title: Anti-cytokine autoantibodies preceding onset of autoimmune polyendocrine syndrome type I features in early childhood.
abstract: OBJECTIVE
  Almost all patients with autoimmune polyendocrine syndrome (APS)-I have high titer neutralizing autoantibodies to type I interferons (IFN), especially IFN-ω and IFN-α2, whatever their clinical features and onset-ages. About 90 % also have antibodies to interleukin (IL)-17A, IL-17F and/or IL-22; they correlate with the chronic mucocutaneous candidiasis (CMC) that affects ~90 % of patients. Our aim was to explore how early the manifestations and endocrine and cytokine autoantibodies appear in young APS-I patients. That may hold clues to very early events in the autoimmunization process in these patients.
  
  
  METHODS
  Clinical investigations and autoantibody measurements in 13 APS-I patients sampled before age 7 years, and 3 pre-symptomatic siblings with AIRE-mutations in both alleles.
  
  
  RESULTS
  Antibody titers were already high against IFN-α2 and IFN-ω at age 6 months in one sibling-8 months before onset of APS-I-and also against IL-22 at 7 months in another (still unaffected at age 5 years). In 12 of the 13 APS-I patients, antibody levels were high against IFN-ω and/or IL-22 when first tested, but only modestly positive against IFN-ω in one patient who had only hypo-parathyroidism. Endocrine organ-specific antibodies were present at age 6 months in one sibling, and as early as 36 and 48 months in two of the six informative subjects.
  
  
  CONCLUSIONS
  This is the first study to collate the onset of clinical features, cytokine and endocrine autoantibodies in APS-I infants and siblings. The highly restricted early autoantibody responses and clinical features they show are not easily explained by mere loss of broad-specific self-tolerance inducing mechanisms, but hint at some more sharply focused early event(s) in autoimmunization.
authors.affiliation: Department of Clinical Science, University of Bergen, Laboratory building, 8th floor, 5021, Bergen, Norway, Anette.boe@med.uib.no.
authors.forename: A S B
authors.initials: AS
authors.lastname: Wolff
authors.forename: A K
authors.initials: AK
authors.lastname: Sarkadi
authors.forename: L
authors.initials: L
authors.lastname: Maródi
authors.forename: J
authors.initials: J
authors.lastname: Kärner
authors.forename: E
authors.initials: E
authors.lastname: Orlova
authors.forename: B E V
authors.initials: BE
authors.lastname: Oftedal
authors.forename: K
authors.initials: K
authors.lastname: Kisand
authors.forename: E
authors.initials: E
authors.lastname: Oláh
authors.forename: A
authors.initials: A
authors.lastname: Meloni
authors.forename: A G
authors.initials: AG
authors.lastname: Myhre
authors.forename: E S
authors.initials: ES
authors.lastname: Husebye
authors.forename: R
authors.initials: R
authors.lastname: Motaghedi
authors.forename: J
authors.initials: J
authors.lastname: Perheentupa
authors.forename: P
authors.initials: P
authors.lastname: Peterson
authors.forename: N
authors.initials: N
authors.lastname: Willcox
authors.forename: A
authors.initials: A
authors.lastname: Meager
mesh_terms: D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000096:biosynthesis / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000276:immunology*; D042241:Early Diagnosis; D005260:Female; D006801:Humans; D007223:Infant; D016898:Interferon-alpha / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D007378:Interleukins / Q000276:immunology; D008297:Male; D016884:Polyendocrinopathies, Autoimmune / Q000175:diagnosis* / Q000276:immunology* / Q000378:metabolism; D013577:Syndrome; D055815:Young Adult; D000097043:Interleukin-22
chemical_list: D001323:Autoantibodies; D016207:Cytokines; D016898:Interferon-alpha; D020381:Interleukin-17; D007378:Interleukins; D000097043:Interleukin-22