Journal of Clinical Immunology

, Volume 33, Issue 8, pp 1341–1348 | Cite as

Anti-Cytokine Autoantibodies Preceding Onset of Autoimmune Polyendocrine Syndrome Type I Features in Early Childhood

  • A. S. B. Wolff
  • A. K. Sarkadi
  • L. Maródi
  • J. Kärner
  • E. Orlova
  • B. E. V. Oftedal
  • K. Kisand
  • É. Oláh
  • A. Meloni
  • A. G. Myhre
  • E. S. Husebye
  • R. Motaghedi
  • J. Perheentupa
  • P. Peterson
  • N. Willcox
  • A. Meager



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.


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.


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.


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.

Key words

APECED AIRE autoimmune polyendocrine syndrome autoimmune immuno-deficiency cytokine autoantibodies Interferon omega Interleukin 22 Interleukin 17 candidiasis autoimmunization 



Addison’s disease


Autoimmune regulator


Autoimmune polyendocrine syndrome


Chronic mucocutaneous candidiasis


Enzyme-linked immunosorbent assay








Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome


Helper T-cell



Anette B. Wolff thanks the Bergen Medical Research Foundation and Western Norway Health Authorities for funding this study. This work was also supported by the UD Faculty of Medicine Research Fund (Bridging Fund 2012) and the TÁMOP 4.2.2.A-11/1/KONV-2012-0023 “VÉD-ELEM” project to LM.

We are grateful to Elisabeth Halvorsen for performing RIAs, Dr. Phillipp Pymm for help and advice and Prof NK Maclaren and Dr. S. Ten for patient samples.

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

10875_2013_9938_MOESM1_ESM.doc (40 kb)
Supplementary Table 1 (DOC 40 kb)


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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • A. S. B. Wolff
    • 1
  • A. K. Sarkadi
    • 2
  • L. Maródi
    • 2
  • J. Kärner
    • 3
  • E. Orlova
    • 4
  • B. E. V. Oftedal
    • 1
  • K. Kisand
    • 3
  • É. Oláh
    • 2
  • A. Meloni
    • 5
  • A. G. Myhre
    • 6
  • E. S. Husebye
    • 1
    • 7
  • R. Motaghedi
    • 8
  • J. Perheentupa
    • 9
  • P. Peterson
    • 3
  • N. Willcox
    • 10
  • A. Meager
    • 11
  1. 1.Department of Clinical ScienceUniversity of BergenBergenNorway
  2. 2.Department of Infectious and Pediatric ImmunologyUniversity of Debrecen Medical and Health Science CenterDebrecenHungary
  3. 3.Molecular Pathology Group, Institute of General and Molecular PathologyUniversity of TartuTartuEstonia
  4. 4.Endocrinological Research Centre, Institute of Paediatric EndocrinologyMoscowRussia
  5. 5.Pediatric Clinic II, Ospedale Microcitemico and Department of Biomedical and Biotechno-logical ScienceUniversity of CagliariCagliariItaly
  6. 6.Department of PediatricsOslo University HospitalOsloNorway
  7. 7.Department of MedicineHaukeland University HospitalBergenNorway
  8. 8.Department of Endocrinology and MetabolismSeattle Children’s Hospital-University of WashingtonSeattleUSA
  9. 9.The Hospital for Children and AdolescentsUniversity of HelsinkiHelsinkiFinland
  10. 10.Neurosciences Group, Weatherall Institute of Molecular MedicineUniversity of OxfordOxfordUK
  11. 11.Biotherapeutics GroupNational Institute for Biological Standards and ControlPotter’s BarUK

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