Insights from Mendelian Interferonopathies: Comparison of CANDLE, SAVI with AGS, Monogenic Lupus.
Autoinflammatory disorders are sterile inflammatory conditions characterized by episodes of early-onset fever and disease-specific patterns of organ inflammation. Recently, the discoveries of monogenic disorders with strong type I interferon (IFN) signatures caused by mutations in proteasome degradation and cytoplasmic RNA and DNA sensing pathways suggest a pathogenic role of IFNs in causing autoinflammatory phenotypes. The IFN response gene signature (IGS) has been associated with systemic lupus erythematosus (SLE) and other autoimmune diseases. In this review, we compare the clinical presentations and pathogenesis of two IFN-mediated autoinflammatory diseases, CANDLE and SAVI, with Aicardi Goutières syndrome (AGS) and monogenic forms of SLE (monoSLE) caused by loss-of-function mutations in complement 1 (C1q) or the DNA nucleases, DNASE1 and DNASE1L3. We outline differences in intracellular signaling pathways that fuel a pathologic type I IFN amplification cycle. While IFN amplification is caused by predominantly innate immune cell dysfunction in SAVI, CANDLE, and AGS, autoantibodies to modified RNA and DNA antigens interact with tissues and immune cells including neutrophils and contribute to IFN upregulation in some SLE patients including monoSLE, thus justifying a grouping of "autoinflammatory" and "autoimmune" interferonopathies. Understanding of the differences in the cellular sources and signaling pathways will guide new drug development and the use of emerging targeted therapies.
Lawrence Shulman Scholar in Translational Research, Pediatric Translational Research Branch, National Institute of Arthritis Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA. hanna.kim@nih.gov.
Hanna
0000-0002-0595-6533
H
Kim
Translational Autoinflammatory Disease Studies, National Institute of Allergy and Infectious Diseases (NIAID), and NIAMS, National Institutes of Health (NIH), Bethesda, MD, USA.
Gina A Montealegre
GA
Sanchez
Translational Autoinflammatory Disease Studies, National Institute of Allergy and Infectious Diseases (NIAID), and NIAMS, National Institutes of Health (NIH), Bethesda, MD, USA. goldbacr@mail.nih.gov.
Raphaela
R
Goldbach-Mansky
D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D007370:Interferon Type I / Q000276:immunology*; D007375:Interleukin-1 / Q000276:immunology
D007370:Interferon Type I; D007375:Interleukin-1
Autoimmune; Autoinflammatory; Candle; Interferonopathies; SAVI; Type I IFN
Am J Hum Genet. 2010 Dec 10;87(6):866-72
21129723
Arthritis Rheum. 1997 Sep;40(9):1725
9324032
Am J Med Genet A. 2015 Feb;167A(2):296-312
25604658
Epigenetics Chromatin. 2015 Nov 16;8:46
26579211
Cell. 2008 Aug 22;134(4):587-98
18724932
J Am Acad Dermatol. 2010 Mar;62(3):489-95
20159315
EMBO J. 2016 Apr 15;35(8):831-44
26903602
Cell Rep. 2014 Nov 20;9(4):1482-94
25456137
Rheumatology (Oxford). 2007 Oct;46(10):1612-4
17890276
Nat Genet. 2007 Sep;39(9):1068-70
17660820
Ann Rheum Dis. 2017 Feb;76(2):468-472
27566796
Arthritis Rheum. 2009 Aug;60(8):2304-13
19644874
Front Immunol. 2012 Dec 14;3:380
23248629
J Immunol. 1998 Nov 1;161(9):5016-26
9794439
J Immunol. 2013 Sep 1;191(5):2647-56
23904163
Nat Genet. 2011 Oct 23;43(12):1186-8
22019780
Dermatology. 2013;227(1):26-30
23942189
JAMA Dermatol. 2015 Aug;151(8):872-7
25992765
Nat Rev Rheumatol. 2012 Aug;8(8):458-68
22664835
J Invest Dermatol. 2012 Dec;132(12):2855-7
22718116
Drugs. 2011 Oct 1;71(14):1865-91
21942977
Ann Rheum Dis. 2010 Jul;69(7):1396-402
20472592
J Immunol. 2010 Oct 15;185(8):4738-49
20844193
Clin Exp Nephrol. 2005 Sep;9(3):183-91
16189625
Cell. 2016 Jun 30;166(1):88-101
27293190
J Biol Chem. 2004 Oct 15;279(42):44123-32
15302890
Ann Rheum Dis. 2015 Mar;74(3):e17
24445253
J Exp Med. 2003 Mar 17;197(6):711-23
12642603
Intern Med. 1993 Jan;32(1):42-5
8495043
Am J Hum Genet. 2015 Feb 5;96(2):266-74
25620203
Nat Genet. 2000 Jun;25(2):177-81
10835632
Cell. 2010 Mar 19;140(6):784-90
20303869
Thorax. 2000 Feb;55(2):159-66
10639536
Nat Genet. 2001 Aug;28(4):313-4
11479590
Neurodegener Dis. 2012;10(1-4):7-22
22327508
Best Pract Res Clin Rheumatol. 2013 Jun;27(3):391-404
24238695
Trends Immunol. 2011 Dec;32(12):574-81
21940216
Am J Hum Genet. 2006 Oct;79(4):731-7
16960810
J Clin Invest. 2015 Nov 2;125(11):4196-211
26524591
Cell Host Microbe. 2013 Oct 16;14(4):422-34
24139400
Ann N Y Acad Sci. 2011 Nov;1238:91-8
22129056
Expert Rev Clin Immunol. 2014 Sep;10(9):1151-64
25081199
Nat Genet. 2006 Aug;38(8):917-20
16845398
Nat Genet. 2012 Nov;44(11):1243-8
23001123
Immunity. 2012 Jan 27;36(1):120-31
22284419
Eur J Pediatr. 2016 May;175(5):735-40
26567544
Am J Hum Genet. 2014 Jul 3;95(1):121-5
24995871
Br Med Bull. 2009;89:183-201
19129251
Mol Cell. 2011 Dec 23;44(6):978-88
22195970
Front Immunol. 2016 Feb 15;7:36
26913032
Am J Med Genet A. 2011 Jan;155A(1):235-7
21204240
Science. 2015 Sep 4;349(6252):1115-20
26275108
Autoimmunity. 2012 Dec;45(8):597-601
22913420
J Clin Invest. 2015 Jan;125(1):413-24
25500883
Neurol Neuroimmunol Neuroinflamm. 2014 Dec 23;2(1):e55
25566545
Gut. 2005 Jul;54(7):1014-20
15951552
Lancet. 1985 Aug 10;2(8450):294-8
2862466
Neurology. 2011 Jun 14;76(24):2079-88
21670437
Neuropediatrics. 2000 Jun;31(3):155-8
10963105
Rev Hosp Clin Fac Med Sao Paulo. 2004 Jun;59(3):138-44
15286835
DNA Repair (Amst). 2004 Aug-Sep;3(8-9):1039-47
15279791
Curr Opin Microbiol. 2016 Aug;32:113-9
27288760
Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):12061-6
19574451
Nephron. 1981;28(4):179-85
7029321
Nat Genet. 2011 Feb;43(2):132-7
21217752
J Clin Invest. 2014 Dec;124(12):5516-20
25401470
Nature. 2002 Jul 11;418(6894):191-5
12110890
Nat Genet. 2006 Aug;38(8):910-6
16845400
Ann Rheum Dis. 2011 Nov;70(11):2029-36
21803750
Nat Genet. 2014 May;46(5):503-9
24686847
Nat Genet. 2009 Jul;41(7):829-32
19525956
Exp Clin Immunogenet. 1998;15(4):231-4
10072632
Arthritis Rheum. 2012 Mar;64(3):895-907
21953331
Am J Hum Genet. 2015 Feb 5;96(2):275-82
25620204
Nat Immunol. 2010 Sep;11(9):785-97
20720586
Nat Immunol. 2013 Jan;14(1):19-26
23238760
N Engl J Med. 2014 Aug 7;371(6):507-18
25029335
Nature. 2002 Apr 11;416(6881):603-7
11948342
Arthritis Rheumatol. 2015 Mar;67(3):808
25510345
Arthritis Rheum. 2004 Feb;50(2):640-9
14872509
Cell. 2007 Nov 30;131(5):873-86
18045533
Pediatr Dermatol. 2011 Sep-Oct;28(5):538-41
20553399
Ann Intern Med. 1980 Jun;92(6):748-52
7387017
Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):14914-9
21852578
J Am Acad Dermatol. 2016 Jan;74(1):186-9
26584874
Immunol Cell Biol. 2012 May;90(5):498-504
22430248
Ann Neurol. 1998 Dec;44(6):900-7
9851434
Immunol Cell Biol. 2011 Jan;89(1):90-9
20548325
J Clin Immunol. 2015 Apr;35(3):235-43
25731743
Lancet Neurol. 2013 Dec;12(12):1159-69
24183309
Front Immunol. 2016 Feb 08;7:35
26904025
Arthritis Rheum. 2009 Jun;60(6):1733-42
19479824
J Clin Pathol. 2015 Dec;68(12):954-62
26602413
Neuropediatrics. 2010 Feb;41(1):18-23
20571986
Proc Natl Acad Sci U S A. 2010 May 25;107(21):9813-8
20439745
JAMA Dermatol. 2015 Apr;151(4):426-31
25517357
Annu Rev Immunol. 2016 May 20;34:395-420
26907212
J Mol Med (Berl). 2007 May;85(5):531-7
17440703
J Exp Med. 2016 Mar 7;213(3):329-36
26880576
J Clin Endocrinol Metab. 2010 Sep;95(9):E58-63
20534754
Mol Med. 2007 Jan-Feb;13(1-2):59-68
17515957
Annu Rev Immunol. 2015;33:823-74
25706096
J Exp Med. 2008 Dec 22;205(13):3007-18
19064698
J Am Acad Dermatol. 2013 Jul;69(1):e29-32
23768303
Annu Rev Med. 2014;65:223-44
24422572
Semin Immunopathol. 2015 Jul;37(4):323-33
25963519
Arthritis Rheum. 2010 May;62(5):1469-77
20131292
J Clin Invest. 2011 Oct;121(10):4150-60
21881205
Nat Med. 2016 Feb;22(2):146-53
26779811
Kidney Int. 1996 Aug;50(2):635-42
8840296
Autoimmunity. 2009 May;42(4):325-7
19811290
J Exp Med. 1994 Apr 1;179(4):1317-30
7511686
Nat Genet. 2011 Feb;43(2):127-31
21217755
Br J Dermatol. 2015 Dec;173(6):1505-13
26284909
J Exp Med. 2010 Sep 27;207(10):2053-63
20837696
Mol Cell. 2006 Jul 7;23(1):133-42
16818237
Arthritis Rheum. 1996 Apr;39(4):663-70
8630118
J Invest Dermatol. 2014 May;134(5):1456-9
24270665