ReviewInborn errors of IL-12/23- and IFN-γ-mediated immunity: molecular, cellular, and clinical features
Introduction
Mendelian susceptibility to mycobacterial diseases (MSMD) (MIM 209950, [1]) is a rare congenital syndrome that was probably first described in 1951 in an otherwise healthy child with disseminated disease caused by bacillus Calmette-Guérin (BCG) vaccine [2]. It is defined by severe clinical disease, either disseminated or localized and recurrent, caused by weakly virulent mycobacterial species, such as BCG vaccines and non-tuberculous, environmental mycobacteria (EM), in otherwise healthy individuals [3], [4], [5], [6], [7]. Understandably, patients with MSMD are also susceptible to the more virulent species Mycobacterium tuberculosis [8], [9], [10], [11], [12]. Severe disease caused by non-typhoidal and, to a lesser extent, typhoidal Salmonella serotypes is also common—observed in nearly half the cases, including patients who did not have any mycobacterial disease before the diagnosis of salmonellosis, or even at last follow-up [6], [7], [13]. The title “MSMD” is therefore misleading, and it may be more accurate to refer to the underlying genetic defects: inborn errors of the IL-12/23-IFN-γ circuit. Other infectious diseases have rarely been reported in these patients, and have mostly involved pathogens phylogenetically (e.g. Nocardia) or pathologically (e.g. Paracoccidioidomyces) related to mycobacteria, suggesting that these infections were not coincidental. However, most of these infections occurred in single patients, making it impossible to draw definitive conclusions as to whether these infections truly reflect syndromal predisposition [14], [15], [16], [17], [18], [19]. As always in human genetics, there is a need to explore both the disease-causing genotypes of patients with MSMD and the clinical phenotype of patients with known disorders of the IL-12-IFN-γ circuit.
The first genetic etiology of MSMD was described in 1996, with null recessive mutations in IFNGR1, encoding the IFN-γ receptor ligand-binding chain, in two kindreds [20], [21]. Ten years later, distinct types of disease-causing mutations were reported in IFNGR1 [8], [20], [21], [22], [23] and four other autosomal genes: IFNGR2, encoding the accessory chain of the IFN-γ receptor [24], [25], [26], [27]; IL12B, encoding the p40 subunit shared by IL-12 and IL-23 [28]; IL12RB1, encoding the β1 chain shared by the receptors for IL-12 and IL-23 [29], [30], [31], and STAT1, encoding the signal transducer and activator of transcription 1 (Stat-1) [32], [33]. Specific mutations in an X-linked gene – NEMO, encoding the NF-κB essential modulator (NEMO) – were also recently found [34]. The six gene products are physiologically related, as all are involved in IL-12/23-IFN-γ-dependent immunity. Defects in IFNGR1, IFNGR2, and STAT1 are associated with impaired cellular responses to IFN-γ, whereas defects in IL12B, IL12RB1 and NEMO are associated with impaired IL-12/IL-23-dependent IFN-γ production. Causal mutations have been found in 220 patients and 140 kindreds from 43 countries (Fig. 1). IL-12Rβ1 deficiency is the most common genetic etiology of MSMD, being responsible for ∼40% of cases, closely followed by IFN-γR1 deficiency (∼39%) (Fig. 2). IL-12p40 deficiency was identified in only ∼9% of the patients, Stat-1 deficiency in 5%, IFN-γR2 deficiency in 4%, and NEMO deficiency in only 3% of the cases (Fig. 2).
However, these six deficiencies are not the most clinically relevant genetic diagnoses, as there is considerable allelic heterogeneity (Fig. 3, Fig. 4), probably greater than that for all other known primary immunodeficiencies, owing to the occurrence of MSMD-causing genes with dominant and recessive alleles (IFNGR1) [21], [22], hypomorphic and null alleles (IFNGR1, IFNGR2) [8], [24], [27], null alleles with or without protein production (IFNGR1, IFNGR2, IL12RB1) [23], [26], [29], [30], [31], and alleles that affect different functional domains of the same protein (STAT1) [32], [33]. In total, the various alleles of the six genes define 13 different genetic disorders associated with MSMD (Table 1). Additional novel types of MSMD-causing alleles may exist for these six genes, as a null allele of IFNGR2 was shown to be dominant in vitro [25], and a recessive allele of IL12RB1 has been reported to be hypomorphic [35]. The study of MSMD and its genetic etiologies has even led to the description of a related clinical syndrome of vulnerability to mycobacterial and viral diseases, caused by null recessive alleles in STAT1 resulting in impaired cellular responses to both IFN-γ and IFN-α/β [36], [37a], [37b]. Similarly, MSMD-causing mutations in NEMO were identified only after other NEMO mutations had been reported to cause anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) [38], [39], [40]. Many reviews have focused specifically on MSMD and disorders of the IL-12/23-IFN-γ circuit (Fig. 4) [6], [7], [13], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58]. Ten years after identification of the first genetic etiology of MSMD, we review here the molecular, cellular, and clinical features of inborn errors of the IL-12/23-IFN-γ circuit.
Section snippets
IFN-γR1 deficiency
IFN-γ is a pleiotropic cytokine produced principally by natural killer (NK) cells and T lymphocytes [59]. Its heterodimeric surface receptor is ubiquitously expressed and consists of a ligand-binding chain (IFN-γR1) and an associated chain (IFN-γR2) [60], [61]. Homodimeric IFN-γ recruits two IFN-γR1 and two IFN-γR2 chains, and formation of the resulting tetramer activates two constitutively associated kinases, Jak1 and Jak2, which phosphorylate IFN-γR1, allowing the docking of Stat-1 molecules,
IFN-γR2 deficiency
IFN-γR2, like IFN-γR1, belongs to the class II cytokine receptor family [60], [61]. IFN-γR2 binds strongly to IFN-γR1 upon stimulation with IFN-γ. The organization of the IFN-γR2 gene resembles that of the IFN-γR1 gene, with seven exons (Fig. 3) encoding an extracellular domain that interacts with the IFN-γ-IFN-γR1 complex (but not itself playing a major role in ligand binding), a transmembrane domain, and a cytoplasmic domain required for signal tranduction [59], [61]. IFN-γR2 is
Stat-1 deficiency
Signal transducer and activator of transcription-1 (Stat-1) is critical for cellular responses to type I (IFN-α/β) and type II (IFN-γ) IFNs, and to the less well characterized type III IFNs (IFN-λ) [90]. IFN-γ stimulation induces the phosphorylation and homodimerization of Stat-1 (gamma activating factors, GAF), whereas IFN-α/β stimulation specifically leads to the formation of ISGF-3 heterotrimers, composed of Stat-1, Stat-2, and IRF-9 [90]. The activation of GAF homodimers and ISGF-3
IL-12p40 deficiency
IL-12 comprises two disulfide-linked subunits, p35 and p40, encoded by the IL12A and IL12B genes, respectively [92], [93]. The p40 subunit may also associate with the p19 subunit to form IL-23 [92], [93]. IL-12 binds to a heterodimeric receptor consisting of two chains (IL-12Rβ1 and IL-12Rβ2) expressed on NK and T lymphocytes, and induces the production of large amounts of IFN-γ and enhances the proliferation and cytotoxic activity of NK and T cells [92], [93]. IL-23 binds to a heterodimeric
IL-12Rβ1 deficiency
Functional IL-12 receptors are expressed primarily on activated T and NK cells [92], [93]. The coexpression of IL-12Rβ1 and IL-12Rβ2 is required for high-affinity IL-12 binding and signaling. IL-12Rβ1 also combines with IL-23R to constitute the IL-23R complex for IL-23 signaling [92], [93]. IL-12 and IL-23 activate Janus kinase 2 (Jak2) and Tyk2, which in turn activate several Stat proteins [92], [93], [97]. However, IL-12 and IL-23 strongly induce the phosphorylation of Stat-4 and Stat-3,
Mutations in the NEMO leucine zipper domain
The five genes involved in MSMD described above are all autosomal. NEMO, encoding NF-κB essential modulator (NEMO), is an X-linked gene consisting of 10 exons (Fig. 3). NEMO is a regulatory subunit of the IKK complex that activates the canonical NF-κB signaling pathway, thereby regulating the expression of numerous target genes [112]. Multiple receptors from several superfamilies, including that containing TNF-αR and IL-1R, can activate NF-κB via IKK and NEMO. The IKK complex phosphorylates the
Conclusion
The genetic dissection of the molecular and cellular basis of the clinical syndrome of MSMD, over the last 10 years, has had important clinical, genetic, and immunological implications. Molecular diagnosis can now be offered to patients with MSMD, improving the prediction of individual clinical outcome and facilitating treatment based on a rational understanding of the pathogenesis of infections. IFN-γ has been a life-saving treatment in patients producing little IFN-γ, because it replaced the
Acknowledgments
We warmly thank Laurent Abel, Frédéric Altare, Rainer Döffinger, Salma Lamhamedi, and all past and present members of the laboratory who were involved in the study of patients with MSMD. We thank Michael Levin, Dinakantha Kumararatne, Steven Holland, and Joachim Roesler for friendly collaboration over the years. We thank Claire Soudais, Anne Puel, and the other members of the laboratory for helpful discussions. Needless to say, we are much indebted to the patients, their families, and their
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