Chronic Mucocutaneous Candidiasis in Humans with Inborn Errors of Interleukin-17 Immunity

Abstract

Chronic mucocutaneous candidiasis disease (CMCD) is characterized by recurrent or persistent infections of the skin, nails, oral and genital mucosae caused by Candida albicans and, to a lesser extent, Staphylococcus aureus, in patients with no other infectious or autoimmune manifestations. We report two genetic etiologies of CMCD: autosomal recessive deficiency in the cytokine receptor, interleukin-17 receptor A (IL-17RA), and autosomal dominant deficiency of the cytokine IL-17F. IL-17RA deficiency is complete, abolishing cellular responses to IL-17A and IL-17F homo- and heterodimers. By contrast, IL-17-F deficiency is partial, with mutant IL-17F-containing homo- and heterodimers displaying impaired, but not abolished activity. These experiments of nature indicate that human IL-17A and IL-17F are essential for mucocutaneous immunity against C. albicans, but otherwise largely redundant.

Mechanisms of NDV-3 vaccine efficacy in MRSA skin versus invasive infection

“…Our results are congruent with recent reports supporting a key function of T cells and the Th17 pathway (including IL-17 family, IL-22, and IL-23 cytokines) in defense against infections at skin and mucocutaneous barriers (59)(60)(61)(62)(63)(64)(65)(66). Corticosteroid inhibition of IL-22 production has been associated with impaired barrier protection and increased bacterial invasion (67).…”

“…The adoptive transfer of CD4 + T cells but not B220 + B cells from immunized mice afforded protection (47,48). Collectively, this body of evidence is consistent with the immunobiology of natural S. aureus SSSI in humans (2, 3), Th17 pathway requirements for mucocutaneous host defense against S. aureus (33,34,(61)(62)(63)(64)(65), and human responses to the NDV-3 vaccine (49).…”

Sensing of mammalian IL-17A regulates fungal adaptation and virulence

“…In line with what is observed in humans 7 , Candida overgrowth occurs under conditions of defective interleukin (IL)-17F 8 or IL-17RA signalling [8][9][10] , which suggests the importance of IL-17RA signalling in preventing infection. Under specific circumstances, IL-17A may, in fact, contribute to disease susceptibility in a host-autonomous fashion, perhaps by modifying the intrinsic virulence of the fungus 8 .…”

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

“…As IL‐17 production in γδ T cells is found at the early stage after infection, γδ 17 cells are suggested to play an important role in early host defence before establishment of acquired immunity. In humans, patients carrying mutations in either STAT3, IL‐17RA, or IL‐17F or producing anti‐IL‐17F autoantibodies are also highly susceptible to skin infection with Staphylococcus aureus and C. albicans 86, 87. However, the involvement of γδ 17 cells in host defence in humans against these pathogens remains to be elucidated.…”