Anti-Cytokine Autoantibodies Preceding Onset of Autoimmune Polyendocrine Syndrome Type I Features in Early Childhood
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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 wordsAPECED AIRE autoimmune polyendocrine syndrome autoimmune immuno-deficiency cytokine autoantibodies Interferon omega Interleukin 22 Interleukin 17 candidiasis autoimmunization
Autoimmune polyendocrine syndrome
Chronic mucocutaneous candidiasis
Enzyme-linked immunosorbent assay
Immunodysregulation polyendocrinopathy enteropathy X-linked syndrome
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.
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