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

Abstract

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.

Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy

“…APECED patients also develop high titer neutralizing autoantibodies against IL-22, IL-17F and IL-17A [29,69]. Although the autoantibodies neutralizing IL-22 and IL-17F (but not those against IL-17A) were correlated with CMC in a study of 162 APECED patients, high titers against IL-17A were associated with severe CMC in a recent case study [69,83]. Whether the susceptibility for candidiasis is primarily caused by the neutralizing autoantibodies to Th17 cytokines or by the impaired production of IL-22 and IL-17A is unknown.…”

“…Whether the susceptibility for candidiasis is primarily caused by the neutralizing autoantibodies to Th17 cytokines or by the impaired production of IL-22 and IL-17A is unknown. Some follow-up studies of APECED patient siblings AIRE defects lead to a devastating disease that affects multiple organs and tissues as depicted on the figure have indicated that autoantibodies to IL-22 and IL-17F can persist almost starting from birth to at least 5 years of age without causing any signs of CMC [22,83].…”

Treatment of Chronic Mucocutaneous Candidiasis, an Unsolved Issue. Case Report and Literature Review

“…Some genetic etiologies of CMC have been well-described, mutations in some genes like: AIRE, STAT1, STAT3 (2,4,11,12,13,14,15,16,17) Other genetic syndromes are associated with far smaller numbers of cases, such as those due to mutations of IL-17RA, ACT1, IL-17F, PTPN22, CLEC7A, TLR3, CARD 9 (5,6,10,11,12,19,20,21,22,23). There are distinct forms of CMC for which the genetic defects have not yet identified (24).…”

Cutaneous manifestations of autoimmune polyglandular syndrome type 1 – case report and literature review

“…W wielu przypadkach profil wykrywanych w surowicy autoprzeciwciał nie koreluje z obrazem klinicznym i nie pozwala na rozpoznanie choroby na podstawie samej ich obecności w surowicy [15]. Jednak w zespole APS-1 prawie wszyscy chorzy (98-100%) wytwarzają neutralizujące autoprzeciwciała przeciwko interferonowi (IFN) w oraz α2, bez względu na kliniczny przebieg choroby oraz czas wystąpienia poszczególnych składowych poliendokrynopatii [17][18][19][20]. Ponadto pojawienie się autoprzeciwciał poprzedza wystąpienie schorzeń autoimmunologicznych, a nawet kandydozy śluzów-kowo-skórnej (ang.…”

“…Obecnie podejrzewa się, że limfocyty Th17 i ich cytokiny -interleukina 17A, 17F i 22 (IL-17A, IL-17F, IL-22), odgrywają główną rolę w mechanizmie odporności przeciwgrzybiczej poprzez indukcję produkcji peptydów przeciwbakteryjnych i rekrutację czynników chemotaktycznych dla neutrofilów [24]. W surowicy pacjentów z przewlekłą kandydozą skóry i błon śluzowych stwier- [18,20,25]. Lindh i wsp.…”