2005) J Exp Med , vol.202 , Issue.10 , pp. 1375-1386
    • Knoechel, B.1    Lohr, J.2    Kahn, E.3    Bluestone, J.A.4    Abbas, A.K.5
  • 54
    • 84907909000 scopus 로고    scopus 로고
    • Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4
    • Kuehn HS, et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science. 2014;345(6204): 1623-1627.
    • (2014) Science , vol.345 , Issue.6204 , pp. 1623-1627
    • Kuehn, H.S.1
  • 55
    • 84938070889 scopus 로고    scopus 로고
    • Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations
    • Schubert D, et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med. 2014;20(12): 1410-1416.
    • (2014) Nat Med , vol.20 , Issue.12 , pp. 1410-1416
    • Schubert, D.1


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