Novel sequence variation of <i>AIRE</i> and detection of interferon‐ω antibodies in early infancy

Töth, Beáta; Wolff, Anette S. B.; Halász, Zita; Tar, Attila; Szüts, P; Ilyés, I; Erdős, Melinda; Szegedi, Gyula; Husebye, Eystein S.; Zeher, Margit; Maródi, László

doi:10.1111/j.1365-2265.2009.03740.x

Cited by 41 publications

(33 citation statements)

References 31 publications

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“…Previous studies have suggested that anti-cytokine autoantibodies are involved in CMC pathogenesis in APECED patients [11,27,28,36]. It has been suggested that autoantibodies against cytokines, including IL-17A, IL-17F and IL-22, may underlie CMC in patients with APECED [11,28].…”

Section: Discussionmentioning

confidence: 99%

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Autoantibodies to IL-17A may be Correlated with the Severity of Mucocutaneous Candidiasis in APECED Patients

et al. 2014

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The relative roles of various autoantibodies against IL-17-type cytokines in susceptibility to chronic mucocutaneous candidiasis (CMC) in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) remain poorly defined. The purpose of this longitudinal study was to analyze the relationship between the occurrence of mucocutaneous candidiasis and levels of anti-IL-17A, anti-IL-17F and anti-IL-22 autoantibodies. We studied six APECED patients from four families with various disease manifestations. Clinical data were collected during regular follow-up. Anti-endocrine organ antibody levels and clinical chemistry and immunology parameters were determined in routine laboratory assays on freshly isolated serum. Levels of autoantibodies against IL-17A, IL-17F, IL-22, IFN-α, IFN-ω and TNF-α, and cytokine release by Candidaexposed blood cells were determined by ELISA. Mutations were analyzed by sequencing genomic DNA. Four patients carried the germline c.769C>T homozygous nonsense mutation, which results in R257X truncation of the AIRE protein, and two patients from the same family were compound heterozygous for the c.769C>T/c.1344delC mutation. We found persistently high levels of antibodies against IL-17A in the serum samples of one patient presenting CMC since infancy and low or undetectable anti-IL-17A antibody levels in the sera of five patients with no candidiasis or without severe candidiasis. By contrast, levels of autoantibodies against IL-17F and IL-22 were higher in all patients than in healthy controls. Release of IL-17-type cytokines by Candidaexposed blood mononuclear cells was low or negligible in all patients tested. We suggest that anti-IL-17A antibodies may play an important role in the predisposition to candidiasis of APECED patients. However, the lack of severe CMC in APECED patients with high levels of IL-17F and anti-IL-22 autoantibodies clearly calls into question the role of these antibodies as the principal cause of cutaneous and mucosal candidiasis in at least some APECED patients. These data also suggest that the impaired release of IL-17-type cytokines by blood cells may be an element of the immunopathology of CMC in APECED patients.

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Section: Discussionmentioning

confidence: 99%

“…Patients P4 and P5 carry the c.769C>T/c.1344delC compound heterozygous mutation in the AIRE gene, as described in detail elsewhere [36].…”

Section: Genetic Data and Clinical Presentationmentioning

confidence: 99%

Autoantibodies to IL-17A may be Correlated with the Severity of Mucocutaneous Candidiasis in APECED Patients

et al. 2014

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“…Mutation analysis of the AIRE gene is the most direct way to confirm the diagnosis; however, the process can be time-consuming and expensive if the associated mutations are not common. Instead, autoantibodies directed against type I interferons (especially IFN-ω and IFN-α) can be used for APECED diagnosis [16][17][18][19][20][21]. High-titer neutralizing autoantibodies against type I IFNs are detectable in AIRE-deficient children as early as a few months of age, before the appearance of clinical symptoms or organ-specific autoantibodies [18,22,23].…”

Section: Diagnosismentioning

confidence: 98%

“…Autoantibodies that are useful for screening, diagnostics or for prognostic purposes in patients are highlighted in bold in Table 1. The anti-cytokine autoantibodies stand out due to their high prevalence and early emergence [18,22,70]. Neutralizing autoantibodies specific for type I IFNs in APECED were discovered in 2006 by Meager and coworkers [16], and their diagnostic value was appreciated soon [17,19,20,28].…”

Section: Autoantibodies and Their Diagnostic And Prognostic Value In mentioning

confidence: 98%

Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy

Kisand

Peterson

2015

J Clin Immunol

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Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is an autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene. This review focuses on the clinical and immunological features of APECED, summarizes the current knowledge on the function of AIRE and discusses the importance of autoantibodies in disease diagnosis and prognosis. Additionally, we review the outcome of recent immunomodulatory treatments in APECED patients.

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“…Exons 1-6 of SMPD1 and the flanking intronic regions were amplified using polymerase chain reaction (PCR) (Erdős et al 2005;Jiao et al 2008). Mutational analysis was performed using the BigDye Terminator Cycle sequencing kit v3.1 (Applied Biosystems, Foster City, CA), and an ABI 3130 DNA analyzer (Applied Biosystems) (Tóth et al 2010). Sequence data were compared to the published sequence of SMPD1 (GeneCards GC11P006368 and HGMD).…”

Section: Molecular Geneticsmentioning

confidence: 99%

Molecular Genetic Characterization of Novel Sphingomyelin Phosphodiesterase 1 Mutations Causing Niemann–Pick Disease

et al. 2011

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Niemann-Pick disease (NPD) types A and B are autosomal recessive disorders caused by acid sphingomyelinase (ASM) deficiency due to mutation in the sphingomyelin phosphodiesterase 1 gene (SMPD1). Although a number of SMPD1 mutations were reported, expression studies were performed for only a small number of missense mutations. We evaluated three unrelated patients with clinical manifestations of NPD. Sequence analysis revealed two previously described (S248R and W391G) and two novel (G247D and F572L) missense mutations. To analyze the effects of the novel mutations on ASM function, cDNA was generated by site-directed mutagenesis and expressed in COS-7 cells. In vitro biochemical assays revealed marked deficiency of ASM activity consistent with the disease phenotype in cells homoallelic for each mutation. We show that each mutation dramatically reduced half-life and catalytic activity of ASM with more pronounced decrease by the G247D mutation. These data suggest that impaired protein stability and decreased enzyme activity are responsible for the disease in sphingomyelinase-deficient patients carrying the G247D and F572L mutations.

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Novel sequence variation of AIRE and detection of interferon‐ω antibodies in early infancy

Abstract: This is the first overview of patients diagnosed with APS I in Hungary. A novel c.1344delC mutation in AIRE was detected. Anti-IFN-omega antibodies seem to appear very early in life and are helpful to differentiate APS I from other multi-organ autoimmune diseases.

Cited by 41 publications

References 31 publications

Autoantibodies to IL-17A may be Correlated with the Severity of Mucocutaneous Candidiasis in APECED Patients

Autoantibodies to IL-17A may be Correlated with the Severity of Mucocutaneous Candidiasis in APECED Patients

Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy

Molecular Genetic Characterization of Novel Sphingomyelin Phosphodiesterase 1 Mutations Causing Niemann–Pick Disease

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