Genetic etiologies of chronic mucocutaneous candidiasis (CMC) disrupt human IL-17A/F-dependent immunity at mucosal surfaces, whereas those of connective tissue disorders (CTDs) often impair the TGF-β-dependent homeostasis of connective tissues.
Therapy with IL-17-targeted agents (secukinumab, brodalumab and ixekizumab) may result in the development of mild-to-moderate mucocutaneous candidiasis.
Since chronic mucocutaneous candidiasis (CMC) is caused by defects in the IL-17 pathway, CMC risk data have been touted as providing reassurance about the safety of IL-17 antagonism.
Chronic mucocutaneous candidiasis (CMC) occurs in patients with mutations in genes affecting IL-17-mediated immunity, such as <i>STAT3, AIRE, RORC, CARD9, IL12B</i>, and <i>IL12RB1</i>, or gain of function (GOF) mutations in <i>STAT1</i>.
A picture is emerging of inborn errors of IL-17 immunity selectively underlying chronic mucocutaneous candidiasis, with little inter-individual variability, and of inborn errors of CARD9 immunity underlying various life-threatening invasive fungal diseases, differing between patients.
All eight TYK2-deficient patients displayed impaired but not abolished cellular responses to (a) IL-12 and IFN-α/β, accounting for mycobacterial and viral infections, respectively; (b) IL-23, with normal proportions of circulating IL-17(+) T cells, accounting for their apparent lack of mucocutaneous candidiasis; and (c) IL-10, with no overt clinical consequences, including a lack of inflammatory bowel disease.
Mutations affecting the STAT3/interleukin 17 (IL-17) pathway cause selective susceptibility to fungal (Candida) infections, a hallmark of chronic mucocutaneous candidiasis (CMC).
Human inborn errors of immunity mediated by the cytokines interleukin-17A and interleukin-17F (IL-17A/F) underlie mucocutaneous candidiasis, whereas inborn errors of interferon-γ (IFN-γ) immunity underlie mycobacterial disease.
During recent years, inborn errors of human IL-17 immunity have been demonstrated to underlie primary immunodeficiencies with chronic mucocutaneous candidiasis (CMC).
Two novel gain-of-function mutations of STAT1 responsible for chronic mucocutaneous candidiasis disease: impaired production of IL-17A and IL-22, and the presence of anti-IL-17F autoantibody.
The purpose of this longitudinal study was to analyze the relationship between the occurrence of mucocutaneous candidiasis and levels of anti-IL-17A, anti-IL-17F and anti-IL-22 autoantibodies.
Examples include antigranulocyte macrophage-colony stimulating factor (GM-CSF) autoantibodies and pulmonary alveolar proteinosis; anti-interferon (IFN)-γ autoantibodies and disseminated nontuberculous mycobacteria (NTM); anti-interleukin-(IL)-6 autoantibodies and severe staphylococcal skin infection; anti-IL-17A, anti-IL-17F, or anti-IL-22 autoantibodies in patients with mucocutaneous candidiasis in the setting of both the autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy (APECED) syndrome and in cases of thymoma.