Response to Comments on "Aberrant type 1 immunity drives susceptibility to mucosal fungal infections"

Abstract

Puel and Casanova and Kisand et al. challenge our conclusions that interferonopathy and not IL-17/IL-22 autoantibodies promote candidiasis in autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy. We acknowledge that conclusive evidence for causation is difficult to obtain in complex human diseases. However, our studies clearly document interferonopathy driving mucosal candidiasis with intact IL-17/IL-22 responses in Aire-deficient mice, with strong corroborative evidence in patients.

Figure 1.. Enhanced mucosal type 1 responses and intact mucosal type 17 responses in APECED patients are evident across all age groups and regardless of the presence of Sjögren’s syndrome.

(A) Concentrations of IL-17- and IL-22-dependent S100A8 and S100A9 in saliva of healthy volunteers (HV) (n=33) and APECED patients of the indicated age groups (n=11, 30, 12, 13, and 8 for 0-10, 10-20, 20-30, 30-40, and >40-year-old APECED patients, respectively). (B) Concentrations of IL-17- and IL-22-dependent S100A8 and S100A9 in saliva of HV (n=33) and APECED patients with (n=25) or without Sjögren’s syndrome (n=49). (C) Concentrations of IFN-γ-inducible CXCL9 and CXCL10 in saliva of HV (n=28-31) and APECED patients of the indicated age groups (n=12, 30-32, 10-12, 13-14, and 8-9 for 0-10, 10-20, 20-30, 30-40, and >40-year-old APECED patients, respectively). (D) Concentrations of IFN-γ-inducible CXCL9 and CXCL10 in saliva of HV (n=28-31) and APECED patients with (n=23-28) or without Sjögren’s syndrome (n=50-51). Data are excerpted from Figures 2D, 5E, and 5F of Break et al (1). All quantitative data are means ± SEM. ns, not significant, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 as calculated using Kruskal–Wallis H test with Dunn’s multiple-comparisons test.

Figure 2.. A conceptual framework for classifying molecular subtypes of chronic mucocutaneous candidiasis.

Susceptibility to chronic mucocutaneous candidiasis can be explained on the basis of either impaired antifungal resistance caused by type 17 mucosal immune defects and/or immunopathology promoted by excessive type 1 mucosal inflammation. CMC, chronic mucocutaneous candidiasis.