Chronic Mucocutaneous Candidiasis in Autoimmune Polyendocrine Syndrome Type 1

Abstract

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) is an autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene, characterized by the clinical triad of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and adrenal insufficiency. CMC can be complicated by systemic candidiasis or oral squamous cell carcinoma (SCC), and may lead to death. The role of chronic Candida infection in the etiopathogenesis of oral SCC is unclear. Long-term use of fluconazole has led to the emergence of Candida albicans strains with decreased susceptibility to azoles. CMC is associated with an impaired Th17 cell response; however, it remains unclear whether decreased serum IL-17 and IL-22 levels are related to a defect in cytokine production or to neutralizing autoantibodies resulting from mutations in the AIRE gene.

Keywords: IL-17; IL-22; autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED); autoimmune regulator (AIRE) gene; chronic mucocutaneous candidiasis (CMC).

Figure 1

Familial CMC and APECED syndrome. APECED syndrome is characterized by the association of endocrine autoimmune disorders (such as hypoparathyroidism, hypothyroidism, adrenocortical insufficiency, and gonadal failure), non-endocrine autoimmune disorders (such as autoimmune hepatitis, celiac disease, and chronic atrophic gastritis), and chronic mucocutaneous candidiasis (CMC). These manifestations are related to the presence of tissue specific antibodies and cytokine antibodies. IL-17 mediated immunity is represented by cooperation between cells recognizing C. albicans (phagocytes and epithelial cells) and IL-17 cytokine-producing cells (T-cells). On C. albicans recognition by PRRs (pathogen recognition receptors; including Dectin-1, Dectin-2, or Mincle), the adaptor molecule CARD9 mediates the induction of pro-inflammatory cytokines, such as IL 1β, IL-6, and IL-23. On binding to their receptors expressed on T-lymphocytes, pro-inflammatory cytokines, such as IL-6 or IL-23, activate T-lymphocytes via the transcription factor STAT3 resulting in their differentiation into IL-17-producing T-cells. Genes in which mutations are associated with CMC are indicated in pink: dectin 1, CARD 9, STAT 1, STAT3, IL22, and IL17F. IL-17RA and IL-12RB1 are not represented. Y designates cytokine-neutralizing autoantibodies that develop in AIRE-deficient (APECED and rare thymoma cases) patients.