The A946T variant of the RNA sensor IFIH1 mediates an interferon program that limits viral infection but increases the risk for autoimmunity

Nature Immunology

Volumn 18, Issue 7, 2017, Pages 744-752

  Gorman, Jacquelyn A ^a   Hundhausen, Christian ^b   Errett, John S ^c   Stone, Amy E ^c   Allenspach, Eric J ^a,d   Ge, Yan ^e   Arkatkar, Tanvi ^a   Clough, Courtnee ^a   Dai, Xuezhi ^a   Khim, Socheath ^a   Pestal, Kathleen ^c   Liggitt, Denny ^c   Cerosaletti, Karen ^b   Stetson, Daniel B ^c   James, Richard G ^a,d   Oukka, Mohamed ^a,c,d   Concannon, Patrick ^e   Gale, Michael ^c   Buckner, Jane H ^b   Rawlings, David J ^a,c,d  

^a SEATTLE CHILDREN S RESEARCH INSTITUTE   (United States)

^b BENAROYA RESEARCH INSTITUTE   (United States)

^c UNIVERSITY OF WASHINGTON   (United States)

^d UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE   (United States)

^e UNIVERSITY OF FLORIDA COLLEGE OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

INTERFERON INDUCED HELICASE C DOMAIN CONTAINING PROTEIN 1; LIGAND; THREONINE; IFIH1 PROTEIN, HUMAN; IFIH1 PROTEIN, MOUSE; INTERFERON;

ADULT; ALLELE; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; AUTOIMMUNE DISEASE; AUTOIMMUNITY; CARBOXY TERMINAL SEQUENCE; CODON; CONTROLLED STUDY; FEMALE; GENETIC VARIATION; HAPLOTYPE; HUMAN; HUMAN CELL; HUMAN EXPERIMENT; IMMUNOBLOTTING; IN VITRO STUDY; IN VIVO STUDY; MALE; MOUSE; NONHUMAN; NORMAL HUMAN; PENETRANCE; PERIPHERAL BLOOD MONONUCLEAR CELL; PRIORITY JOURNAL; QUANTITATIVE ANALYSIS; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; SINGLE NUCLEOTIDE POLYMORPHISM; SURVIVAL; VIRUS INFECTION; ADOLESCENT; ANIMAL; CARDIOVIRUS INFECTION; ENCEPHALOMYOCARDITIS VIRUS; EXPERIMENTAL DIABETES MELLITUS; GENETIC PREDISPOSITION; GENETICS; HEK293 CELL LINE; IMMUNOLOGY; INSULIN DEPENDENT DIABETES MELLITUS; MIDDLE AGED; REAL TIME POLYMERASE CHAIN REACTION; SOUTHERN BLOTTING; YOUNG ADULT;

ADOLESCENT; ADULT; ANIMALS; AUTOIMMUNE DISEASES; AUTOIMMUNITY; BLOTTING, SOUTHERN; CARDIOVIRUS INFECTIONS; DIABETES MELLITUS, EXPERIMENTAL; DIABETES MELLITUS, TYPE 1; ENCEPHALOMYOCARDITIS VIRUS; FEMALE; GENETIC PREDISPOSITION TO DISEASE; HEK293 CELLS; HUMANS; IMMUNOBLOTTING; INTERFERON TYPE I; INTERFERON-INDUCED HELICASE, IFIH1; MALE; MICE; MIDDLE AGED; POLYMORPHISM, SINGLE NUCLEOTIDE; REAL-TIME POLYMERASE CHAIN REACTION; REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION; VIRUS DISEASES; YOUNG ADULT;

EID: 85021032664     PISSN: 15292908     EISSN: 15292916     Source Type: Journal    
DOI: 10.1038/ni.3766     Document Type: Article

References (58)

1. Wandstrat, A. & Wakeland, E. The genetics of complex autoimmune diseases: non-MHC susceptibility genes. Nat. Immunol. 2, 802-809 (2001).
2. Theofilopoulos, A.N., Baccala, R., Beutler, B. & Kono, D.H. Type I interferons (/) in immunity and autoimmunity. Annu. Rev. Immunol. 23, 307-336 (2005).
3. Ferreira, R.C. et al. A type I interferon transcriptional signature precedes autoimmunity in children genetically at risk for type 1 diabetes. Diabetes 63, 2538-2550 (2014).
4. Münz, C., Lünemann, J.D., Getts, M.T. & Miller, S.D. Antiviral immune responses: triggers of or triggered by autoimmunity? Nat. Rev. Immunol. 9, 246-258 (2009).
5. Errett, J.S., Suthar, M.S., McMillan, A., Diamond, M.S. & Gale, M. Jr. The essential, nonredundant roles of RIG-I and MDA5 in detecting and controlling West Nile virus infection. J. Virol. 87, 11416-11425 (2013).
6. Loo, Y.-M. & Gale, M. Jr. Immune signaling by RIG-I-like receptors. Immunity 34, 680-692 (2011).
7. del Toro Duany, Y., Wu, B. & Hur, S. MDA5-filament, dynamics and disease. Curr. Opin. Virol. 12, 20-25 (2015).
8. Leung, D.W. & Amarasinghe, G.K. Structural insights into RNA recognition and activation of RIG-I-like receptors. Curr. Opin. Struct. Biol. 22, 297-303 (2012).
9. Kato, H. et al. Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5. J. Exp. Med. 205, 1601-1610 (2008).
10. Pichlmair, A. et al. Activation of MDA5 requires higher-order RNA structures generated during virus infection. J. Virol. 83, 10761-10769 (2009).
11. Rice, G.I. et al. Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nat. Genet. 46, 503-509 (2014).
12. Rutsch, F. et al. A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome. Am. J. Hum. Genet. 96, 275-282 (2015).
13. Van Eyck, L. et al. Brief report: IFIH1 mutation causes systemic lupus erythematosus with selective IgA deficiency. Arthritis Rheumatol. 67, 1592-1597 (2015).
14. Funabiki, M. et al. Autoimmune disorders associated with gain of function of the intracellular sensor MDA5. Immunity 40, 199-212 (2014).
15. Smyth, D.J. et al. A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nat. Genet. 38, 617-619 (2006).
16. Nejentsev, S., Walker, N., Riches, D., Egholm, M. & Todd, J.A. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324, 387-389 (2009).
17. Enevold, C. et al. Multiple sclerosis and polymorphisms of innate pattern recognition receptors TLR1-10, NOD1-2, DDX58, and IFIH1. J. Neuroimmunol. 212, 125-131 (2009).
18. Cunninghame Graham, D.S. et al. Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with systemic lupus erythematosus. PLoS Genet. 7, e1002341 (2011).
19. Li, Y. et al. Carriers of rare missense variants in IFIH1 are protected from psoriasis. J. Invest. Dermatol. 130, 2768-2772 (2010).
20. Martínez, A. et al. Association of the IFIH1-GCA-KCNH7 chromosomal region with rheumatoid arthritis. Ann. Rheum. Dis. 67, 137-138 (2008).
21. Jin, Y., Andersen, G.H.L., Santorico, S.A. & Spritz, R.A. Multiple functional variants of IFIH1, a gene involved in triggering innate immune responses, protect against vitiligo. J. Invest. Dermatol. 137, 522-524 (2017).
22. Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285-291 (2016).
23. Onengut-Gumuscu, S. et al. Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers. Nat. Genet. 47, 381-386 (2015).
24. Concannon, P. et al. Genome-wide scan for linkage to type 1 diabetes in 2,496 multiplex families from the Type 1 Diabetes Genetics Consortium. Diabetes 58, 1018-1022 (2009).
25. Wang, C. et al. Contribution of IKBKE and IFIH1 gene variants to SLE susceptibility. Genes Immun. 14, 217-222 (2013).
26. Liu, S. et al. IFIH1 polymorphisms are significantly associated with type 1 diabetes and IFIH1 gene expression in peripheral blood mononuclear cells. Hum. Mol. Genet. 18, 358-365 (2009).
27. Chen, G. et al. Genetic variants in IFIH1 play opposite roles in the pathogenesis of psoriasis and chronic periodontitis. Int. J. Immunogenet. 39, 137-143 (2012).
28. Hoffmann, F.S. et al. Polymorphisms in melanoma differentiation-associated gene 5 link protein function to clearance of hepatitis C virus. Hepatology 61, 460-470 (2015).
29. Chistiakov, D.A., Voronova, N.V., Savost'Anov, K.V. & Turakulov, R.I. Loss-of-function mutations E6 27X and I923V of IFIH1 are associated with lower poly(I:C)-induced interferon-production in peripheral blood mononuclear cells of type 1 diabetes patients. Hum. Immunol. 71, 1128-1134 (2010).
30. Kato, H. et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature 441, 101-105 (2006).
31. Dai, X. et al. A disease-associated PTPN22 variant promotes systemic autoimmunity in murine models. J. Clin. Invest. 123, 2024-2036 (2013).
32. Perry, D., Sang, A., Yin, Y., Zheng, Y.-Y. & Morel, L. Murine models of systemic lupus erythematosus. J. Biomed. Biotechnol. 2011, 271694 (2011).
33. Klarquist, J. & Janssen, E.M. The bm12 inducible model of systemic lupus erythematosus (SLE) in C57BL/6 mice. J. Vis. Exp. 105, e53319 (2015).
34. Ma, Z., Chen, F., Madaio, M.P., Cohen, P.L. & Eisenberg, R.A. Modulation of autoimmunity by TLR9 in the chronic graft-vs-host model of systemic lupus erythematosus. J. Immunol. 177, 7444-7450 (2006).
35. Robinson, T. et al. Autoimmune disease risk variant of IFIH1 is associated with increased sensitivity to IFN-and serologic autoimmunity in lupus patients. J. Immunol. 187, 1298-1303 (2011).
36. Liddicoat, B.J. et al. RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science 349, 1115-1120 (2015).
37. Pestal, K. et al. Isoforms of RNA-editing enzyme ADAR1 independently control nucleic acid sensor MDA5-driven autoimmunity and multi-organ development. Immunity 43, 933-944 (2015).
38. Heraud-Farlow, J.E. & Walkley, C.R. The role of RNA editing by ADAR1 in prevention of innate immune sensing of self-RNA. J. Mol. Med. 94, 1095-1102 (2016).
39. Schlee, M. & Hartmann, G. Discriminating self from non-self in nucleic acid sensing. Nat. Rev. Immunol. 16, 566-580 (2016).
40. Rice, G.I. et al. Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature. Nat. Genet. 44, 1243-1248 (2012).
41. Niewold, T.B., Hua, J., Lehman, T.J.A., Harley, J.B. & Crow, M.K. High serum IFN-activity is a heritable risk factor for systemic lupus erythematosus. Genes Immun. 8, 492-502 (2007).
42. Downes, K. et al. Reduced expression of IFIH1 is protective for type 1 diabetes. PLoS One 5, e12646 (2010).
43. Lincez, P.J., Shanina, I. & Horwitz, M.S. Reduced expression of the MDA5 gene IFIH1 prevents autoimmune diabetes. Diabetes 64, 2184-2193 (2015).
44. Buers, I., Nitschke, Y. & Rutsch, F. Novel interferonopathies associated with mutations in RIG-I like receptors. Cytokine Growth Factor Rev. 29, 101-107 (2016).
45. Rodero, M.P. & Crow, Y.J. Type I interferon-mediated monogenic autoinflammation: The type I interferonopathies, a conceptual overview. J. Exp. Med. 213, 2527-2538 (2016).
46. Fumagalli, M. et al. Population genetics of IFIH1: ancient population structure, local selection, and implications for susceptibility to type 1 diabetes. Mol. Biol. Evol. 27, 2555-2566 (2010).
47. Vasseur, E. et al. The selective footprints of viral pressures at the human RIG-I-like receptor family. Hum. Mol. Genet. 20, 4462-4474 (2011).
48. Vergara, C., Thio, C.L., Thomas, D. & Duggal, P. Polymorphisms in melanoma differentiation-associated gene 5 are not associated with clearance of hepatitis C virus in a European American population. Hepatology 63, 1061-1062 (2016).
49. Pedergnana, V. et al. Refined association of melanoma differentiation-associated gene 5 variants with spontaneous hepatitis C virus clearance in Egypt. Hepatology 63, 1059-1061 (2016).
50. Hartner, J.C. et al. Liver disintegration in the mouse embryo caused by deficiency in the RNA-editing enzyme ADAR1. J. Biol. Chem. 279, 4894-4902 (2004).
51. Laird, N.M., Horvath, S. & Xu, X. Implementing a unified approach to family-based tests of association. Genet. Epidemiol. 19 (Suppl. 1), S36-S42 (2000).
52. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559-575 (2007).
53. Sharma, S. et al. Widely divergent transcriptional patterns between SLE patients of different ancestral backgrounds in sorted immune cell populations. J. Autoimmun. 60, 51-58 (2015).
54. Börnsen, L. et al. Endogenous interferon-inducible gene expression and interferon-treatment are associated with reduced T cell responses to myelin basic protein in multiple sclerosis. PLoS One 10, e0118830 (2015).
55. Scheler, M. et al. Indoleamine 2,3-dioxygenase (IDO): the antagonist of type I interferon-driven skin inflammation? Am. J. Pathol. 171, 1936-1943 (2007).
56. Indraccolo, S. et al. Identification of genes selectively regulated by IFNs in endothelial cells. J. Immunol. 178, 1122-1135 (2007).
57. Vandesompele, J. et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 3, RESEARCH0034 (2002).
58. Jackson, S.W. et al. Opposing impact of B cell-intrinsic TLR7 and TLR9 signals on autoantibody repertoire and systemic inflammation. J. Immunol. 192, 4525-4532 (2014).