title: Anti-cytokine autoantibodies suggest pathogenetic links with autoimmune regulator deficiency in humans and mice.
abstract: Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is a recessive disorder resulting from mutations in the autoimmune regulator (AIRE). The patients' autoantibodies recognize not only multiple organ-specific targets, but also many type I interferons (IFNs) and most T helper type 17 (Th17) cell-associated cytokines, whose biological actions they neutralize in vitro. These anti-cytokine autoantibodies are highly disease-specific: otherwise, they have been found only in patients with thymomas, tumours of thymic epithelial cells that fail to express AIRE. Moreover, autoantibodies against Th17 cell-associated cytokines correlate with chronic mucocutaneous candidiasis in both syndromes. Here, we demonstrate that the immunoglobulin (Ig)Gs but not the IgAs in APECED sera are responsible for neutralizing IFN-ω, IFN-α2a, interleukin (IL)-17A and IL-22. Their dominant subclasses proved to be IgG1 and, surprisingly, IgG4 without IgE, possibly implicating regulatory T cell responses and/or epithelia in their initiation in these AIRE-deficiency states. The epitopes on IL-22 and IFN-α2a appeared mainly conformational. We also found mainly IgG1 neutralizing autoantibodies to IL-17A in aged AIRE-deficient BALB/c mice - the first report of any target shared by these human and murine AIRE-deficiency states. We conclude that autoimmunization against cytokines in AIRE deficiency is not simply a mere side effect of chronic mucosal Candida infection, but appears to be related more closely to disease initiation.
authors: Molecular Pathology Group, University of Tartu, Tartu, Estonia.
authors: J
authors: J
authors: Kärner
authors: A
authors: A
authors: Meager
authors: M
authors: M
authors: Laan
authors: J
authors: J
authors: Maslovskaja
authors: M
authors: M
authors: Pihlap
authors: A
authors: A
authors: Remm
authors: E
authors: E
authors: Juronen
authors: A S B
authors: AS
authors: Wolff
authors: E S
authors: ES
authors: Husebye
authors: K T
authors: KT
authors: Podkrajšek
authors: N
authors: N
authors: Bratanic
authors: T
authors: T
authors: Battelino
authors: N
authors: N
authors: Willcox
authors: P
authors: P
authors: Peterson
authors: K
authors: K
authors: Kisand
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D016207:Cytokines / Q000276:immunology*; D006801:Humans; D016056:Immunodominant Epitopes; D007074:Immunoglobulin G / Q000097:blood; D016898:Interferon-alpha / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D007378:Interleukins / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016884:Polyendocrinopathies, Autoimmune / Q000276:immunology*; D014157:Transcription Factors / Q000172:deficiency* / Q000502:physiology; D000096927:AIRE Protein; D000097043:Interleukin-22
chemical_list: D001323:Autoantibodies; D016207:Cytokines; D016056:Immunodominant Epitopes; D007074:Immunoglobulin G; D016898:Interferon-alpha; D020381:Interleukin-17; D007378:Interleukins; D014157:Transcription Factors; D000096927:AIRE Protein; D000097043:Interleukin-22; C508717:IL17A protein, human
references: Annu Rev Immunol. 2009;27:287-312
references: 19302042
references: Clin Chim Acta. 2009 May;403(1-2):37-41
references: 19408348
references: J Exp Med. 2010 Feb 15;207(2):291-7
references: 20123958
references: Scand J Immunol. 2011 Sep;74(3):327-333
references: 21535082
references: J Immunol. 2009 Mar 15;182(6):3902-18
references: 19265170
references: Curr Protoc Protein Sci. 2002 Aug;Chapter 18:18.3.1-18.3.19
references: 18429227
references: Nat Genet. 1997 Dec;17(4):399-403
references: 9398840
references: Eur J Endocrinol. 2010 Aug;163(2):309-17
references: 20498138
references: J Exp Med. 2010 Feb 15;207(2):299-308
references: 20123959
references: Curr Opin Rheumatol. 2011 Jan;23(1):114-8
references: 21045701
references: Clin Endocrinol (Oxf). 2010 May;72(5):641-7
references: 19863576
references: J Vis Exp. 2009 Oct 07;(32):
references: 19812534
references: Int Arch Allergy Immunol. 2008;147(3):171-8
references: 18594146
references: Nat Genet. 1997 Dec;17(4):393-8
references: 9398839
references: Microbes Infect. 2010 Jul;12(7):518-27
references: 20381638
references: Lancet. 1997 Nov 29;350(9091):1596-7
references: 9393342
references: J Clin Invest. 2010 May;120(5):1762-73
references: 20364087
references: J Intern Med. 2009 May;265(5):514-29
references: 19382991
references: Eur J Immunol. 2011 Jan;41(1):235-45
references: 21182094
references: Immunol Rev. 2004 Dec;202:8-32
references: 15546383
references: J Clin Endocrinol Metab. 2008 Nov;93(11):4389-97
references: 18728167
references: Semin Immunopathol. 2010 Mar;32(1):17-31
references: 20127093
references: Hum Immunol. 2012 Mar;73(3):287-90
references: 22261388
references: Science. 2007 Sep 14;317(5844):1554-7
references: 17872445
references: Eur J Endocrinol. 2004 Jan;150(1):49-56
references: 14713279
references: Ann N Y Acad Sci. 2011 Dec;1246:77-91
references: 22236432
references: Allergy. 2011 Jul;66 Suppl 95:28-30
references: 21668848
references: J Clin Endocrinol Metab. 2012 Apr;97(4):1114-24
references: 22344197
references: Eur J Immunol. 2011 Jun;41(6):1517-27
references: 21574164
references: Blood. 2010 Dec 2;116(23):4848-58
references: 20716769
references: Blood. 2006 Sep 15;108(6):1941-8
references: 16709926
references: Dermatol Clin. 2011 Jul;29(3):413-8, viii
references: 21605806
references: Front Immunol. 2012 Mar;3(March):19
references: 22448160
references: Neurology. 2005 Jan 25;64(2):399; author reply 399
references: 15668461
references: Curr Opin Immunol. 2010 Aug;22(4):467-74
references: 20674321
references: Curr Opin Allergy Clin Immunol. 2005 Aug;5(4):343-7
references: 15985817
references: Hum Mol Genet. 2002 Feb 15;11(4):397-409
references: 11854172
references: J Clin Endocrinol Metab. 2007 Feb;92(2):595-603
references: 17118990
references: J Autoimmun. 2006 Sep;27(2):96-104
references: 16820279
references: APMIS. 1998 Sep;106(9):884-92
references: 9808415
references: Blood. 2008 Oct 1;112(7):2657-66
references: 18606876
references: Nat Med. 1997 Jul;3(7):797-801
references: 9212111
references: Nat Rev Immunol. 2007 Oct;7(10):1
references: 17932495
references: Protein Sci. 2006 Nov;15(11):2656-68
references: 17001036
references: J Immunol. 2005 Feb 15;174(4):1862-70
references: 15699112
references: Nat Rev Immunol. 2008 Dec;8(12):948-57
references: 19008896
references: J Exp Med. 2005 Sep 19;202(6):805-15
references: 16172259
references: PLoS Med. 2006 Jul;3(7):e289
references: 16784312
references: FEBS Lett. 2008 Sep 3;582(20):2985-92
references: 18675809