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


OBJECTIVE
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.


METHODS
The study was designed to detect autoantibodies against interferon-alpha2 and interferon-omega in antiviral neutralization assays.


METHODS
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.


RESULTS
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.
Meloni
Antonella
A
Pediatric Clinic II, Ospedale Microcitemico and Dipartimento di Sciencze Biomediche e Biotechno-logiche, University of Cagliari, Cagliari, Sardinia, Italy.
Furcas
Maria
M
Cetani
Filomena
F
Marcocci
Claudio
C
Falorni
Alberto
A
Perniola
Roberto
R
Pura
Mikulás
M
Bøe Wolff
Anette S
AS
Husebye
Eystein S
ES
Lilic
Desa
D
Ryan
Kelli R
KR
Gennery
Andrew R
AR
Cant
Andrew J
AJ
Abinun
Mario
M
Spickett
Gavin P
GP
Arkwright
Peter D
PD
Denning
David
D
Costigan
Colm
C
Dominguez
Maria
M
McConnell
Vivienne
V
Willcox
Nick
N
Meager
Anthony
A
D001323:Autoantibodies / Q000097:blood*; D001327:Autoimmune Diseases / Q000097:blood / Q000175:diagnosis / Q000235:genetics / Q000276:immunology; D003937:Diagnosis, Differential; D006801:Humans; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology*; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology; D009157:Myasthenia Gravis / Q000097:blood / Q000175:diagnosis / Q000276:immunology; D017354:Point Mutation; D016884:Polyendocrinopathies, Autoimmune / Q000097:blood / Q000175:diagnosis* / Q000276:immunology; D012680:Sensitivity and Specificity; D013577:Syndrome; D013601:T-Lymphocytes / Q000276:immunology; D013961:Thyroid Gland / Q000276:immunology
D001323:Autoantibodies; D007370:Interferon Type I; D016898:Interferon-alpha