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: Becausevariability in clinical featuresandageatonsetin APS-I frequently results inunusual 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-a2 and interferon-w in antiviral neutralization assays. Setting and Patients: Patients included 14 British/Irish, 15 Sardinian, and 10 Southern Italian AIREmutant 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-a2 and/or interferon-w in all 39 APS-I patients vs. zero of 48 unaffected relatives and zero of 19 British/Irish CMC patients. Especially against interferon-w, 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.
Autoantibodies against type I Interferons as an additional diagnostic criteria for Autoimmune Polyendocrine Syndrome type I
FALORNI, Alberto;
2008
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: Becausevariability in clinical featuresandageatonsetin APS-I frequently results inunusual 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-a2 and interferon-w in antiviral neutralization assays. Setting and Patients: Patients included 14 British/Irish, 15 Sardinian, and 10 Southern Italian AIREmutant 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-a2 and/or interferon-w in all 39 APS-I patients vs. zero of 48 unaffected relatives and zero of 19 British/Irish CMC patients. Especially against interferon-w, 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
