Chronic Mucocutaneous Candidiasis in Early Life: Insights Into Immune Mechanisms and Novel Targeted Therapies

Abstract

Children with chronic mucocutaneous candidiasis (CMC) experience recurrent infections with Candida spp. Moreover, immune dysregulation in the early life of these patients induces various autoimmune diseases and affects normal growth and development. The adaptive and innate immune system components play a significant role in anti-fungal response. This response is mediated through IL-17 production by T helper cells. Inborn errors in IL-17-mediated pathways or Candida spp. sensing molecules are known to cause CMC. In this review, we describe underlying immune mechanisms of monogenic primary immune deficiency disorders known to cause CMC. We will explore insights into current management of these patients and novel available therapies.

Case Report: Disseminated Talaromyces marneffei Infection in a Patient With Chronic Mucocutaneous Candidiasis and a Novel STAT1 Gain-of-Function Mutation

“…Most patients have only persistent and recurrent superficial candidiasis, but some patients have additional infections with other fungi, viruses and bacteria ( 8 , 13 ). CMC is also the most common infection occurring in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) ( 3 , 14 ). The patient in our study presented with only recurrent and persistent infections of the skin, nails and mucous membranes, occurring since birth, and he did not have invasive candidiasis or autoimmune endocrine disease, which could be explained by his normal hormone levels.…”

“…CMC can be acquired or caused by PID ( 3 , 13 , 16 ). Advances in genetic testing in the recent decade have expanded our knowledge of the immune mechanisms underlying CMC.…”

“…Autosomal-dominant heterozygous missense STAT1 GOF mutations are the most common genetic cause of isolated CMC or CMC disease ( 4 , 7 ). STAT1 GOF mutations influence the appropriate regulation of cellular responses to interferons, cytokines, growth factors and hormones and result in increased susceptibility to infection, immune dysregulation and malignancy ( 3 ). Toubiana et al.…”

“…From the literature, we know that mutations in some genes associated with primary immune deficiency(PID) can be responsible for susceptibility to CMC ( 6 ). Examples include STAT1 gain-of-function (GOF) mutations, STAT3 defects, and AIRE defects ( 3 , 7 ). Clinical symptoms of CMC and persistent decreased lymphocytes led us to suspect that PID may be the cause of CMC in our patient; therefore, we used whole exome sequencing of the peripheral blood to explore the cause of PID and CMC.…”

“…Chronic mucocutaneous candidiasis (CMC) is classified as a primary immunodeficiency disease by the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency in 2015 ( 1 ). It primarily presents as recurrent and persistent superficial infections with Candida albicans , affecting the mucous membranes, skin and nails ( 2 , 3 ). CMC is associated with an impaired Th17 cell response caused by signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations.…”