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J Clin Endocrinol Metab. 2008 Nov;93(11):4389-97. doi: 10.1210/jc.2008-0935. Epub 2008 Aug 26.

Autoantibodies against type I interferons as an additional diagnostic criterion for autoimmune polyendocrine syndrome type I.

Author information

1
Pediatric Clinic II, Ospedale Microcitemico and Dipartimento di Sciencze Biomediche e Biotechno-logiche, University of Cagliari, Cagliari, Sardinia, Italy.

Abstract

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-alpha2 and interferon-omega 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-alpha2 and/or interferon-omega in all 39 APS-I patients vs. zero of 48 unaffected relatives and zero of 19 British/Irish CMC patients. Especially against interferon-omega, 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.

PMID:
18728167
DOI:
10.1210/jc.2008-0935
[Indexed for MEDLINE]

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