Increased IL‐17A secretion in response to <i>Candida albicans</i> in autoimmune polyendocrine syndrome type 1 and its animal model

Ahlgren, Kerstin M.; Moretti, Silvia; Lundgren, Brita Ardesjö; Karlsson, Iulia; Åhlin, Erik; Norling, Anna; Hallgren, Åsa; Perheentupa, Jaakko; Gustafsson, Jan Åke; Rorsman, Fredrik; Crewther, Pauline E.; Rönnelid, Johan; Bensing, Sophie; Scott, Hamish S.; Kämpe, Olle; Romani, Luigina; Lobell, Anna

doi:10.1002/eji.200939883

Cited by 41 publications

(38 citation statements)

References 33 publications

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“…8). Considering that IL-17 expression is differentially regulated by different pathogens in the same cell [44], our conclusions concerning C. albicans may not be transferable to infection of other pathogens. To address these concerns, we are currently undertaking comparative studies with other pathogens.…”

Section: Discussionmentioning

confidence: 74%

IL‐17 plays a central role in initiating experimental Candida albicans infection in mouse corneas

Zou

et al. 2013

Eur J Immunol

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The pathogenesis of fungal infection in the cornea remains largely unclear. To understand how the immune system influences the progression of fungal infection in corneas, we inoculated immunocompetent BALB/c mice, neutrophil-or CD4+ T-cell-depleted BALB/c mice, and nude mice with Candida albicans. We found that only immunocompetent BALB/c mice developed typical Candida keratitis (CaK), while the other mouse strains lacked obvious clinical manifestations. Furthermore, CaK development was blocked in immunocompetent mice treated with anti-IL-17A or anti-IL-23p19 to neutralize IL-17 activity. However, no significant effects were observed when Treg cells, γδ T cells, or IFN-γ were immunodepleted. Upon infection, the corneas of BALB/c mice were infiltrated with IL-17-producing leukocytes, including neutrophils and, to a lesser degree, CD4 + T cells.In contrast, leukocyte recruitment to corneas was significantly diminished in nude mice. Indeed, nude mice produced much less chemokines (e.g. CXCL1, CXCL2, CXCL10, CXCL12, CCL2, and IL-6) in response to inoculation. Remarkably, addition of CXCL2 during inoculation restored CaK induction in nude mice. In contrast to its therapeutic effect on CaK, neutralization of IL-17 exacerbated Candida-induced dermatitis in skin. We conclude that IL-17, mainly produced by neutrophils and CD4 + T cells in the corneas, is essential in the pathogenesis of CaK. Keywords: Candida albicans · Corneal infection · Fungal infection · IL-17 · NeutrophilAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionFungal infection of the cornea, namely fungal keratitis (FK), is among the main causes of blindness in many parts of the world. While the causative pathogens differ by geographic region, the most prevalent genera are Fusarium, Aspergillus, and Candida [1][2][3]. The structural characteristics of cornea (i.e. thinness and transparency) and the high proliferation rate of most initiated Correspondence: Dr. Yiqiang Wang e-mail: yiqiangwang99@hotmail.com fungi contribute to the rapid onset of FK and total loss of sight within a few days of infection. Unfortunately, many aspects of FK pathogenicity remain unclear. For example, it is not known whether the avascularity of the cornea, which affords immune and lymphangiogenic "privilege", is responsible for the rapid progression of FK [4,5]. FK progresses even after leukocytes, including neutrophils and lymphocytes, infiltrate infected cornea.Although well-documented in other organs, studies on the host-pathogen interactions in the context of FK are lacking [4][5][6]. The available data suggest an innate immune response plays a vital role in the response to fungal infection of the cornea [7,8]. Eur. J. Immunol. 2013Immunol. . 43: 2671Immunol. -2682 Figure 1. Innate resistance of nude mice to CaK induction. BALB/c mice and nude mice were inoculated with 1 × 10 5 Candida albicans blastospores. (A) The corneas were monitored under a slit lamp, and (B) evaluated with the scoring system. D...

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Section: Discussionmentioning

confidence: 74%

IL‐17 plays a central role in initiating experimental Candida albicans infection in mouse corneas

Zou

et al. 2013

Eur J Immunol

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“…More recently, autoantibodies against the Th17-related cytokines (IL-22, IL-17F, and IL-17A) were identified in APECED patients [29,69]. These autoantibodies are very specific, highly prevalent, neutralizing and develop very early during the disease course [29,69,80,131]. Autoantibodies to IL-22 in APECED patients appear within the first months of life, similar to those against type I IFNs [22,69].…”

Section: Autoantibodies and Their Diagnostic And Prognostic Value In mentioning

confidence: 88%

“…Additionally, IL-22 promotes epithelial barrier integrity, especially in synergy with TNF-α co-secreted by Th22 cells [76,77]. In contrast to several other syndromes associated with CMC [78,79], the circulating lymphocytes of APECED patients produce normal or even increased amounts of IL-17A [80,81], but are deficient in IL-22 and IL-17F secretion [69,80,81]. Moreover, the production of IL-22 is severely impaired by the skin-populating T cells of APECED patients [82].…”

Section: Chronic Mucocutaneous Candidiasismentioning

confidence: 97%

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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“…The role of IL-17A secretion seems somewhat controversial in these studies. One of them found increased numbers of C. albicans-induced IL-17A-producing cells in PBMC from APECED patients, measured by flow cytometry by intracellular staining of IL-17A [1], in contrast with other studies, which consistently found impaired IL-17A responses in APECED patients [8,11,23]. PBMCs from our patients released small amounts of IL-17A and much smaller, or negligible amounts of IL-17F and IL-22 by Candidaexposed cells, compared with healthy controls.…”

Section: Discussionmentioning

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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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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Increased IL‐17A secretion in response to Candida albicans in autoimmune polyendocrine syndrome type 1 and its animal model

Cited by 41 publications

References 33 publications

IL‐17 plays a central role in initiating experimental Candida albicans infection in mouse corneas

IL‐17 plays a central role in initiating experimental Candida albicans infection in mouse corneas

Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy

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

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