Autoantibodies to IL-17A may be correlated with the severity of mucocutaneous candidiasis in APECED patients.

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 Candida-exposed 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 Candida-exposed 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

New and recurrent gain-of-function STAT1 mutations in patients with chronic mucocutaneous candidiasis from Eastern and Central Europe

Background: Chronic mucocutaneous candidiasis disease (CMCD) may result from various inborn errors of interleukin (IL)-17-mediated immunity. Twelve of the 13 causal mutations described to date affect the coiled-coil domain (CCD) of STAT1. Several mutations, including R274W in particular, are recurrent, but the underlying mechanism is unclear. Objective: To investigate and describe nine patients with CMCD in Eastern and Central Europe, to assess the biochemical impact of STAT1 mutations, to determine cytokines in supernatants of Candida-exposed blood cells, to determine IL-17-producing T cell subsets and to determine STAT1 haplotypes in a family with the c.820C>T (R274W) mutation. Results: The novel c.537C>A (N179K) STAT1 mutation was gain-of-function (GOF) for γ-activated factor (GAF)-dependent cellular responses. In a Russian patient, the cause of CMCD was the newly identified c.854 A>G (Q285R) STAT1 mutation, which was also GOF for GAF-dependent responses. The c.1154C>T (T385M) mutation affecting the DNA-binding domain (DBD) resulted in a gain of STAT1 phosphorylation in a Ukrainian patient. Impaired Candida-induced IL-17A and IL-22 secretion by leucocytes and lower levels of intracellular IL-17 and IL-22 production by T cells were found in several patients. Haplotype studies indicated that the c.820C>T (R274W) mutation was recurrent due to a hotspot rather than a founder effect. Severe clinical phenotypes, including intracranial aneurysm, are presented. Conclusions: The c.537C>A and c.854A>G mutations affecting the CCD and the c.1154C>T mutation affecting the DBD of STAT1 are GOF. The c.820C>T mutation of STAT1 in patients with CMCD is recurrent due to a hotspot. Patients carrying GOF mutations of STAT1 may develop multiple intracranial aneurysms by hitherto unknown mechanisms

Candida fertőzéssel szembeni immunitás az I-es típusú autoimmun poliendokrin szindrómás betegekben

Autoimmune polyendocrine syndrome type I is a rare recessively inherited disorder, caused by mutations in the autoimmune regulator (AIRE) gene, characterized by high titers of autoantibodies against a wide variety of endocrine organs and cytokines, that could partly be responsible for the clinical symptoms, mainly endocrine organ hypofunctions and chronic mucocutaneous candidiasis, but the relative roles of these autoantibodies in susceptibility to candidiasis remain poorly defined. In summary, we report here a correlation between anti-IL-17A autoantibody level and predisposition to chronic mucocutaneous candidiasis in APS I patients. We suggest that anti-IL-17A autoantibodies may play a more important role than anti-IL-22 and anti-IL-17F antibodies in rendering APS I patients susceptible to candidiasis. We suggest that high levels of anti-IL-22 and anti-IL-17F autoantibodies may not be correlated with the occurrence of candidiasis in APS I patients. We present data suggesting that the release of IL-17A, IL-17F and IL-22 by peripheral blood mononuclear cells after Candida stimulation is impaired in APS I patients, and this impairment affects only IL-17 and IL-22 secretion, and does not influence secretion of other cytokines. This result is confirmed by the normal secretion of TNF-α of APS I patients, after Candida stimulation. We found, that patients with APS I have a decreased persent of CD3+IL-17+, CD4+IL-17+ and CD4+IL-22+, Il-17 and IL-22 producing T cells, after in vitro differentiation, compared with healthy controls. Moreover, the percents of the IL-17 and IL-22 producing T cells are nearly constant with and without the inhibition of cytokine secretion in APS I, in contrast with the results of healthy controls. Based on this results, we suggest, that the development of IL-17+, IL-22+ T helper cells is impaired in APS I patients, nevertheless, secretion mechanisms of these cells are also affected. We propose that the predisposition to candidiasis of APS I patients is based on a complicated conjuction of diversified factors, included the antifungal cytokine-neutralization by autoantibodies, the impaired development of IL-17 and IL-22 producing T cells, and decreased cytokine secretion capacity of these cells.   Az I-es típusú autoimmune poliendokrin szindróma egy ritka, autoszomális recesszív módon öröklődő kórkép, melynek hátterében az autoimmune regulator (AIRE) gén mutációja áll. A betegség jellegzetessége specifikus anutoantitestek termelése számos szerv, szövet, citokin valamint hormonok szintézisében részt vevő enzimek ellen. Munkánk során az I-es típusú autoimmun poliendokrin szindrómában szenvedő betegek antifungális védekező mechanizmusainak vizsgálatával foglalkoztunk. Az irodalmi adatokban fellelhető eredményekkel ellentétben korrelációt találtunk a betegek IL-17A ellenes autoantitestek mennyisége és a krónikus mucocutan candidiasis előfordulása között. Eredményeinkből arra következtettünk, hogy az IL-17A ellenes antitestek kiemelt szerepet játszanak az APS I-es betegek candidiasisra való hajlamosságában, és a tünetek súlyossága az antitestek mennyiségével korrelál. Emellett az IL-17F és IL-22 ellenes autoantitestek mennyisége és a tünetek előfordulása között nem találtunk összefüggést. További vizsgálatokkal igazoltuk, hogy az APS I-es betegek candidiasisra való fogékonyságának hátterében további defektusok is megfigyelhetőek. APS I-es betegeink mintáiból jelentősen csökkent antifungális citokin szekréciót figyeltünk meg, Candida stimulációt követően, míg egy Th17 vonaltól függetlennek tekinthető citokin, a TNF-α szekréciója normálisnak bizonyult. A sejtes vizsgálatok felvetették, hogy az APS I-es betegek IL-17 illetve IL-22 termelő sejtjeinek aránya csökkent az egészséges kontrollokéhoz viszonyítva, és a sejtek citokin szekréciója is elmarad az egészséges kontrollok eredményeihez képest. Eredményeink alátámasztják, hogy az APS I-es betegek kónikus mukokután candidiasisának hátterében az eddig gondoltnál sokkal szélesebb körű defektus áll, amely nem merül ki az antifungális citokinek elleni autoantitest termelésben, de érinti a testfelszíni Candida ellenes védekezésben kiemelt szerepet játszó Th17 sejtek differenciációját és citokin szekréciós mechanizmusait is.d

Mukokután candida fertőzések klinikai manifesztációi és szövődményei

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