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Autoantibodies against Type I Interferons as an Additional Diagnostic Criterion for Autoimmune Polyendocrine Syndrome Type I

Antonella Meloni¹, Maria Furcas, Filomena Cetani¹, Claudio Marcocci, Alberto Falorni¹, Roberto Perniola¹, Mikulá Pura¹, Anette S. Bøe Wolff, Eystein S. Husebye, Desa Lilic¹, Kelli R. Ryan, Andrew R. Gennery, Andrew J. Cant, Mario Abinun, Gavin P. Spickett, Peter D. Arkwright, David Denning, Colm Costigan, Maria Dominguez, Vivienne McConnell, Nick Willcox and Anthony Meager²

Address all correspondence and requests for reprints to: Nick Willcox, Neuroscience Group, Weatherall Institute of Molecular Medicine, University of Oxford, Headington, OX3 9DS Oxford, United Kingdom. E-mail: nick.willcox{at}imm.ox.ac.uk; or Anthony Meager, Biotherapeutics Group, National Institute for Biological Standards and Control, Blanche Lane, South Mimms EN6 3QG, United Kingdom. E-mail: ameager{at}nibsc.ac.uk.

Context: In autoimmune polyendocrinopathy syndrome type I (APS-I), mutations in the autoimmune regulator gene (AIRE) impair thymic self-tolerance induction in developing T cells. The ensuing autoimmunity particularly targets ectodermal and endocrine tissues, but chronic candidiasis usually comes first. We recently reported apparently APS-I-specific high-titer neutralizing autoantibodies against type I interferons in 100% of Finnish and Norwegian patients, mainly with two prevalent AIRE truncations.

Objectives: Because variability in clinical features and age at onset in APS-I frequently results in unusual presentations, we prospectively checked the diagnostic potential of anti-interferon antibodies in additional APS-I panels with other truncations or rare missense mutations and in disease controls with chronic mucocutaneous candidiasis (CMC) but without either common AIRE mutation.

Design: The study was designed to detect autoantibodies against interferon-2 and interferon- in antiviral neutralization assays.

Setting and Patients: Patients included 14 British/Irish, 15 Sardinian, and 10 Southern Italian AIRE-mutant patients with APS-I; also 19 other patients with CMC, including four families with cosegregating thyroid autoimmunity.

Outcome: The diagnostic value of anti-interferon autoantibodies was assessed.

Results: We found antibodies against interferon-2 and/or interferon- in all 39 APS-I patients vs. zero of 48 unaffected relatives and zero of 19 British/Irish CMC patients. Especially against interferon-, titers were nearly always high, regardless of the exact APS-I phenotype/duration or AIRE genotype, including 12 different AIRE length variants or 10 point substitutions overall (n = 174 total). Strikingly, in one family with few typical APS-I features, these antibodies cosegregated over three generations with autoimmune hypothyroidism plus a dominant-negative G228W AIRE substitution.

Conclusions: Otherwise restricted to patients with thymoma and/or myasthenia gravis, these precocious persistent antibodies show 98% or higher sensitivity and APS-I specificity and are thus a simpler diagnostic option than detecting AIRE mutations.