IFI16 filament formation in salivary epithelial cells shapes the anti-IFI16 immune response in Sjögren's syndrome.

Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 101676073 Publication Model: eCollection Cited Medium: Internet ISSN: 2379-3708 (Electronic) Linking ISSN: 23793708 NLM ISO Abbreviation: JCI Insight Subsets: MEDLINE

Original Publication: Ann Arbor, Michigan : American Society for Clinical Investigation, [2016]-

Autoantibodies*; Epithelial Cells/*metabolism ; Nuclear Proteins/*immunology ; Nuclear Proteins/*metabolism ; Phosphoproteins/*immunology ; Phosphoproteins/*metabolism ; Salivary Glands, Minor/*immunology ; Sjogren's Syndrome/*immunology; Autoantigens ; Cell Death ; Epitopes ; Humans ; Immunoprecipitation ; Nuclear Proteins/genetics ; Phosphoproteins/genetics ; Rheumatic Diseases/immunology ; Salivary Glands, Minor/metabolism ; Salivary Glands, Minor/pathology ; Sjogren's Syndrome/pathology

IFN-inducible protein 16 (IFI16) is an innate immune sensor that forms filamentous oligomers when activated by double-stranded DNA (dsDNA). Anti-IFI16 autoantibodies occur in patients with Sjögren's syndrome (SS) and associate with severe phenotypic features. We undertook this study to determine whether the structural and functional properties of IFI16 play a role in its status as an SS autoantigen. IFI16 immunostaining in labial salivary glands (LSGs) yielded striking evidence of filamentous IFI16 structures in the cytoplasm of ductal epithelial cells, representing the first microscopic description of IFI16 oligomerization in human tissues, to our knowledge. Transfection of cultured epithelial cells with dsDNA triggered the formation of cytoplasmic IFI16 filaments with similar morphology to those observed in LSGs. We found that a majority of SS anti-IFI16 autoantibodies immunoprecipitate IFI16 more effectively in the oligomeric dsDNA-bound state. Epitopes in the C-terminus of IFI16 are accessible to antibodies in the DNA-bound oligomer and are preferentially targeted by SS sera. Furthermore, cytotoxic lymphocyte granule pathways (highly enriched in the SS gland) induce striking release of IFI16•dsDNA complexes from cultured cells. Our studies reveal that IFI16 is present in a filamentous state in the target tissue of SS and suggest that this property of DNA-induced filament formation contributes to its status as an autoantigen in SS. These studies highlight the role that tissue-specific modifications and immune effector pathways might play in the selection of autoantigens in rheumatic diseases.

Proc Natl Acad Sci U S A. 2012 Jun 26;109(26):10558-63. (PMID: 22691496)
Int Rev Immunol. 2017 Mar 4;36(2):74-88. (PMID: 28333574)
Proc Natl Acad Sci U S A. 2006 Feb 21;103(8):2770-5. (PMID: 16477017)
Nat Immunol. 2014 Aug;15(8):738-48. (PMID: 24952504)
J Virol. 2013 Aug;87(15):8606-23. (PMID: 23720728)
Proc Natl Acad Sci U S A. 2015 Apr 7;112(14):E1773-81. (PMID: 25831530)
Elife. 2015 Dec 16;4:e11721. (PMID: 26673078)
Science. 2015 Oct 23;350(6259):455-9. (PMID: 26382853)
J Autoimmun. 2010 May;34(3):J178-206. (PMID: 20031372)
Curr Opin Struct Biol. 2016 Apr;37:134-44. (PMID: 26859869)
Arthritis Res Ther. 2015 Sep 04;17:241. (PMID: 26336930)
J Intern Med. 2009 Jun;265(6):625-31. (PMID: 19493056)
Ann Rheum Dis. 2002 Jun;61(6):554-8. (PMID: 12006334)
J Exp Med. 1999 Sep 20;190(6):815-26. (PMID: 10499920)
J Autoimmun. 2010 Nov;35(3):225-31. (PMID: 20674271)
Autoimmunity. 2010 Apr;43(3):226-31. (PMID: 20187706)
Arthritis Rheumatol. 2016 Nov;68(11):2697-2707. (PMID: 27110677)
Expert Rev Clin Immunol. 2014 Apr;10(4):457-67. (PMID: 24450331)
Immunology. 2005 Sep;116(1):53-63. (PMID: 16108817)
Immunity. 2012 Apr 20;36(4):561-71. (PMID: 22483801)
Arthritis Care Res (Hoboken). 2016 Feb;68(2):254-60. (PMID: 26037655)
J Autoimmun. 2010 Jun;34(4):400-7. (PMID: 19889514)
J Autoimmun. 2015 Sep;63:47-58. (PMID: 26183766)
Eur J Immunol. 2016 Feb;46(2):269-80. (PMID: 26626159)
Annu Rev Immunol. 2011;29:185-214. (PMID: 21219183)
Rheumatology (Oxford). 2010 Mar;49(3):433-40. (PMID: 20015976)
Science. 2014 Jan 24;343(6169):428-32. (PMID: 24356113)
EMBO J. 2014 Aug 1;33(15):1654-66. (PMID: 24970844)
Nat Immunol. 2014 Aug;15(8):727-37. (PMID: 24952505)
Clin Exp Immunol. 2006 Jun;144(3):432-9. (PMID: 16734612)
Arthritis Res Ther. 2017 Jul 25;19(1):178. (PMID: 28743286)
Arthritis Rheum. 2005 Apr;52(4):1185-95. (PMID: 15818675)
Sci Transl Med. 2013 Jul 24;5(195):195ra96. (PMID: 23884468)
Inflamm Bowel Dis. 2015 Nov;21(11):2673-82. (PMID: 26313692)
BMC Evol Biol. 2012 Aug 07;12:140. (PMID: 22871040)
Curr Opin Rheumatol. 2018 Jan;30(1):72-78. (PMID: 28937414)
Proc Natl Acad Sci U S A. 2013 Nov 26;110(48):E4571-80. (PMID: 24154727)
Arthritis Rheumatol. 2016 Nov;68(11):2686-2696. (PMID: 27338297)
Nat Immunol. 2010 Nov;11(11):997-1004. (PMID: 20890285)
Clin Immunol. 2012 Mar;142(3):223-31. (PMID: 22245264)
J Cell Physiol. 1994 Nov;161(2):217-26. (PMID: 7962105)
BMJ. 2012 Jun 14;344:e3821. (PMID: 22700787)
Nat Rev Immunol. 2006 Nov;6(11):823-35. (PMID: 17063184)
Rheum Dis Clin North Am. 2016 Aug;42(3):419-34. (PMID: 27431345)
Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):E62-71. (PMID: 24367117)
Proc Natl Acad Sci U S A. 2015 Oct 20;112(42):E5699-705. (PMID: 26371324)
Nature. 2015 Apr 23;520(7548):553-7. (PMID: 25642965)
J Immunol. 2013 Mar 1;190(5):2311-9. (PMID: 23345332)
Arthritis Rheum. 2001 Oct;44(10):2376-86. (PMID: 11665980)
Annu Rev Immunol. 2017 Apr 26;35:313-336. (PMID: 28142323)
Cell. 2013 Oct 24;155(3):688-98. (PMID: 24119841)
Nat Commun. 2015 Jul 22;6:7827. (PMID: 26197926)
Cell Death Differ. 2017 Feb;24(2):276-287. (PMID: 28141795)
Ann Rheum Dis. 2012 Feb;71(2):295-301. (PMID: 21979002)
Cell Host Microbe. 2011 May 19;9(5):363-75. (PMID: 21575908)
Arthritis Res Ther. 2015 Aug 14;17:208. (PMID: 26271464)
Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17609-14. (PMID: 23045702)
Annu Rev Immunol. 2016 May 20;34:395-420. (PMID: 26907212)
Proc Natl Acad Sci U S A. 2012 Nov 6;109(45):18437-41. (PMID: 23090998)
Clin Rev Allergy Immunol. 2014 Aug;47(1):73-90. (PMID: 24840362)
Mol Cell. 2014 Apr 24;54(2):289-96. (PMID: 24766893)
Arthritis Rheum. 1994 Jul;37(7):1046-54. (PMID: 8024614)
J Immunol. 2015 Apr 1;194(7):3236-45. (PMID: 25710914)
J Autoimmun. 2010 Nov;35(3):219-24. (PMID: 20685080)
Mol Immunol. 2017 Jun;86:10-15. (PMID: 28249679)

P30 AR070254 United States AR NIAMS NIH HHS; R01 DE012354 United States DE NIDCR NIH HHS; T32 AR048522 United States AR NIAMS NIH HHS

Keywords: Autoimmune diseases; Autoimmunity; Rheumatology

0 (Autoantibodies)
0 (Autoantigens)
0 (Epitopes)
0 (Nuclear Proteins)
0 (Phosphoproteins)
148998-64-5 (IFI16 protein, human)

Date Created: 20180921 Date Completed: 20191112 Latest Revision: 20191112

20221213

PMC6237237

10.1172/jci.insight.120179

30232276