Clinical Features of Candidiasis in Patients With Inherited Interleukin 12 Receptor β1 Deficiency

Mendelian susceptibility to mycobacterial diseases (MSMD) is characterized by a selective predisposition to clinical disease caused by mycobacteria and Salmonella [1]. Nine disease-causing genes have been described, including 3 genes controlling the response to interferon (IFN) γ (IFNGR1, IFNGR2, STAT1), 4 involved in IFN-γ production (IL12B, IL12RB1, NEMO, ISG15) [1, 2], 1 involved in the IFN-γ–dependent induction of interleukin 12 (IL-12; IRF8) [3], and another gene controlling the macrophage respiratory burst, which can be triggered by IFN-γ (CYBB) [4]. Interleukin 12Rβ1 (IL-12Rβ1) deficiency is the most common genetic cause of MSMD [5, 6], with 156 patients reported to date (Supplementary Table 1). IL12RB1 encodes the first chain of the IL-12 (IL-12Rβ1) and interleukin 23 (IL-23) receptors. Interleukin 12 is an important cytokine for the development of IFN-γ–producing T cells and for IFN-γ production [7]. Conversely, IL-23 is important for the expansion and maintenance of the interleukin 17 (IL-17)–producing T-cell population [8, 9]. Interleukin 12Rβ1 deficiency is the genetic cause of MSMD for which the most infections other than mycobacteriosis has been reported [1]. Salmonellosis is very common, as in IL-12p40 deficiency, but much more so than in other genetic etiologies of MSMD [1, 10, 11]. However, other infections due to intramacrophagic pathogens have also been reported (Supplementary Table 1) [1, 6]. The impairment of IL-23 immunity, alone or together with IL-12 immunity, may contribute to this relatively broad infectious phenotype [1, 9]. We recently noted that about 25% of IL-12Rβ1–deficient patients also have mild forms of chronic mucocutaneous candidiasis (CMC) [6]. This is consistent with the role of IL-23 in the maintenance of IL-17–producing T cells and the low proportions of IL-17 T cells in the patients with IL-12Rβ1 deficiency studied [9]. Indeed, patients with disorders associated with impaired IL-17–mediated immunity have CMC, including patients with autoimmune polyendocrinopathy syndrome type I (APS-I), autosomal dominant (AD) hyper–immunoglobulin E syndrome (AD-HIES) due to dominant-negative mutations of STAT3, or more rarely those with caspase recruitment domain–containing protein 9 (CARD9) deficiency [12–17]. Isolated CMC, also known as CMC disease (CMCD), has been shown to result from AD IL-17F deficiency, autosomal recessive deficiency of IL-17RA (the receptor for both IL-17A and IL-17F), from NF-κB activator 1 (ACT1) deficiency, or from an AD gain of STAT1 activity [18–22]. Surprisingly, the clinical features of candidiasis have never been studied in series of patients with these inborn errors of immunity. We report here the clinical features of candidiasis in 35 patients with IL-12Rβ1 deficiency.