Chronic Mucocutaneous Candidiasis, ACT1 Deficiency
Nuclear factor-kappa-B activator 1 (ACT1) deficiency is an autosomal recessive disorder that leads to chronic mucocutaneous candidiasis (CMC). CMC is defined as recurrent or persistent mucocutaneous infections caused by fungi of the genus Candida, and primarily by the commensal organism Candida albicans (Kirkpatrick 2001; Puel et al. 2012). ACT1 deficiency leads to CMC through impairments in IL-17-mediated immunity.
ACT1 was first identified in 2000 as an activating protein of NF-kappa B (NF-κB) and Jun Kinase (Awane et al. 1999; Li et al. 2000; Leonardi et al. 2000). NF-κB is a key transcription factor involved in cellular inflammatory, survival, and stress responses (Li et al. 2000; Baeuerle and Baltimore 1996). NF-κB remains latent in the cytoplasm bound to a group of inhibitor proteins that are collectively called the IκB complex (Antonio Leonardi et al. 2000). Upon stimulation of upstream signaling factors, the IκB complex undergoes ubiquitination and proteosomal degradation, leading to release of NFκB followed by its activation and translocation to the nucleus (Leonardi et al. 2000). There, NFκB mediates the transcription of a number of genes, regulating the expression of cytokines, chemokines, and cell adhesion molecules and receptors.
The ACT1 gene (also known as TRAF3IP2) encodes for the ACT1 protein of 574 amino acids and is ubiquitously expressed (Li et al. 2000; Antonio Leonardi et al. 2000). It contains a helix-loop-helix domain at the N-terminus, two TRAF binding sites (EEESE and EERPA), a SEFIR domain, and a coil-coiled domain at the C-terminus (Li et al. 2000; Qian et al. 2002; Li 2008). Through its protein interactions with NFκB, ACT1 impacts both B cell and Th17 cell immunity (Li 2008). NFκB promotes B cell survival and activation by mediating signaling through CD40 and the B cell activating factor receptor (BAFFR). CD40 and BAFFR-mediated activation of the IκB complex occurs through TNF receptor associated factor (TRAF) adaptor molecules (Qian et al. 2004). ACT1 was initially hypothesized to be a positive mediator of BAFFR and CD40 signaling given its original description as a constitutive activator of NFκB. Act1-deficient mice, however, demonstrated an opposite phenotype of B cell hyperproliferation, thus uncovering Act1’s role as a negative B cell regulator (Qian et al. 2004). This effect was reversed in Cd40/Act1 and Baff/Act1 double knockout mouse models, indicating that ACT1 exerts its inhibitory effect on B cell proliferation through both the CD40 and BAFFR pathways (Qian et al. 2004). It is hypothesized that upon stimulation of CD40 and BAFFR, ACT1 complexes with TRAF3 and targets activating proteins involved in NF-κB signaling for proteosomal degradation, thus acting in a negative feedback manner.
While ACT1 thus serves to protect against exaggerated B cell responses and B cell-mediated autoimmunity, it has also been implicated in promoting IL-17-mediated inflammation. IL-17 is a pro-inflammatory cytokine produced by T cells that results in NF-κB activation and is important in the protection against extracellular pathogens (Awane et al. 1999; Curtis and Way 2009). In addition to its protective roles in immunity, IL-17 signaling can also promote certain forms of autoimmunity, such as human and experimental models of multiple sclerosis, psoriasis, and inflammatory bowel disease (Jin et al. 2009). ACT1 is essential for signaling through the IL-17 receptor (IL-17R) and leads to the induction of pro-inflammatory cytokines through NF-kB and non-NF-kB-mediated mechanisms (Li 2008). The IL-17R and ACT1 interact through homotypic binding of their respective SEFIR domains. ACT1 then binds to and causes nondegradative ubiquitination of TRAF6, promoting downstream activation of NF-kB (Liu et al. 2009).
ACT1 deficiency is characterized by a propensity towards chronic mucocutaneous candidiasis (CMC). CMC refers to recurrent or persistent infections involving the mucous membranes, such as skin, nails, oral and genital mucosa, and is caused primarily by the commensal fungal organism Candida albicans (Kirkpatrick 2001; Puel et al. 2012; Boisson et al. 2013). Patients who suffer from CMC, and who generally do not show a predisposition towards other infections, are referred to as having CMC disease (CMCD) (Boisson et al. 2013).
Patients with CMCD may also be affected by skin infections caused by the bacteria Staphylococcus aureus. In addition, those with CMCD have also been found to have a predisposition towards certain forms of autoimmunity, as well as cerebral aneurysms and mucocutaneous carcinomas (Boisson et al. 2013). In 2013, ACT1 deficiency was identified as a genetic cause of CMCD and was therefore added to the list of several genes that have been associated with this clinical phenotype (Boisson et al. 2013). Few cases of ACT1 deficiency have been described, with approximately only four affected patients from two families reported to date (Boisson et al. 2013; Levy et al. 2014). The clinical presentation described is in keeping with CMCD. An early feature often seen in ACT1-deficient patients is infantile seborrheic dermatitis, an inflammatory skin condition commonly affecting the scalp or face (Boisson et al. 2013). Patients with ACT1 deficiency develop persistent or recurrent mucocutaneous candidal infections, which may occur as early as infancy, or later in childhood. CMC affecting the oropharynx may cause oral thrush as well as macrocheilits (swelling and inflammation of the lip). Other affected areas may include: the genitals, the nails resulting in onychomycosis, and the skin folds causing intertrigo (Boisson et al. 2013). Superficial staphylococcal infections have also been reported in ACT1 deficiency, leading to recurrent eyelid and hair follicle infections caused by Staphylococcus aureus (Boisson et al. 2013; Levy et al. 2014). Despite the known importance of ACT1 as a negative B cell regulator, ACT1-deficient patients have thus far not demonstrated evidence of B cell-mediated autoimmune disorders. This is attributed to the described mutations affecting the SEFIR domain required for homotypic interactions with the IL-17 receptor, while keeping the other domains important for CD40 and BAFFR interactions intact (Boisson et al. 2013; Levy et al. 2014).
CMC with or without superficial staphylococcal infections should prompt consideration of ACT1 deficiency. A standard immune workup may be largely unrevealing, therefore a high index of suspicion is required. Evaluation generally demonstrates normal white blood cell and lymphocyte subset enumeration. Immunoglobulin analysis may reveal elevated levels of IgG, variable levels of IgA and IgM, and normal levels of IgE (Boisson et al. 2013). Microbial analysis of affected sites concerning CMC often reveals Candida albicans, however, may reveal other candida organisms such as Candida parapsillosis (Boisson et al. 2013). No commercial assays to evaluate ACT1 function are currently available. Therefore, when ACT1 deficiency is suspected, targeted sequencing of the ACT1 gene located on chromosome 6q21 should be performed. This may be performed as part of a broader genetic panel to screen for the numerous genes associated with CMCD, such as whole exome sequencing. Sequencing of the ACT1 gene reveals biallelic mutations.
Treatment of ACT1 deficiency involves targeted infection prophylaxis measures as well as management of established infections (Okada et al. 2016). Oral antifungal prophylaxis with fluconazole should be considered to protect against mucocutaneous candidiasis (Okada et al. 2016). Fluconazole is also a reasonable first-line oral treatment for Candida infections, with alternative options including itraconazole, voriconazole, and posaconazole (Okada et al. 2016). Topical therapy with nystatin may also be considered. Patients affected by superficial staphylococcal infections may benefit from antibiotic prophylaxis with sulfamethoxazole-trimethoprim (Okada et al. 2016). Inflammatory conditions involving the skin, such as seborrheic dermatitis or scalp inflammation caused by staphylococcal infection, may also require the use of corticosteroids (Boisson et al. 2013).
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