Abstract
IL-17 and related cytokines are direct and indirect targets of selective immunosuppressive agents for the treatment of autoimmune diseases and other diseases of pathologic inflammation. Insights into the potential adverse effects of IL-17 blockade can be drawn from the experience of patients with deficiencies in the IL-17 pathway. A unifying theme of susceptibility to mucocutaneous candidiasis is seen in both mice and humans with a variety of genetic defects that converge on this pathway. Mucocutaneous candidiasis is a superficial infection of mucosal, nail or skin surfaces usually caused by the fungal pathogen Candida albicans. The morbidity of the disease includes significant pain, weight loss and secondary complications, including carcinoma and aneurysms. This review describes the known human diseases associated with chronic mucocutaneous candidiasis (CMC) as well as the known and proposed connections to IL-17 signaling. The human diseases include defects in IL-17 signaling due to autoantibodies (AIRE deficiency), receptor mutations (IL-17 receptor mutations) or mutations in the cytokine genes (IL17F and IL17A). Hyper-IgE syndrome is characterized by elevated serum IgE, dermatitis and recurrent infections, including CMC due to impaired generation of IL-17-producing Th17 cells. Mutations in STAT1, IL12B and IL12RB1 result in CMC secondary to decreased IL-17 production through different mechanisms. Dectin-1 defects and CARD9 defects result in susceptibility to C. albicans because of impaired host recognition of the pathogen and subsequent impaired generation of IL-17-producing T cells. Thus, recent discoveries of genetic predisposition to CMC have driven the recognition of the role of IL-17 in protection from mucosal fungal infection and should guide counseling and management of patients treated with pharmacologic IL-17 blockade.
Highlights
Considerable attention and research dollars have focused on the cytokine interleukin-17 (IL-17 or IL-17A) and the pathology associated with aberrant IL-17 signaling
We recently demonstrated in mice that the IL‐23/IL‐17 axis of immunity is critical for immunity to Candida in the oropharynx using mice lacking IL‐23 or either IL‐17 receptor subunit (IL‐17RA and IL‐17RC) [16,17]
We recently showed that hyper-IgE syndrome (HIES) patients have defective salivary killing activity towards C. albicans, associated with reduced levels of antimicrobial peptides such as defensins and salivary histatins [44]
Summary
Considerable attention and research dollars have focused on the cytokine interleukin-17 (IL-17 or IL-17A) and the pathology associated with aberrant IL-17 signaling. Newer agents, which inhibit the JAKs and Syk, are associated with increased risk of (presumed bacterial) sino-pulmonary infections, but not CMC [79,80] This is perhaps somewhat surprising, since the JAKs, STATs and Syk are all important for induction of Th17 cells down stream of multiple cytokines and/or PRRs. the cumulative clinical trial evidence suggests that biologics do not confer susceptibility to CMC, it is important to bear in mind that with their increased use, biologics may be found to increase susceptibility to CMC in patients with otherwise subclinical mucosal Candida coloniza tion. Abbreviations APECED, autoimmune polyendocrinopathy candidiasis ectodermal dystrophy; APS, autoimmune polyendocrinopathy syndrome; CARD, caspase recruitment domain-containing protein; CLR, C-type lectin receptor; CMC, chronic mucocutaneous candidiasis; CTLA, cytotoxic T-lymphocyte-associated antigen; DOCK, deficient in dedicator of cytokinesis; GRO, growth-regulated oncogene; HIES, hyper-IgE syndrome; IFN, interferon; IL, interleukin; IL‐17R, IL‐17 receptor; JAK, Janus kinase; MSMD, Mendelian susceptibility to mycobacterial diseases; NF, nuclear factor; PRR, pattern recognition receptor; STAT, signal transducer and activator of transcription; Syk, spleen tyrosine kinase; Th, T helper; TNF, tumor necrosis factor. Competing interests The authors declare that they have no competing interests
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