Discussion
IL-17 immunity is critical for the induction of mucosal pro-inflammatory
cytokines and chemokines involved in mucocutaneous protection againstC. albicans infections [6]. Patients with low proportions of
Th17 cells (e.g AD STAT3, AR ZNF341 or ROR-γ/γT deficiency, or STAT1
GOF), or defects in IL-17 signaling (e.g. AR IL-17RA, IL-17RC, ACT1, AD
IL-17F, JNK1 deficiencies) are particularly susceptible to CMC(Figure 1) [2-4, 7, 8]. Genetic analysis of our index case
revealed variants in STAT1 and TRAF3IP2 (Figure
2) . Considering that STAT1 GOF mutations have been widely described to
cause CMC, we evaluated the functional impact of this variant. High
levels of STAT1 expression and/or STAT1 phosphorylation upon activation
of the IFN pathway are typical immunological features of STAT1 GOF
patients [4, 17, 18]. Based on the similar STAT1 and pSTAT1 levels
found in patient’s cells and healthy controls, and considering that her
father, harboring the same mutation, was asymptomatic, we classified
this variant as likely not pathogenic (Figure 2-3) . We
therefore studied the ACT1 variants and their possible
disease-causing impact. The ACT1 SEFIR domain allows for the recruitment
of ACT1 to the IL-17RA/IL-17RC upon IL-17A stimulation [8, 10-12].
By overexpression, the patient’s alleles were expressed at similar
levels as compared to the WT protein, with p.K454Fsf11* leading to the
expression of a truncated protein, impairing its interaction with
IL-17RA, whereas p.D451G showed a normal interaction (Figure
4A/B). After ACT1-IL-17RA/IL-17RC interaction upon IL-17A/IL-17F
stimulation, the kinase TAK1 and the E3 ubiquitin ligase TRAF6 are
recruited to the receptor to facilitate the activation of the
transcription factor NF-κB (Figure 1) [10, 11]. By
luciferase, we showed that both patient’s ACT1 alleles strongly
impaired constitutive and IL-17-dependent NF-κB activation(Figure 4C) . Furthermore, patient’s SV40-fibroblasts displayed
abolished responses to IL-17A, comparable to that of patients with AR
IL-17RA or IL-17RC deficiency (Figure 4D) [5, 7, 12]. In
contrast, all of them retained the ability to respond to TNF-α and
IL-1β, suggesting that D451G and K454fs11* ACT1 mutations specifically
affect the IL-17A-induced ACT1-mediated GRO-α production, known to play
a protective role in fungal infection through the recruitment of
neutrophils [19]. Finally, as previously reported [12, 16], the
patient displayed enhanced proportions of IL-17A-and IL-22-producing
CD4+ cells upon stimulation whereas baseline Th17
proportions were normal. This observation highlights the importance of
functional assays, as the pattern of T cell differentiation is variable.
Two previous reports [12, 16], as well as our case, revealed normal
or slightly reduced IFN-γ-producing memory CD4+ cells
whereas others observed reduced Th1 proportion [14]. Furthermore,
and in contrast to previous cases [14, 16], levels of IL-4-producing
Th2 cells were higher in our patient than those found in relatives, and
healthy controls (Figure 5) .
Clinical and laboratory findings, and management of all eleven
previously reported patients with AR ACT1 deficiency, including our
report, are summarized in Figure 6 and, in more detail, insupplementary Table 3 [12-16]. Of note, detailed information
was not available for all patients. The overall phenotype was
characterized by CMC in early childhood (9/11, before age 2 years)
requiring medical attention, treatment, or antifungal prophylaxis for a
prolonged time in most cases. Dermatologic manifestations were common,
and Staphylococcus aureus was specifically reported in the
context of skin lesions in 5/11 patients. Treatment responses of CMC
were satisfactory when documented, and no fatal cases have been
described (supplementary Table 3 and Figure 6) . The clinical
course of our patient was similar, as she suffered from CMC, chronic
cheilitis, recurrent wheezing, and skin lesions (supplementary
Table 3) . Importantly, standard immune phenotyping and immunoglobulin
levels were unremarkable in most patients when reported. Raised Th17
percentages appear to be the most common finding (6/7) when tested. In
contrast hyper IgG (P1-P3), hyper IgE (P3, P4), or eosinophilia (P1, P4)
was found in only few cases.
In conclusion, we describe a patient with AR ACT1 deficiency, caused by
novel compound heterozygous (D451G and K454fs11*) variants ofTRAF3IP2 . Although only K454fs11* apparently affected ACT1
binding to IL-17RA, patient’s cells were unresponsive to IL-17A,
explaining the clinical phenotype of CMC, further highlighting the
importance of performing detailed functional studies to understand the
clinical impact of genetic variants found in patients, particularly in
the field of immune dysregulation syndromes.