Mucocutaneous candidiasis: the IL-17 pathway and implications for targeted immunotherapy

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.

Interleukin-17-Induced Protein Lipocalin 2 Is Dispensable for Immunity to Oral Candidiasis

“…Individuals with HIV/ AIDS are particularly prone to this disease, and OPC is considered an AIDS-defining illness (1,2). In addition, OPC is common in patients taking immunodepleting chemotherapy, infants and the elderly, and patients with congenital immunodeficiencies, such as hyper-IgE syndrome (HIES) (3). OPC exhibits considerable morbidity and can cause impaired nutrition due to odynophagia (pain with swallowing) and failure to thrive in infants.…”

Th17 Inflammation Model of Oropharyngeal Candidiasis in Immunodeficient Mice

“…Opportunistic infections and inflammation caused by C. albicans are associated with primary immunodeficiencies (PID) 4,5 , inflammatory disorders such as periodontitis 6,7 , Sjogren's syndrome, and salivary gland disease 8,9 , as well as oral squamous cell carcinoma [10][11][12] . C. albicans is a dimorphic commensal fungus that colonizes the mouths of 60% of healthy humans asymptomatically, yet it is the most common fungal pathogen causing infections when the host defense is weakened [13][14][15] .…”

Candida albicansStimulates IL-23 Release by Human Dendritic Cells and Downstream IL-17 Secretion by Vδ1 T Cells

“…IL-17 induces the production of antimicrobial peptides and chemokines, which recruit neutrophils to sites of infection where they kill extracellular bacteria and fungi by phagocytosis or the release of antimicrobial agents (6,12,13). Pathological C. albicans infections are common in humans with inherited deficiencies of the IL-17 pathway (such as IL-17 deficiency or mutations in the IL-17R or STAT1) (14,15) and in knockout mice that lack IL-17 or IL-23 (6,16). C. albicans-specific T cells in healthy donors are preferentially Th17 cells that coproduce IFN-g (7).…”