Elsevier

Seminars in Immunology

Volume 26, Issue 6, December 2014, Pages 454-470
Seminars in Immunology

Review
Mendelian susceptibility to mycobacterial disease: Genetic, immunological, and clinical features of inborn errors of IFN-γ immunity

https://doi.org/10.1016/j.smim.2014.09.008Get rights and content

Abstract

Mendelian susceptibility to mycobacterial disease (MSMD) is a rare condition characterized by predisposition to clinical disease caused by weakly virulent mycobacteria, such as BCG vaccines and environmental mycobacteria, in otherwise healthy individuals with no overt abnormalities in routine hematological and immunological tests. MSMD designation does not recapitulate all the clinical features, as patients are also prone to salmonellosis, candidiasis and tuberculosis, and more rarely to infections with other intramacrophagic bacteria, fungi, or parasites, and even, perhaps, a few viruses. Since 1996, nine MSMD-causing genes, including seven autosomal (IFNGR1, IFNGR2, STAT1, IL12B, IL12RB1, ISG15, and IRF8) and two X-linked (NEMO, and CYBB) genes have been discovered. The high level of allelic heterogeneity has already led to the definition of 18 different disorders. The nine gene products are physiologically related, as all are involved in IFN-γ-dependent immunity. These disorders impair the production of (IL12B, IL12RB1, IRF8, ISG15, NEMO) or the response to (IFNGR1, IFNGR2, STAT1, IRF8, CYBB) IFN-γ. These defects account for only about half the known MSMD cases. Patients with MSMD-causing genetic defects may display other infectious diseases, or even remain asymptomatic. Most of these inborn errors do not show complete clinical penetrance for the case-definition phenotype of MSMD. We review here the genetic, immunological, and clinical features of patients with inborn errors of IFN-γ-dependent immunity.

Section snippets

IFN-γR1 deficiency

The first genetic etiology of MSMD was identified in 1996, with bi-allelic null mutations in the IFNGR1 gene, underlying autosomal recessive (AR) complete IFN-γR1 deficiency (Fig. 1; Table 1) [65], [66]. Thirty-one patients from 26 families and 25 different mutations (deletions n = 10, insertions n = 4, nonsense n = 2, missense n = 5 and splice site n = 4) have been described to date (Fig. 1). Two genetic forms of AR complete IFN-γR1 deficiency have been described, with [46], [53], [84], [85] or without

IFN-γR2 deficiency

AR IFN-γR2 deficiency is defined by bi-allelic mutations (Fig. 1, Table 1). Two forms of AR complete IFN-γR2 deficiency have been reported, depending on whether or not cell surface expression of the receptor is detectable [140], [141]. In seven patients from five kindreds, no protein is detected, as first documented in 1998 [47], [142], [143], [144], [145]. The residual cell surface expression of non-functional IFN-γR2 has been described in six patients from five families [51], [140], [141].

AD STAT1 deficiency

STAT1 is a transcription factor involved in cellular responses mediated by cytokines including type I (IFN-α/β), type II (IFN-γ), and type III (IFN-λ) IFNs [70]. Different forms of inherited STAT1 deficiency have been described in humans: bi-allelic mutations cause AR complete [154], [155], [156] or partial STAT1 deficiency [157], [158], [159], [160], [161]; mono-allelic mutations cause AD STAT1 deficiency [162] or AD STAT1 gain of activity [163], [164] (Fig. 1, Table 2). AR complete STAT1

Complete IL-12Rβ1 deficiency

The most common genetic etiology of MSMD is AR complete IL-12Rβ1 deficiency, first reported in 1998 [188], [189]. The IL12RB1 gene encodes the IL-12Rβ1 chain, a gp130 protein, consisting of an extracellular N-terminal immunoglobulin (Ig)-like domain, a transmembrane domain and an intracellular domain. The combination of IL-12Rβ1 and IL-12Rβ2 is required for high-affinity IL-12 binding and signaling. IL-12Rβ1 also acts in partnership with IL-23R, to recognize the IL-23 dimer formed from IL-12p40

Complete IL-12p40 deficiency

It was shown in 1998 that patients with MSMD may harbor mutations of the IL12B gene [238]. This condition was the first inherited cytokine defect to be identified (mutations of the genes encoding IL-17F and IL-21 have since been identified [239], [240], [241]). IL12 encodes IL-12p40, which is common to both IL-12 and IL-23. IL-12 binds to its receptors, IL-12Rβ1 and IL-12Rβ2, on T lymphocytes and NK cells and is a potent inducer of IFN-γ. IL-23 binds to its receptors, IL-12Rβ1 and IL-23, for

AD IRF8 deficiency

Interferon regulatory factor 8 (IRF8), also known as interferon consensus sequence-binding protein (ICSBP), is one of the nine members of the IRF family of transcription factors [247], [248], [249]. These proteins bind to IFN-stimulated response elements (ISRE) and regulate the expression of genes stimulated by IFN-α/β. IRF8 is expressed in macrophages and dendritic cells and plays an important role in several aspects of myeloid cells [250], [251]. Mutations of the human IRF8 gene underlie two

ISG15 deficiency

In 2012, whole-exome sequencing led to the identification of bi-allelic mutations of ISG15 [68], [254]. This gene encodes an interferon-induced ubiquitin-like protein that modifies substrates in a process similar to ubiquitination (referred to as ISGylation). ISG15 is present in the gelatinase and secretory granules, but not in the azurophilic or specific granules of steady-state neutrophils, which release this protein upon bacterial challenge [255]. ISG15 is also secreted by many other cell

X-linked recessive NEMO deficiency

Germline mutations of NEMO and CYBB have been shown to cause X-linked recessive (XR) MSMD [22], [69], [262] (Fig. 1, Fig. 2, Fig. 3, Table 1, Table 2). These two genes have long been implicated in other human diseases: incontinentia pigmenti (IP) and anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) (NEMO) [263], [264], [265], and chronic granulomatous disease (CGD) (CYBB) [74], [266], [267]. NEMO is a regulatory subunit of the inhibitor of NF-κB kinase. It consists of a series of

X-linked recessive CYBB deficiency

CYBB (also known as gp91phox or NOX2) is an essential component of the NADPH oxidase complex. It encodes the β-chain of flavocytochrome b558. It is expressed in phagocytes, including granulocytes, monocytes and macrophages, but also, to a lesser extent, in other cells, such as dendritic cells and B lymphocytes. Germline mutations of CYBB are responsible for the most common form of CGD (OMIM 306400), a PID in which phagocytic cells display little or no NADPH oxidase activity (Table 2). Three

Conclusions and future directions

Since the initial clinical description of MSMD, probably in 1951 [4], and the discovery of the first genetic etiology of this condition in 1996 [65], [66], 18 genetic etiologies of MSMD, including mutations in nine genes, have been described and characterized (Fig. 1, Fig. 2, Fig. 3, Table 1). However, about half the MSMD patients known to us do not suffer from any of these 18 MSMD-causing defects, suggesting an even greater degree of genetic heterogeneity underlying MSMD. Investigations of

Conflict of interest

The authors have no financial or commercial conflict of interest to declare.

Acknowledgments

We thank all members of the laboratory for helpful discussions, and Yelena Nemirovskaya, Lahouari Amar, Martine Courat and Eric Anderson for administrative support; in particular, Dusan Bogunovic, Caroline Deswarte, Jacqueline Feinberg, Emmanuelle Jouanguy, Xiao-Fei Kong, Janet Markle, Rubén Martínez-Barricarte, Mélanie Migaud, Marcela Moncada-Vélez, Satoshi Okada, Capucine Picard and Guillaume Vogt. We thank the patients and their families, and referring physicians worldwide for their trust

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