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Review
. 2010 Aug;22(4):467-74.
doi: 10.1016/j.coi.2010.06.009. Epub 2010 Jul 30.

Inborn errors of mucocutaneous immunity to Candida albicans in humans: a role for IL-17 cytokines?

Anne Puel  1 , Capucine Picard, Sophie Cypowyj, Desa Lilic, Laurent Abel, Jean-Laurent Casanova
Affiliations
Review

Inborn errors of mucocutaneous immunity to Candida albicans in humans: a role for IL-17 cytokines?

Anne Puel et al. Curr Opin Immunol. 2010 Aug.

Abstract

The various clinical manifestations of chronic mucocutaneous candidiasis (CMC) often result from acquired T-cell immunodeficiencies. More rarely, CMC results from inborn errors of immunity, the recent dissection of which has shed light on the molecular mechanisms of mucocutaneous immunity to Candida albicans. CMC may accompany various other infectious diseases in patients with almost any broad and profound T-cell primary immunodeficiency. By contrast, CMC is one of the few key infections in patients with autosomal dominant hyper IgE syndrome (mutations in STAT3), and in rare patients with autosomal recessive predisposition to mucocutaneous and invasive fungal infections (mutation in CARD9). In patients with mutations in STAT3 and CARD9, the development of IL-17-producing T cells is impaired. Moreover, CMC is the principal, if not only, infection in patients with autosomal recessive autoimmune polyendocrinopathy syndrome-I (mutations in AIRE). Patients with this condition have high titers of neutralizing autoantibodies (auto-Abs) against the IL-17 cytokines IL-17A, IL-17F, and IL-22. Collectively, these data suggest that human IL-17A, IL-17F, and IL-22 are essential for mucocutaneous immunity to C. albicans. They also suggest that the distinct syndrome of isolated CMC, without auto-immunity or other infections, may be caused by inborn errors of IL-17 immunity.

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Figures

Figure 1
Figure 1. Inborn errors of mucocutaneous immunity to Candida albicans in humans
The recognition of C. albicans by myeloid and epithelial receptors induces the production of pro-inflammatory cytokines. One such pathway is triggered by the Dectin-1-mediated recognition of the C. albicans cell wall component β-glucan, and is mediated by SYK and CARD9, which is also essential for other pathways (DECTIN-2, MINCLE, TREM-1, NOD etc). Pro-inflammatory cytokines, such as IL-6 and IL-23, activate T lymphocytes via STAT3, which induces production of the transcription factor ROR-γt and T-cell differentiation into IL-17-producing T cells. These T cells express the skin and mucosa homing receptors CCR4 and CCR6, and secrete IL-21 and the IL-17 cytokines IL-17A, IL-17F, IL-22, and IL-26. These cytokines act locally to activate epithelial cells and to induce the recruitment and activation of granulocytes (e.g. by inducing anti-microbial peptides, such as β-defensins), thereby helping to clear the fungal infection. In patients with autosomal recessive CARD9 deficiency (pink), autosomal dominant STAT3 deficiency (blue), or in patients with autosomal recessive APS-I (mutations in AIRE, not represented here) with high titers of neutralizing autoantibodies against IL-17A, IL-17F, and IL-22 (purple), IL-17-mediated immunity is impaired, probably accounting for the greater susceptibility of these patients to CMC. It will not be possible to confirm this conclusion until CMC-causing mutations are found in the genes encoding individual IL-17 cytokines or their receptors.
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