Chronic mucocutaneous candidiasis associated with impaired TH17 cell differentiation

In this month’s issue, Hanna and Etzoni (J Allergy Clin Immunol 2011;127:1433-1437) shed light on the primary players in the pathogenesis of chronic mucosal candidiasis (CMC). They review current knowledge of CMC as it is most commonly observed; namely, as secondary to other clinical conditions, particularly those that cause immunocompromise, such as HIV, diabetes mellitus, and T-cell deficiency disorders. Hanna and Etzoni then discuss CMC as a primary symptom in immunodeficiency disease, such as in hyper-IgE syndrome (HIES) and autoimmune polyendocrinopathy with candidiasis and ectodermal dysplasia (APECED), or, more rarely, with no other related clinical presentation.

The authors review the primary innate immune defense against Candida albicans, noting that activation of the Dectin-1 and -2 receptors mediate host response through spleen tyrosine kinase (Syk) and caspase recruitment domain member 9 (CARD9) to initiate T cell differentiation to produce multiple cytokines, particularly those associated with TH17 differentiation, IL-17 and IL-22. T regulatory cells are also mobilized and critical for containing the TH17 inflammatory response to C. albicans.

Hanna and Etzoni move on to discuss CMC as the primary clinical feature of HIES and point to research that has shown that a heterozygous mutation in the transcription factor, STAT3, is the cause of this syndrome. Impaired STAT3 signaling negatively impacts RORγt function, which is required for TH17 cell development. The authors point out that this is supported by clinical findings of very low circulating markers for TH17 cell lineage in patients with HIES.

They also review severe CMC as a major feature of the autoimmune disease, APECED. Unlike the transcription dysregulation in HIES, CMC in APECED results from high titers of neutralizing autoantibodies against IL-17 and IL-22. Finally, Hanna and Etzoni describe less common presentations of non-syndromic CMC, some of which are idiopathic, while others have autosomal inheritance associations. In the latter, the authors discuss a genetic analysis of familial CMC in 5 generations of an Iranian family, which revealed a loss-of-function mutation in CARD9.

The authors conclude noting that in most non-syndromic CMC cases the genetic defects are still unknown, though abnormal TH17 function or production was observed.

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