Document Detail

Anti-cytokine autoantibodies suggest pathogenetic links with autoimmune regulator deficiency in humans and mice.
MedLine Citation:
PMID:  23379432     Owner:  NLM     Status:  MEDLINE    
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.
J Kärner; A Meager; M Laan; J Maslovskaja; M Pihlap; A Remm; E Juronen; A S B Wolff; E S Husebye; K T Podkrajšek; N Bratanic; T Battelino; N Willcox; P Peterson; K Kisand
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Clinical and experimental immunology     Volume:  171     ISSN:  1365-2249     ISO Abbreviation:  Clin. Exp. Immunol.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-05     Completed Date:  2013-04-02     Revised Date:  2014-03-06    
Medline Journal Info:
Nlm Unique ID:  0057202     Medline TA:  Clin Exp Immunol     Country:  England    
Other Details:
Languages:  eng     Pagination:  263-72     Citation Subset:  IM    
Copyright Information:
© 2012 British Society for Immunology.
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MeSH Terms
Autoantibodies / blood,  immunology*
Cytokines / immunology*
Immunodominant Epitopes
Immunoglobulin G / blood
Interferon-alpha / immunology
Interleukin-17 / immunology
Interleukins / immunology
Mice, Inbred BALB C
Mice, Inbred C57BL
Polyendocrinopathies, Autoimmune / immunology*
Transcription Factors / deficiency*,  physiology
Reg. No./Substance:
0/APECED protein; 0/Autoantibodies; 0/Cytokines; 0/IL17A protein, human; 0/Immunodominant Epitopes; 0/Immunoglobulin G; 0/Interferon-alpha; 0/Interleukin-17; 0/Interleukins; 0/Transcription Factors; 0/interleukin-22

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