Inborn errors of human IL-17 immunity underlie chronic mucocutaneous candidiasis

Abstract

Purpose of review Chronic mucocutaneous candidiasis (CMC) is characterised by recurrent or persistent symptomatic infection of the nails, skin and mucosae mostly by Candida albicans. CMC is common in patients with profound primary T-cell immunodeficiency, who often display multiple infectious and autoimmune diseases. Patients with syndromic CMC, including autosomal dominant (AD) hyper IgE syndrome (HIES) and autosomal recessive (AR) autoimmune polyendocrinopathy syndrome type I (APS-I), display fewer other infections. Patients with isolated CMC (CMCD) rarely display any other severe disease. We review here recent progress in the genetic dissection of these three types of inherited CMC. Recent findings Low IL-17 T cell proportions were reported in patients with AD-HIES bearing heterozygous STAT3 mutations, prone to CMC and staphylococcal diseases, and in a kindred with AR CARD9 deficiency, prone to CMC and other fungal infections. High levels of neutralising autoantibodies against IL-17 cytokines were documented in patients with APS-I presenting with CMC as their only infectious disease. The first three genetic aetiologies of CMCD were then reported: AR IL-17RA and AD IL-17F deficiencies and AD STAT1 gain-of-function, impairing IL-17-producing T cell development. Summary Inborn errors of human IL-17 immunity underlie CMC. Impaired IL-17 immunity may therefore account for CMC in other settings, including patients with acquired immunodeficiency.

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

“…Previous studies have suggested that anti-cytokine autoantibodies are involved in CMC pathogenesis in APECED patients [11,27,28,36]. It has been suggested that autoantibodies against cytokines, including IL-17A, IL-17F and IL-22, may underlie CMC in patients with APECED [11,28].…”

Gain‐of‐function STAT1 mutations impair STAT3 activity in patients with chronic mucocutaneous candidiasis (CMC)

“…Mucosal infections with Candida species indicate an underlying T-cell deficiency, which is most often secondary to immunosuppressive and/or chemotherapy, antibiotics, biological therapies, HIV, or other permissive circumstances. However, in rare patients, these infections present as a severe syndrome coined CMC, a primary immune deficiency in which the underlying cause is a genetic mutation affecting immune pathways essential for fungal protection [3]. Research in primary immune deficiency patients with isolated CMC has documented the crucial role of the signal transducer and activator of transcription 3 (STAT3)/retinoic acid receptor related orphan receptor C (RORC/ interleukin 17 (IL-17) pathway for protection against mucocutaneous fungal disease [3].…”

“…However, in rare patients, these infections present as a severe syndrome coined CMC, a primary immune deficiency in which the underlying cause is a genetic mutation affecting immune pathways essential for fungal protection [3]. Research in primary immune deficiency patients with isolated CMC has documented the crucial role of the signal transducer and activator of transcription 3 (STAT3)/retinoic acid receptor related orphan receptor C (RORC/ interleukin 17 (IL-17) pathway for protection against mucocutaneous fungal disease [3]. As proof of principle, it was found that the candidiasis in patients with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy who suffer with autoimmunity as a result of AIRE gene mutations was linked to autoantibodies against Th-17 cytokines (IL-17A, IL-17F, and IL-22), elegantly explaining the CMC in the context of autoimmunity [4].…”

Inflammation induces dermal Vγ4 + γδT17 memory-like cells that travel to distant skin and accelerate secondary IL-17–driven responses

“…A prominent condition in IL-17-deficient humans is mucocutaneous candidiasis (14). IL-17 also has an established role in chronic inflammatory conditions in humans, including psoriasis (3, 15, 16).…”