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

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Abstract

Purpose

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.

Conclusion

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.

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Abbreviations

AD:

Addison’s disease

AIRE:

Autoimmune regulator

APS:

Autoimmune polyendocrine syndrome

CMC:

Chronic mucocutaneous candidiasis

ELISA:

Enzyme-linked immunosorbent assay

HP:

Hypoparathyroidism

IL:

Interleukin

IFN:

Interferon

IPEX:

Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome

Th:

Helper T-cell

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Acknowledgments

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.

Author information

Authors and Affiliations

  1. Department of Clinical Science, University of Bergen, Laboratory building, 8th floor, 5021, Bergen, Norway

    A. S. B. Wolff, B. E. V. Oftedal & E. S. Husebye

  2. Department of Infectious and Pediatric Immunology, University of Debrecen Medical and Health Science Center, Debrecen, 4032, Hungary

    A. K. Sarkadi, L. Maródi & É. Oláh

  3. Molecular Pathology Group, Institute of General and Molecular Pathology, University of Tartu, Tartu, Estonia

    J. Kärner, K. Kisand & P. Peterson

  4. Endocrinological Research Centre, Institute of Paediatric Endocrinology, Moscow, 117036, Russia

    E. Orlova

  5. Pediatric Clinic II, Ospedale Microcitemico and Department of Biomedical and Biotechno-logical Science, University of Cagliari, 09121, Cagliari, Italy

    A. Meloni

  6. Department of Pediatrics, Oslo University Hospital, 0424, Oslo, Norway

    A. G. Myhre

  7. Department of Medicine, Haukeland University Hospital, 5021, Bergen, Norway

    E. S. Husebye

  8. Department of Endocrinology and Metabolism, Seattle Children’s Hospital-University of Washington, Seattle, WA, 98105, USA

    R. Motaghedi

  9. The Hospital for Children and Adolescents, University of Helsinki, 00290, Helsinki, Finland

    J. Perheentupa

  10. Neurosciences Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, OX3 9DS, UK

    N. Willcox

  11. Biotherapeutics Group, National Institute for Biological Standards and Control, South Mimms, Potter’s Bar, EN6 3QG, UK

    A. Meager

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  1. A. S. B. Wolff
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Corresponding author

Correspondence to A. S. B. Wolff.

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Wolff, A.S.B., Sarkadi, A.K., Maródi, L. et al. Anti-Cytokine Autoantibodies Preceding Onset of Autoimmune Polyendocrine Syndrome Type I Features in Early Childhood. J Clin Immunol 33, 1341–1348 (2013). https://doi.org/10.1007/s10875-013-9938-6

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  • DOI: https://doi.org/10.1007/s10875-013-9938-6

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