Skip to main content

Mendelian susceptibility to mycobacterial disease: an overview

Abstract

Background

Mycobacteria include ubiquitous species of varying virulence. However, environmental and individual-specific factors, particularly host genetics, play a crucial role in the outcome of exposure to mycobacteria. The first molecular evidence of a monogenic predisposition to mycobacteria came from the study of Mendelian susceptibility to mycobacterial disease (MSMD), a rare inborn error of IFN-γ immunity conferring a selective susceptibility to infections even with low virulent mycobacteria, in patients, mostly children, without recognizable immune defects in routine tests. This article provides a global and updated description of the most important molecular, cellular, and clinical features of all known monogenic defects of MSMD.

Results

Over the last 20 years, 19 genes were found to be mutated in MSMD patients (IFNGR1, IFNGR2, IFNG, IL12RB1, IL12RB2, IL23R, IL12B, ISG15, USP18, ZNFX1, TBX21, STAT1, TYK2, IRF8, CYBB, JAK1, RORC, NEMO, and SPPL2A), and the allelic heterogeneity at these loci has led to the definition of 35 different genetic defects. Despite the clinical and genetic heterogeneity, almost all genetic etiologies of MSMD alter the interferon gamma (IFN-γ)-mediated immunity, by impairing or abolishing IFN-γ production or the response to this cytokine or both. It was proven that the human IFN-γ level is a quantitative trait that defines the outcome of mycobacterial infection.

Conclusion

The study of these monogenic defects contributes to understanding the molecular mechanism of mycobacterial infections in humans and to the development of new diagnostic and therapeutic approaches to improve care and prognosis. These discoveries also bridge the gap between the simple Mendelian inheritance and complex human genetics.

Background

The genus Mycobacterium includes over 190 recognized species, of which the most pathogenic are Mycobacterium tuberculosis (M. tb), M. leprae, and M. ulcerans [1]. Humans are constantly exposed to environmental mycobacteria (EM) which are isolated in soil, water, and aerosols. In addition, most children worldwide are vaccinated with Mycobacterium bovis Bacille Calmette-Guérin (BCG) vaccines. These pathogens can cause localized or disseminated clinical disease in rare cases. Indeed, environmental and individual-specific factors, particularly host genetics, play a crucial role in the outcome of exposure to mycobacteria and the heterogeneity of clinical manifestations [2,3,4,5]. Although genome-wide association studies have identified loci associated with host predisposition or resistance to infections with the more virulent M. tb, their results were not consistent or reproducible [6,7,8].

The understanding of the pathogenesis of mycobacterial diseases has been improved by studies of the rare syndrome of Mendelian susceptibility to mycobacterial disease (MSMD), an inborn error of immunity (IEI) or primary immunodeficiency (PID) classified by the International Union of Immunology Societies (IUIS) as a defect in intrinsic and innate immunity [9, 10]. This condition is characterized by selective susceptibility to infections with weakly virulent mycobacteria, including the M. bovis Bacille Calmette-Guérin (BCG) vaccines and various environmental mycobacteria in patients without classical immune defects [4, 11]. These patients may also present severe forms of primary tuberculosis caused by M. tb [8, 11, 12]. In addition, about half of patients develop non-typhoidal salmonellosis of varying severity [11, 13, 14]. In some cases, patients also suffer from chronic mucocutaneous candidiasis (CMC) [11, 13, 15, 16]. Other severe infections have more rarely been reported, including viral diseases (caused by cytomegalovirus, human herpesvirus 8, parainfluenza virus type 3, respiratory syncytial virus, and varicella zoster virus), parasitic diseases (leishmaniasis, toxoplasmosis), fungal diseases (histoplasmosis, paracoccidioidomycosis, coccidioidomycosis), and bacterial diseases (listeriosis, nocardiosis, klebsiellosis) [11, 17,18,19,20,21,22]. Severe forms of MSMD can lead to life-threatening infections at an early age, while mild forms may appear late or remain asymptomatic [11].

Since 1996, mutations causing MSMD have been identified in 19 genes (IFNGR1, IFNGR2, IFNG, IL12RB1, IL12RB2, IL23R, IL12B, ISG15, USP18, ZNFX1, TBX21, STAT1, TYK2, IRF8, CYBB, JAK1, RORC, NEMO, and SPPL2A). Allelic heterogeneity at these loci has led to the definition of 35 different genetic defects, based on the impact of the mutation (null or hypomorphic), the mode of transmission (dominant or recessive, autosomal or X-linked), the expression of the mutant allele (normal, low or absent), and the function affected (e.g., phosphorylation, binding to DNA or both) (Table 1) [15, 23,24,25,26,27,28,29]. Except for ZNFX1 deficiency, all genetic disorders have in common the alteration of the production or response to interferon-gamma (IFN-γ) or both. IFN-γ is a macrophage activation factor that plays a crucial, non-redundant role in antimycobacterial immunity [12, 30]. The severity and penetrance of MSMD depend on the genetic etiology and are inversely correlated with residual production of or response to IFN-γ [30]. More profound IFN-γ deficiency is associated with a greater vulnerability to weakly virulent mycobacteria, whereas more selective IFN-γ deficiency is associated with a more selective predisposition to mycobacterial disease [12].

Table 1 List of 19 known genes and their defects associated with Mendelian susceptibility to mycobacterial infections
Fig. 1
figure 1

Schematic diagram of the cooperation between phagocytes/dendritic cells and T/NK cells during mycobacterial infection. Proteins for which mutations in the corresponding genes have been associated with MSMD are indicated in red. Following phagocytosis of mycobacteria, pattern recognition receptors (PRRs) activate and induce the production and release of IL-12, IL-23, and ISG15. These cytokines bind to their receptors (IL-12R, IL-23R, and LFA-1) on T-helper and NK cells, inducing the production of IFN-γ via TYK2/JAK2-dependent pathways, using STAT4 and STAT3 dimers, as well as the transcription factors RORC and T-bet. In turn, secreted IFN-γ binds to its receptor (IFNγR) on the surface of macrophages and dendritic cells leading to the activation of JAK1/JAK2-dependent pathway involving STAT1, IRF8, and IRF1 transcription factors, which enhances the production of IL-12, IL-23, and ISG15 and promotes expression of interferon-stimulated genes (ISGs). USP18 liberates ISG15 from other bound proteins and ISG15 protects USP18 from degradation. Besides, the interaction of CD40 with its ligand leads to the activation of NEMO, which activates and releases the NF-kB transcription factors. This enhances the ability of phagocytes to eliminate intracellular microorganisms

Two types of MSMD have been defined: isolated MSMD, in which patients are sensitive only to mycobacterial infections, and syndromic MSMD, in which patients suffer from mycobacterial infection in the context of one or a few other diseases [8, 11, 13, 15]. The study of these monogenic defects contributes to understanding the molecular mechanism of mycobacterial infections in humans and allows the development of new diagnostic and therapeutic approaches to improve care and prognosis. For example, MSMD patients with impaired production of IFN-γ may benefit from injections of human recombinant IFN-γ, while for patients with abolished response to this cytokine, hematopoietic stem cell transplantation (HSCT) and promising gene therapy are the only current therapeutic options [31,32,33,34]. In this review, we describe the most important molecular, cellular and clinical features of all monogenic defects of MSMD discovered over the last 25 years.

Main text

IL12RB1

In response to activation signals induced by pattern recognition receptors (PRRs), interleukin-12 (IL-12) is produced by dendritic cells, macrophages, and neutrophils. This cytokine stimulates the production of IFN-γ and TNF-α by T and NK cells and promotes the differentiation of naïve T cells into Th1 cells [35,36,37,38]. The IL-12 receptor is a heterodimer formed by two chains, IL-12Rβ1 and IL-12Rβ2 [39]. The IL-12Rβ1 chain also binds with the IL-23R subunit to form the IL-23 receptor [40] (Fig. 1). Autosomal recessive (AR) complete IL-12Rβ1 deficiency, or Immunodeficiency 30 (OMIM #614891), therefore alters signaling by IL-12 and IL-23. It is the most common genetic defect of MSMD, found in about 60% of diagnosed MSMD patients [13, 15]. All mutant alleles are loss of function (LOF) and their transmission is AR, without expression of IL-12Rβ1 or, more rarely, with the expression of a non-functional protein on the cell surface (Table 1) [11, 13, 41,42,43,44]. Cells from these patients do not respond to stimulation by either IL-12 or IL-23, resulting in impaired production of IFN-γ by T and NK cells [41, 45]. The clinical phenotype associated with this defect is very heterogeneous, the affected patients are likely to be infected with BCG, EM, M. tb, and/or Salmonella sp. [16, 41, 43, 44, 46]. Leukocytoclastic vasculitis is also reported in some patients with IL-12Rβ1 deficiency, probably related to salmonellosis. CMC is observed in a third of these patients and is attributed to impaired development of Th17 cells caused by the absence of IL-23 [16, 41, 45]. Even rarer, other fungal infectious diseases, such as coccidioidomycosis, paracoccidioidomycosis, or histoplasmosis, have been diagnosed in IL-12Rβ1-deficient patients [20, 42, 47, 48]. Visceral leishmaniasis is also associated with this group of patients [19, 22]. Asymptomatic individuals have been reported, attesting to an incomplete clinical penetrance for this type of genetic disease in MSMD, with only 50–70% of adults being symptomatic by the age of 40 years [15, 41].

IL12RB2

An AR complete IL-12Rβ2 deficiency has been identified in a consanguineous Turkish family [45]. Two of the three patients who carried the homozygous loss-of-function (LOF) variant had clinical manifestations of mycobacterial infections. The first developed a disseminated BCG infection one year after vaccination. The second patient had pulmonary tuberculosis at the age of 5 years. They have never had salmonellosis or fungal infections. The third patient is asymptomatic [45]. No candidiasis was reported in all three patients as IL-17 immunity is maintained. These patients have low numbers of Th1 cells, while their Th17 cells are slightly low or normal [15, 45]. Indeed, the penetrance for MSMD is incomplete, probably as low as 0.5%, because IL-23 can largely compensate for the loss of IL-12 signaling [15].

IL23R

A new AR deficiency caused by a homozygous LOF mutation in the extracellular domain of the IL-23R subunit has been identified in a consanguineous Iranian family with two MSMD-affected children [45]. The first girl was vaccinated by BCG, after which she developed persistent lymphadenopathy for one year, with spontaneous recovery. Her brother was also vaccinated at birth by BCG, he developed axillary lymphadenopathy, hepatosplenomegaly, and mediastinal adenopathy. He died of disseminated BCG infection despite treatment with antibiotics for a year and a half and then with recombinant IFN-γ [45]. Another patient has been reported as having disseminated BCG disease [43]. The last reported patient is a 48-year-old man of Turkish origin carrying a homozygous LOF mutation in the intracellular domain of the IL23R subunit [29]. He suffered from disseminated multi-mycobacterial infection, with pulmonary (MAC), bone marrow, and gastrointestinal (Mycobacterium tilburgii) manifestations [29]. These patients had normal frequencies of various leukocyte subsets, but low levels of MAIT cells (mucosal-associated invariant T cells), an abnormal decrease in Th1 lymphocytes and a slight decrease in Th17 and Th2 cells. Cells from these patients may express, or not, the IL-23R protein, but they present abolished phosphorylation of STAT3 in response to IL-23, resulting in impaired production of IFN-γ in vitro [29, 45].

IL12B

IL-12 is a heterodimeric cytokine composed of two subunits encoded by 2 distinct genes, p35 subunit (IL12A) and p40 subunit (IL12B) [36]. The p40 subunit also heterodimerizes with the p19 subunit of IL-23 (IL23A) to form IL-23 [38]. IL-23 is important for the expansion and survival of Th17 cells [49]. Defect of the IL12B gene (p40 subunit) causes immunodeficiency 29 (OMIM #614890), a frequently reported cause of MSMD with AR transmission. Patients usually develop BCG and/or salmonellosis infections [11, 25, 50,51,52,53]. Cases of tuberculosis and EM infection have also been reported [50]. These patients also suffer from CMC due to disruption of IL-17 secretion induced by IL-23 [11, 50, 54]. Other infectious diseases, such as nocardiosis, klebsiellosis, or leishmaniasis, have been also associated with this group of MSMD [22, 50]. The prognosis of this defect is generally good, with a strong similarity to IL-12Rβ1 deficiency [41, 50].

TYK2

TYK2 is a Janus kinase (JAK) involved in various signaling pathways, including responses to IL-12, IL-23, IFN-α/β, and IL-10. Once activated, TYK2 phosphorylates the intracellular part of the receptor and the recruited STATs. AR complete TYK2 deficiency, or immunodeficiency 35 (#611,521), was first described in 2006 in a Japanese patient with the hyper-IgE syndrome (HIES) and BCG infection [55]. He had a history of infections with viruses, fungi, mycobacteria, and Salmonella sp. [55]. Then, other patients from Argentina, Iran, Saudi Arabia, Turkey, Pakistan, Malaysia, and China had been reported [28, 56,57,58,59,60,61]. Overall, out of 25 reported patients with AR complete TYK2 deficiency, eight patients had a history of BCG infections (localized or regional or disseminated) five had M. tb infection, and one patient had EM disease [28, 55,56,57,58,59,60], including two patients with salmonellosis [55, 58]. Fifteen patients suffered from viral diseases, which is consistent with their poor cellular response to IFN-α/β [28, 55, 56, 61]. Six patients had fungal diseases caused by C. albicans, including one case of CMC. Interestingly, only 36% (8/22) of BCG-vaccinated patients with AR complete TYK2 deficiency have suffered from BCG disease, which indicates an incomplete penetrance of this defect for MSMD. This incomplete penetrance for mycobacterial and viral diseases results from impaired, but not abolished, responses to IL-12, IL-23, and IFN-α/IFN-β due to residual TYK2-independent responses implying other molecules, such as other JAK kinases [56]. Only one patient suffered from HIES [55] and another had elevated IgE level without HIES [57]. The HIES phenotype in this patient was attributed to impaired fibroblastic responses to IL-6, which was not rescued by wild-type TYK2 [56]. Thus, HIES and high serum IgE levels may be caused by genetic variants at loci other than TYK2 [28, 56]. Except for one, all identified variants/mutations altered the expression of the TYK2 protein [28, 55,56,57,58,59,60,61].

In this context, ten other homozygous patients for a common variant of TYK2, P1104A, have recently been reported [62]. Three patients from Iran, Sweden, and the USA have BCG and M. avium complex (MAC) infections, while the other seven patients from Algeria, Brazil, Chile, Morocco, and Turkey have M. tb infections (6 pulmonary and 1 miliary tuberculosis) [62]. Patients’ leukocytes respond poorly to IL-23 in terms of IFN-γ production. Homozygosity for P1104A selectively affects IL-23 signaling, as cellular responses to IL-12, IFN-α/β and IL-10 are intact in these patients [62]. Patients had normal development of IL-17 + CD4 + T cells ex vivo, which corresponds to the absence of CMC in these individuals. These patients are also normally resistant to other infectious diseases [62]. The homozygosity of P1104A is present in 1/600 humans of European origin, but the penetrance of this variant is much lower for MSMD (less than 0.5%) than for tuberculosis (greater than 50% in areas of endemic tuberculosis) [62, 63]. Furthermore, the frequency of the variant significantly decreased in Europe over the last 2000 years, by negative selection probably reflecting endemicity for TB [64].

RORC

The RORC gene can encode two nuclear receptor isoforms that act as transcription factors: RORγ which is ubiquitously expressed, and ROR-γT, which is restricted to leukocytes. The RORγT isoform promotes the differentiation of thymocytes into Th17 cells [65]. Three homozygous mutations of RORC were discovered in seven patients from three unrelated consanguineous families [66]. Mutant alleles are LOF with AR segregation and cause immunodeficiency 42 (OMIM: #616622). The patients suffered from early childhood from mycobacterial infections (BCG or M. tb) or CMC, impaired lymphoid development, and a small thymus [66]. The cells of these patients have impaired production of IL-17A, IL-17F, and IL-22 and an apparent defect in IFN-γ production in response to stimulation by BCG and IL-12 [66]. The impaired secretion of IL-17A /F by patients’ T cells justifies CMC in these patients [66]. IFN-γ secretion was normal in naïve or memory CD4+ T, but was strongly impaired in γδ and Th1 T cells, which explains mycobacterial infections [66].

TBX21

T-bet or T-box protein 21 (TBX21) is a transcription factor that governs the development or function of several IFN-γ-producing lymphocytes, including T helper 1 (TH1) cells, NK and invariant NKT (iNKT) cells in particular. Recently, a patient from a consanguineous family from Morocco has been identified with AR complete T-bet deficiency (immunodeficiency 88 (OMIM #619630)) [24, 67]. The patient suffered from BCG disease following vaccination and persistent reactive airway disease associated with increased production of Th2 cytokines [24, 67]. T-bet-deficient mice are highly vulnerable to mycobacteria. Thus, mycobacterial disease and T-bet deficiency in this patient are consistent with the data in mice. Cellular immunophenotyping showed a strong diminution of circulating NK, invariant NKT, and Th1 cells in vivo. The frequency of Vδ2+γδ T and MAIT cells was also impaired. HVS-T cells from the patient express normal volumes of TBX21 RNA but protein expression is diminished [24]. The discovery of inherited T-bet deficiency provides a unique opportunity to analyze the role of this fundamental transcription factor in human leukocyte subsets, especially Th cells.

IFNGR1

The receptor of IFN-γ is a heterodimer formed by two chains IFN-γR1 (binding to IFN-γ) and IFN-γR2 (signal transduction). IFN-γR1 or IFN-γR2 deficiency may be AR or AD, complete or partial, with or without expression of the protein on the cell surface [11, 13]. The AR complete IFN-γR1 deficiency (immunodeficiency 27A (OMIM #209950) was identified in 1996 as the first genetic etiology of MSMD [68, 69]. This defect is characterized by severe and early infections by BCG and/or EM, often resulting in the death of patients in the absence of hematopoietic stem cell transplantation (HSTC) [68,69,70]. Tuberculosis has been identified in two patients, one of whom died of disseminated infection [70, 71]. Salmonellosis has also been reported in three patients [68,69,70]. The plasma of patients contains high levels of IFN-γ [70, 72]. The cellular phenotype of AR complete IFN-γR1 deficiency is characterized by the absence of response to IFN-γ in vitro, resulting in an abolished activation of gamma-activating factor (GAF: STAT1 homodimers) and production of IL-12p70 by leukocytes [68, 70, 73].

AR partial IFN-γR1 deficiency is characterized by a less severe clinical phenotype than that of AR complete IFN-γR1 deficiency [74,75,76,77]. Patients’ cells express the receptor on their surface but show an altered response to stimulation by high concentrations of IFN-γ [75]. These patients suffer from mycobacterial infections with BCG and/or EM, causing osteomyelitis in more than half of them [70, 77]. M. tb infection has been reported in a child who had not been vaccinated with BCG [74]. IFN-γ was detectable in the plasma of these patients [75].

Autosomal dominant (AD) IFN-γR1 deficiency (immunodeficiency 27B (OMIM #615978)) results in detectable activation of GAF with less severe and late mycobacterial infections [78]. Bone disease and MAC osteomyelitis are more common in this AD form [70, 79]. All variants confer a similar cellular phenotype, characterized by the impaired response to IFN-γ in vitro. Large amounts of IFN-γR1 are detected on the surface of cells, due to the accumulation of truncated IFN-γR1 receptors lacking the recycling domain or STAT1 and JAK1 docking sites, altering the normal signaling of IFN-γ by negative dominance, despite the presence of receptors encoded by the wild-type allele [70, 78].

IFNGR2

AR defects in IFN-γR2 (immunodeficiency 28 (OMIM #614889) also lead to severe and early mycobacterial infections. Two complete and two partial forms of AR IFN-γR2 deficiency have been reported, which differ in the absence or expression of the mutant or wild-type IFN-γR2 on the cell surface. The two forms of AR complete IFNγR2 deficiency (with or without expression of the protein on the cell surface) are manifested in early childhood by severe and often fatal infections with BCG, M. abscessus, M. avium, M. fortuitum, M. porcium, and M. simiae [80,81,82,83,84,85]. In both forms, the cellular response to IFN-γ is abolished [80,81,82,83,84,85].

The AR partial IFN-γR2 deficiency with the expression of functionally impaired protein has been described in six patients with mycobacterial infections caused by BCG, M. abscessus, M. bovis, M. elephantis, M. fortuitum, and M. simiae [82, 86, 87]. Among them, two patients (33%) died [82, 87]. A particular form of AR partial IFN-γR2 deficiency, with the expression of a small amount of normal IFN-γR2 (wild type), was described in three patients having BCG infection, one of whom died of infection with M. chelonei at the age of five [88]. The alteration of the cellular response to IFN-γ was more severe than that caused by the previously reported form of AR partial IFN-γR2 deficiency, but less severe than that of the AR complete deficiency [88].

Finally, an AD form of partial IFN-γR2 deficiency was found in a Polish patient with mild BCG infection [89]. The patient and other heterozygous individuals for the mutation showed low levels of IFN-γR2 expression at the cell surface and an impaired response to IFN-γ [89]. The clinical penetrance of this deficit for MSMD is very low, as only one case among the 18 heterozygous individuals was found to be affected [89, 90]. The mechanism underlying the incomplete penetrance remains unknown [90].

IFNG

The first mutation in IFN-γR1 has been identified in 1996 [68, 69]. Surprisingly, only one deleterious mutation has been reported in the IFN-γ cytokine [91]. Two Lebanese distant cousins living in Kuwait were both homozygous for the frameshift c.354_357del mutation in the IFNG gene. Both children suffered from severe and disseminated BCG disease. The patients had no other severe infections. The development of myeloid and lymphoid cells is intact in IFN-γ-deficient patients. Their lymphocytes failed to express and secrete detectable IFN-γ, and the secretion of TNF was very impaired [91]. An early diagnosis of patients with this deficiency should be useful to indicate recombinant IFN-γ as treatment.

JAK1

The signal from the IFN-γ receptor, as well as that of the IFN type I receptor, is transduced via a JAK/STAT pathway using JAK1 [92]. AR partial JAK1 deficiency has been reported in a 22-year-old Pakistani patient from consanguineous parents [93]. The patient presented with an infection by EM and a history of viral, fungal, and parasitic skin infections. He died of urothelial carcinoma at the age of 22 [93, 94]. Cellular responses to IFN-γ and IFN-α were altered but not suppressed by this mutant allele [93]. Altered responses to IL-2, IL-4, IL-10, and IL-27 have also been observed in leukocytes [93]. Probably, this defect can also be the cause of early susceptibility to cancer [93]. AR partial JAK1 deficiency, therefore, results in susceptibility to mycobacteria due to an altered IFN-γ signaling pathway and to other infections due to defective responses to other cytokines, including IFN-α.

STAT1

STAT1 (signal transducer and activator of transcription) is a transcription factor involved in the response to type I (IFN-α/β), type II (IFN-γ), and type III (IFN-λ) IFNs [92, 95, 96]. The defect may segregate as AD (immunodeficiency 31A (OMIM #614892)) or AR (immunodeficiency 31B (OMIM #613796)). AR STAT1 deficiency is characterized by the absence or impaired protein expression and the abolition or impaired cellular responses to IFN-γ, IFN-α/β, and IFN-λ, leading to severe and potentially fatal mycobacterial and viral infections [95, 97,98,99,100,101]. Cells from patients with complete or partial AR STAT1 deficiencies show an abolished or impaired response to STAT1-dependent cytokines [98, 99]. AD STAT1 deficiency is caused by LOF or hypomorphic monoallelic mutations affecting phosphorylation or DNA binding, or both (Table 1) [102,103,104,105,106]. This AD form produces relatively mild infections due to BCG and M. avium. Multifocal osteomyelitis occurs frequently in these patients [102, 103]. Clinical penetrance for MSMD is incomplete, as five people known to be genetically affected have not developed the disease [102, 106]. Cells from heterozygous patients show a defect only for activation of GAF after stimulation with IFN-γ (or IFN-α), with no detectable defect for activation of ISGF3 in response to stimulation with IFN-α [102]. Therefore, these patients are normally resistant to viral infections and likely to have mycobacterial infections [102, 106].

IRF8

Interferon regulatory factor 8 (IRF8) is part of a family of transcription factors regulating the expression of IFN type I genes and is involved in the development of the myeloid lineage [107, 108]. IRF8 deficiency can present as AD or AR forms [11, 13]. AD form of IRF8 deficiency (immunodeficiency 32A (OMIM #614893)) was found in two patients originating from Chile and Brazil suffering from recurrent episodes of disseminated BCG infections [109]. They carry the same de novo heterozygous mutation as they were absent from parents and siblings [109]. This variant, affecting the DNA binding domain of IRF8, causes poor transactivation of target genes, such as IL12B or NOS2 [109, 110]. Both patients had no decline in circulating lymphocytes and granulocytes. However, they exhibited the loss of one type of circulating dendritic cells (CD11c + CD1c +). These cells are potent producers of IL-12, suggesting that the depletion of these IL-12-producing cells contributes to the susceptibility to mycobacterial infection in these patients [109].

The AR IRF8 deficiency (immunodeficiency 32B (OMIM #226990) causes severe monocytopenia and a deficiency in dendritic cells, resulting in severe and recurrent infections, including disseminated BCG infections and candidiasis [109, 111]. Peripheral mononuclear blood cells (PBMC) from patients did not produce IL-12 in response to stimulations by BCG, phytohemagglutinin (PHA), and lipopolysaccharide (LPS), causing very low production of IFN-γ [109, 111]. AR complete IRF8 deficiency combines mycobacterial and fungal infections, myeloproliferation, and absence of circulating monocytes and dendritic cells [109, 111]. A recent patient with AR complete IRF8 deficiency has been described as having pulmonary alveolar proteinosis (PAP) with neutrophilia and absence of circulating monocytes and DCs [112].

SPPL2A

SPPL2a (signal peptide peptidase-like 2A) is an intracellular transmembrane protease with several substrates [113], including, in particular, the N-terminal fragment (NTF) of the HLA invariant chain (CD74) expressed by HLA-II+ antigen-presenting cells [114]. The SPPL2A-deficient mice display impaired CD74 degradation in B lymphocytes and dendritic cells. The description of a new genetic etiology of MSMD was recently illustrated in three patients from two Moroccan and Turkish families [114]. Patients develop BCG infections a few months after vaccination [114]. SPPL2a deficiency leads to a decrease in the number of conventional type 2 dendritic cells (cDC2), such as the AD IRF8 deficiency which also causes a somewhat greater depletion of the cDC [109]. Thus, IRF8 connects with SPPL2A via IL-12-producing myeloid dendritic cells. In mouse macrophages, a binding site for IRF8 was identified in the SPPL2a promoter, suggesting that the decrease in cDC2 in AD IRF8 deficiency might reflect an altered induction of SPPL2A [114]. Memory T cells from donors deficient in SSPL2a and IRF8 exhibited altered IFN-γ production in response to BCG and M. tb antigens [114].

CYBB

NADPH oxidase (NOX) is a membrane enzyme complex. It is the key enzyme of the oxidative burst that occurs in phagocytes and contributes to the degradation of internalized particles and bacteria. NADPH oxidase is assembled from seven subunits, including cytochrome b (− 245), which is a heterodimer composed of a beta subunit (CYBB or gp91phox) and an alpha subunit (CYBA or p22phox). Mutations in one gene of the NADPH oxidase complex can cause chronic granulomatosis disease (CGD) [115]. In contrast, seven male patients with X-linked (XR) gp91phox deficiency (immunodeficiency 34 (OMIM #300645)) from two unrelated families developed mycobacterial infections without further signs of CGD [115, 116]. Six patients had BCG infections (BCG-itis or BCG-osis) and the seventh, who had not been vaccinated with BCG, developed disseminated tuberculosis [115, 116]. Contrary to what had been observed in patients with CGD, circulating phagocytic cells (neutrophils, monocytes) and dendritic cells of these patients exhibited normal NADPH oxidase activity with very impaired NADPH oxidase activity in monocyte-derived macrophages (MDMs) and EBV-B cells [115, 116].

NEMO (IKBKG)

NEMO (NF-kB essential modulator) is a protein encoded in humans by the IKBKG gene. NEMO (or IKKγ) is a subunit of the IKK kinase complex. This complex consists of two catalytic kinases, IKKα and IKKβ, and a regulatory subunit IKKγ. Once the complex is activated, it activates and releases NF-KB [117]. NF-kB is a transcription factor regulating the activity of several genes involved in ontogeny, homeostasis, activation, and maintenance of self-tolerance in lymphocytes [117, 118].

NEMO mutations may exhibit various characteristics, including immunodeficiency 33 (OMIM #300636), which manifests as XR susceptibility to mycobacterial infections. Two variants, p.E315A and p.R319Q have been identified as responsible for XR-linked MSMD. Patients presented with M. avium, or M. tb infections without any other severe infections and little dental abnormalities (conical teeth) [119, 120]. Low levels of IFN-γ and IL-12 secretion by the peripheral mononuclear blood cells (PBMCs) of the patients in response to PHA or CD3-specific antibodies were observed in these patients. The mechanism underlying this susceptibility involves the impairment of CD40-dependent IL-12 production. These hypomorphic recessive mutations of NEMO selectively impair the T cell-dependent, CD40- dependent, c-Rel-mediated NF-κB pathway in the myeloid cells of these patients [120].

ISG15

ISG15 encodes a ubiquitin-like protein that is attached to substrates in a process called ISGylation, which closely resembles ubiquitination [86]. Moreover, ISG15 is secreted by neutrophils and other myeloid cells (e.g. monocytes) upon bacterial challenge and acts as a very potent IFN-γ inducing cytokine in lymphocytes (particularly NK cells), in synergy with IL-12 [86]. In the absence of the ISG15, the amount of IFN-γ production is reduced, which may explain the increased susceptibility to mycobacterial infections in the AR complete ISG15 deficiency (immunodeficiency 38 (OMIM #616126). The first description of this IEI reported three patients with severe BCG and mycobacterial infections [121]. Intracranial calcification is also reported, attributed to the role of ISG15 stabilization of USP18, a potent negative regulator of IFN-I-mediated inflammation [122]. Other new ISG15-deficient patients were reported presenting mycobacterial diseases in the context of severe skin inflammation, as a third clinical phenotype of AR complete ISG15 deficiency [123, 124]. Stimulation of T and NK cells, by IL-12, IL-23, and ISG15, to produce IFN-γ is therefore essential for effective immunity against mycobacteria.

USP18

Ubiquitin-specific protease 18 (USP18) belongs to a family of deubiquitinating enzymes that cleave the bond between ubiquitin and a lysine residue of a ubiquitin-modified protein. USP18 specifically removes covalently linked ISG15 from other proteins, in a process called deISGylation. In turn, ISG15 prevents USP18 from being degraded by the proteasome [122]. The expression of USP18 is strongly induced by type I and type III interferons and PRRs after viral or bacterial infection. USP18 downregulates the IFN-I response by blocking JAK1 interaction with the subunit 2 (IFNAR2) of the IFN-I receptor independently of its protease activity [125]. Complete USP18 deficiency is responsible for the most severe interferonopathy (to overt type I IFN inflammation) with no complications of the BCG vaccine [126, 127]. Recently, three patients from a Moroccan consanguineous family have been identified with AR partial USP18 deficiency [26]. All patients suffered from disseminated BCG disease associated with intracranial calcifications. The homozygous variant, c.179T > A (p.I60N) is situated in exon 3 of USP18 and does not affect the protein expression in an overexpression system [26]. The secretion of IFN-γ or IL-12 in whole blood activation is intact in these patients. However, the persistent IFN-I signaling impairs the ability of myeloid cells to produce IL-12 and IL-23 and contributes to MSMD [26].

ZNFX1

The ZNFX1 gene encodes the zinc finger NFX1-type containing 1 (ZNFX1) protein, a helicase of the superfamily 1 (SF1), important for the direct induction of IFNα/β-stimulated gene (ISG) with antiviral activities. ZNFX1 is highly expressed in myeloid cells and very few studies have investigated the structure and function of this protein. AR ZNFX1 deficiency (immunodeficiency 91 (OMIM #619644)) was reported in three patients from 2 unrelated consanguineous families from Iran and Morocco [23]. The first patient had BCG-osis following BCG vaccination at age of three months and later developed recurrent respiratory infections, including CMV infections, associated with pneumonia and interstitial lung disease. The Moroccan kindred is living in Belgium and none of the patients has received BCG vaccination, one developed disseminated tuberculosis at the age of 11 years and the other did not suffer from severe infectious diseases. The two patients also had recurrent and unexplained episodes of fever, thrombocytopenia, and organomegaly. A brother of these two patients died at 14 months of age from M. tuberculosis meningoencephalitis. This patient was not genotyped. The two homozygous variants were predicted to be LOF [23]. Cells from patients produced IFN-γ and IL-12 similarly to cells of healthy controls [23]. Other patients with a more complex phenotype associating monocytosis, thrombocytopenia, hepatosplenomegaly, recurrent infections, and macrophagic activation were also reported [27, 128]. ZNFX1 protein is localized in stress granules of cells. Future studies are necessary to determine the connection of ZNFX1 with IFN-γ.

Conclusion

The constant progress of genomics and the establishment of new functional tests have paved the way for the identification of monogenic hereditary defects conferring a selective predisposition to infections by certain types of microbes, as a new type of IEIs [9]. Studies on these IEIs allow us to understand the molecular basis of the immune response against diverse types of pathogens. MSMD, which predisposes mainly to mycobacterial infections, is the most studied of these IEIs, with 35 different disorders found in 19 distinct genes. Despite the clinical and genetic heterogeneity of MSMD, functional studies have shown remarkable physiological homogeneity. Indeed, all genetic etiologies of MSMD alter IFN-γ-mediated immunity. The IL-12/IL-23/ISG15/IFN-γ axis is critical for human defense against mycobacterial infection [30]. The discovery of these genetic etiologies of MSMD has important diagnostic, therapeutic, and preventive implications. Indeed, the molecular diagnosis of MSMD allows for offering a better therapeutic approach and genetic counseling to affected families. Patients with defects in IFN-γ production may benefit from treatment with recombinant human IFN-γ, in addition to antibiotics. In contrast, HSCT is the only medical option to date for patients with a completely defective response to IFN-γ. In addition, gene therapy represents a promising therapeutic intervention for these defects after being successfully tested [33, 34]. In addition, BCG vaccine is contraindicated in patients with MSMD and newborn siblings until genetic assertion, as most patients are diagnosed after being vaccinated and developing BCG complications. However, suspending BCG vaccination can be detrimental to patients in tuberculosis-endemic regions. Early newborn screening, preemptive treatment with antimycobacterial therapy and the development of safer vaccine platforms for patients with genetic immune disorders may be alternative strategies. Thus, targeted genotyping or whole exome/genome sequencing has become a diagnostic necessity even in emerging countries. Despite these recent discoveries, the genetic puzzle of mycobacterial infections remains far from complete, as no genetic etiology has yet been identified for nearly half of all MSMD patients. Other pathways could be identified as being involved soon.

Availability of data and materials

Not applicable.

Abbreviations

AD:

Autosomal dominant

AR:

Autosomal recessive

BCG:

Bacille Calmette-Guérin

cDC2:

Conventional type 2 dendritic cells

CGD:

Chronic granulomatosis disease

CMC:

Chronic mucocutaneous candidiasis

DCs:

Dendritic cells

EM:

Environmental mycobacteria

GAF:

Gamma-activating factor

HSCT:

Hematopoietic stem cell transplantation

IEI:

Inborn error of immunity

IFN-γ :

Interferon gamma

IL-12:

Interleukin 12

IRF8:

Interferon regulatory factor 8

ISGF3:

Interferon-stimulated gene factor 3

ISGs:

Interferon-stimulated genes

IUIS:

International Union of Immunology Societies

JAK:

Janus kinase

LOF:

Loss of function

LPS:

Lipopolysaccharide

M. tb:

Mycobacterium tuberculosis

MSMD:

Mendelian susceptibility to mycobacterial disease

NEMO:

NF-kB essential modulator

NOX:

NADPH oxidase

OMIM:

Online Mendelian inheritance in man

PBMC:

Peripheral mononuclear blood cells

PHA:

Phytohemagglutinin

PID:

Primary immunodeficiency

PRRs:

Pattern recognition receptors

STAT1:

Signal transducer and activator of transcription 1

SF1:

Superfamily 1

TBX21:

T-box protein 21

USP18:

Ubiquitin-specific protease 18

XR:

X-linked recessive

ZNFX1:

Zinc finger NFX1-type containing 1

References

  1. Robertson RE (2020) Mycobacterium spp. in Reference Module in Food Science. Elsevier, USA.

  2. Newport M, Levin M (1994) Familial disseminated atypical mycobacterial disease. Immunol Lett 43(1–2):133–138

    Article  CAS  Google Scholar 

  3. Casanova JL et al (1995) Immunological conditions of children with BCG disseminated infection. Lancet 346(8974):581

    Article  CAS  Google Scholar 

  4. Casanova JL, Abel L (2002) Genetic dissection of immunity to mycobacteria: the human model. Annu Rev Immunol 20:581–620

    Article  CAS  Google Scholar 

  5. Poyhonen L et al (2019) Life-threatening infections due to live-attenuated vaccines: early manifestations of inborn errors of immunity. J Clin Immunol 39(4):376–390

    Article  Google Scholar 

  6. Abel L et al (2014) Human genetics of tuberculosis: a long and winding road. Philos Trans R Soc Lond B Biol Sci 369(1645):20130428

    Article  Google Scholar 

  7. Abel L et al (2018) Genetics of human susceptibility to active and latent tuberculosis: present knowledge and future perspectives. Lancet Infect Dis 18(3):e64–e75

    Article  CAS  Google Scholar 

  8. Boisson-Dupuis S (2020) The monogenic basis of human tuberculosis. Hum Genet 139(6–7):1001–1009

    Article  Google Scholar 

  9. Bousfiha AA et al (2022) The 2022 Update of IUIS Phenotypical Classification for Human Inborn Errors of Immunity. J Clin Immunol. 42(7):1508–1520. https://doi.org/10.1007/s10875-022-01352-z

    Article  Google Scholar 

  10. Tangye SG et al (2021) The ever-increasing array of novel inborn errors of immunity: an interim update by the IUIS committee. J Clin Immunol 41(3):666–679

    Article  Google Scholar 

  11. Bustamante J et al (2014) Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-gamma immunity. Semin Immunol 26(6):454–470

    Article  CAS  Google Scholar 

  12. Boisson-Dupuis S, Bustamante J (2021) Mycobacterial diseases in patients with inborn errors of immunity. Curr Opin Immunol 72:262–271

    Article  CAS  Google Scholar 

  13. Rosain J et al (2019) Mendelian susceptibility to mycobacterial disease: 2014–2018 update. Immunol Cell Biol 97(4):360–367

    Article  Google Scholar 

  14. Zahid MF et al (2014) Recurrent salmonellosis in a child with complete IL-12Rbeta1 deficiency. J immunodefic Disord. 3:1000109. https://doi.org/10.4172/2324-853X.1000109

    Article  Google Scholar 

  15. Bustamante J (2020) Mendelian susceptibility to mycobacterial disease: recent discoveries. Hum Genet 139(6–7):993–1000

    Article  CAS  Google Scholar 

  16. Ouederni M et al (2014) Clinical features of Candidiasis in patients with inherited interleukin 12 receptor beta1 deficiency. Clin Infect Dis 58(2):204–213

    Article  CAS  Google Scholar 

  17. Roesler J et al (2011) Meningoencephalitis caused by varicella-zoster virus reactivation in a child with dominant partial interferon-gamma receptor-1 deficiency. Pediatr Infect Dis J 30(3):265–266

    Article  Google Scholar 

  18. Dorman SE et al (1999) Viral infections in interferon-gamma receptor deficiency. J Pediatr 135(5):640–643

    Article  CAS  Google Scholar 

  19. Sanal O et al (2007) A case of interleukin-12 receptor beta-1 deficiency with recurrent leishmaniasis. Pediatr Infect Dis J 26(4):366–368

    Article  Google Scholar 

  20. Moraes-Vasconcelos D et al (2005) Paracoccidioides brasiliensis disseminated disease in a patient with inherited deficiency in the beta1 subunit of the interleukin (IL)-12/IL-23 receptor. Clin Infect Dis 41(4):e31–e37

    Article  Google Scholar 

  21. Pedraza S et al (2010) Clinical disease caused by Klebsiella in 2 unrelated patients with interleukin 12 receptor beta1 deficiency. Pediatrics 126(4):e971–e976

    Article  Google Scholar 

  22. Parvaneh N et al (2017) Visceral leishmaniasis in two patients with IL-12p40 and IL-12Rβ1 deficiencies. Pediatr Blood Cancer 64(6):e26362

    Article  Google Scholar 

  23. Le Voyer T et al (2021) Inherited deficiency of stress granule ZNFX1 in patients with monocytosis and mycobacterial disease. Proc Natl Acad Sci USA. https://doi.org/10.1073/pnas.2102804118

    Article  Google Scholar 

  24. Yang R et al (2021) Human T-bet governs innate and innate-like adaptive IFN-gamma immunity against mycobacteria. Cell 183(7):1826–1847

    Article  Google Scholar 

  25. Noma K et al (2022) Mendelian susceptibility to mycobacterial diseases: state of the art. Clin Microbiol Infect. https://doi.org/10.1016/j.cmi.2022.03.004

    Article  Google Scholar 

  26. Martin-Fernandez M et al (2022) A partial form of inherited human USP18 deficiency underlies infection and inflammation. J Exp Med 219(4).

  27. Alawbathani S et al (2022) Biallelic ZNFX1 variants are associated with a spectrum of immuno-hematological abnormalities. Clin Genet 101(2):247–254

    Article  CAS  Google Scholar 

  28. Ogishi M et al (2022) Impaired IL-23-dependent induction of IFN-gamma underlies mycobacterial disease in patients with inherited TYK2 deficiency. J Exp Med 219(10)

  29. Staels F et al (2022) A novel homozygous stop mutation in IL23R causes mendelian susceptibility to mycobacterial disease. J Clin Immunol. 42(8):1638–1652

    Article  CAS  Google Scholar 

  30. Dupuis S et al (2000) Human interferon-gamma-mediated immunity is a genetically controlled continuous trait that determines the outcome of mycobacterial invasion. Immunol Rev 178:129–137

    Article  CAS  Google Scholar 

  31. Holland SM (2001) Immunotherapy of mycobacterial infections. Semin Respir Infect 16(1):47–59

    Article  CAS  Google Scholar 

  32. Radwan N et al (2021) Outcome of hematopoietic stem cell transplantation in patients with mendelian susceptibility to mycobacterial diseases. J Clin Immunol. https://doi.org/10.1007/s10875-021-01116-1

    Article  Google Scholar 

  33. Hahn K et al (2020) Human lentiviral gene therapy restores the cellular phenotype of autosomal recessive complete IFN-gammaR1 deficiency. Mol Ther Methods Clin Dev 17:785–795

    Article  CAS  Google Scholar 

  34. Hetzel M et al (2018) Hematopoietic stem cell gene therapy for IFNgammaR1 deficiency protects mice from mycobacterial infections. Blood 131(5):533–545

    Article  CAS  Google Scholar 

  35. Hsieh CS et al (1993) Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science 260(5107):547–549

    Article  CAS  Google Scholar 

  36. Wolf SF et al (1991) Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells. J Immunol 146(9):3074–3081

    Article  CAS  Google Scholar 

  37. Trinchieri G (1995) Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu Rev Immunol 13:251–276

    Article  CAS  Google Scholar 

  38. Oppmann B et al (2000) Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13(5):715–725

    Article  CAS  Google Scholar 

  39. Presky DH et al (1996) A functional interleukin 12 receptor complex is composed of two beta-type cytokine receptor subunits. Proc Natl Acad Sci USA 93(24):14002–14007

    Article  CAS  Google Scholar 

  40. Parham C et al (2002) A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. J Immunol 168(11):5699–5708

    Article  CAS  Google Scholar 

  41. de Beaucoudrey L et al (2010) Revisiting human IL-12Rbeta1 deficiency: a survey of 141 patients from 30 countries. Medicine (Baltimore) 89(6):381–402

    Article  Google Scholar 

  42. Rosain J et al (2018) A variety of alu-mediated copy number variations can underlie IL-12Rbeta1 deficiency. J Clin Immunol 38(5):617–627

    Article  CAS  Google Scholar 

  43. Mahdaviani SA et al (2020) Mendelian susceptibility to mycobacterial disease (MSMD): clinical and genetic features of 32 Iranian patients. J Clin Immunol 40(6):872–882

    Article  CAS  Google Scholar 

  44. Taur PD et al (2021) Clinical and molecular findings in mendelian susceptibility to mycobacterial diseases: experience from India. Front Immunol 12:631298

    Article  CAS  Google Scholar 

  45. Martinez-Barricarte R et al (2018) Human IFN-gamma immunity to mycobacteria is governed by both IL-12 and IL-23. Sci Immunol 3(30):eaau6759. https://doi.org/10.1126/sciimmunol.aau6759

    Article  Google Scholar 

  46. Esteve-Sole A et al (2018) Severe BCG-osis misdiagnosed as multidrug-resistant tuberculosis in an IL-12Rbeta1-deficient peruvian girl. J Clin Immunol 38(6):712–716

    Article  CAS  Google Scholar 

  47. Leon-Lara X et al (2020) Disseminated infectious disease caused by histoplasma capsulatum in an adult patient as first manifestation of inherited IL-12Rbeta1 deficiency. J Clin Immunol 40(7):1051–1054

    Article  Google Scholar 

  48. Vinh DC et al (2011) Interleukin-12 receptor beta1 deficiency predisposing to disseminated coccidioidomycosis. Clin Infect Dis 52(4):e99–e102

    Article  CAS  Google Scholar 

  49. Veldhoen M et al (2006) TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24(2):179–189

    Article  CAS  Google Scholar 

  50. Prando C et al (2013) Inherited IL-12p40 deficiency: genetic, immunologic, and clinical features of 49 patients from 30 kindreds. Medicine (Baltimore) 92(2):109–122

    Article  CAS  Google Scholar 

  51. Mahdaviani SA et al (2021) Disseminated mycobacterium simiae Infection in a patient with complete IL-12p40 Deficiency. Iran J Allergy Asthma Immunol 20(3):376–381

    Google Scholar 

  52. Alodayani AN et al (2018) Mendelian susceptibility to mycobacterial disease caused by a novel founder IL12B mutation in Saudi Arabia. J Clin Immunol 38(3):278–282

    Article  Google Scholar 

  53. Sharifinejad N et al (2021) Leukocytoclastic vasculitis in patients with IL12B or IL12RB1 deficiency: case report and review of the literature. Pediatr Rheumatol Online J 19(1):121

    Article  Google Scholar 

  54. Puel A et al (2011) Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science 332(6025):65–68

    Article  CAS  Google Scholar 

  55. Minegishi Y et al (2006) Human tyrosine kinase 2 deficiency reveals its requisite roles in multiple cytokine signals involved in innate and acquired immunity. Immunity 25(5):745–755

    Article  CAS  Google Scholar 

  56. Kreins AY et al (2015) Human TYK2 deficiency: mycobacterial and viral infections without hyper-IgE syndrome. J Exp Med 212(10):1641–1662

    Article  CAS  Google Scholar 

  57. Fuchs S et al (2016) Tyrosine kinase 2 is not limiting human antiviral type III interferon responses. Eur J Immunol 46(11):2639–2649

    Article  CAS  Google Scholar 

  58. Wu P et al (2020) A TYK2 gene mutation c.2395G>a leads to TYK2 deficiency: a case report and literature review. Front Pediatr 8:253.

    Article  Google Scholar 

  59. Sarrafzadeh SA et al (2020) A new patient with inherited TYK2 deficiency. J Clin Immunol 40(1):232–235

    Article  Google Scholar 

  60. Kilic SS et al (2012) A patient with tyrosine kinase 2 deficiency without hyper-IgE syndrome. J Pediatr 160(6):1055–1057

    Article  Google Scholar 

  61. Zhang Q et al (2022) Recessive inborn errors of type I IFN immunity in children with COVID-19 pneumonia. J Exp Med 219(8)

  62. Boisson-Dupuis S et al (2018) Tuberculosis and impaired IL-23-dependent IFN-gamma immunity in humans homozygous for a common TYK2 missense variant. Sci Immunol 3(30):993

    Article  Google Scholar 

  63. Kerner G et al (2019) Homozygosity for TYK2 P1104A underlies tuberculosis in about 1% of patients in a cohort of European ancestry. Proc Natl Acad Sci U S A 116(21):10430–10434

    Article  CAS  Google Scholar 

  64. Kerner G et al (2021) Human ancient DNA analyses reveal the high burden of tuberculosis in Europeans over the last 2,000 years. Am J Hum Genet 108(3):517–524

    Article  CAS  Google Scholar 

  65. Zhou L et al (2008) TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 453(7192):236–240

    Article  CAS  Google Scholar 

  66. Okada S et al (2015) Impairment of immunity to Candida and mycobacterium in humans with bi-allelic RORC mutations. Science 349(6248):606–613

    Article  CAS  Google Scholar 

  67. Yang R et al (2021) High Th2 cytokine levels and upper airway inflammation in human inherited T-bet deficiency. J Exp Med 218(8). https://doi.org/10.1084/jem.20202726

    Article  Google Scholar 

  68. Jouanguy E et al (1996) Interferon-gamma-receptor deficiency in an infant with fatal bacille Calmette-Guerin infection. N Engl J Med 335(26):1956–1961

    Article  CAS  Google Scholar 

  69. Newport MJ et al (1996) A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection. N Engl J Med 335(26):1941–1949

    Article  CAS  Google Scholar 

  70. Dorman SE et al (2004) Clinical features of dominant and recessive interferon gamma receptor 1 deficiencies. Lancet 364(9451):2113–2121

    Article  CAS  Google Scholar 

  71. Edeer Karaca N et al (2012) Granulomatous skin lesions, severe scrotal and lower limb edema due to mycobacterial infections in a child with complete IFN-gamma receptor-1 deficiency. Immunotherapy 4(11):1121–1127

    Article  CAS  Google Scholar 

  72. Fieschi C et al (2001) High levels of interferon gamma in the plasma of children with complete interferon gamma receptor deficiency. Pediatrics 107(4):E48

    Article  CAS  Google Scholar 

  73. Costa-Pereira AP et al (2005) Signaling through a mutant IFN-gamma receptor. J Immunol 175(9):5958–5965

    Article  CAS  Google Scholar 

  74. Jouanguy E et al (1997) Partial interferon-gamma receptor 1 deficiency in a child with tuberculoid bacillus Calmette-Guerin infection and a sibling with clinical tuberculosis. J Clin Invest 100(11):2658–2664

    Article  CAS  Google Scholar 

  75. Sologuren I et al (2011) Partial recessive IFN-gammaR1 deficiency: genetic, immunological and clinical features of 14 patients from 11 kindreds. Hum Mol Genet 20(8):1509–1523

    Article  CAS  Google Scholar 

  76. Remiszewski P et al (2006) Disseminated mycobacterium avium infection in a 20-year-old female with partial recessive IFNgammaR1 deficiency. Respiration 73(3):375–378

    Article  Google Scholar 

  77. Allende LM et al (2001) A point mutation in a domain of gamma interferon receptor 1 provokes severe immunodeficiency. Clin Diagn Lab Immunol 8(1):133–137

    Article  CAS  Google Scholar 

  78. Jouanguy E et al (1999) A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection. Nat Genet 21(4):370–378

    Article  CAS  Google Scholar 

  79. Storgaard M et al (2006) Novel mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infections. Scand J Immunol 64(2):137–139

    Article  CAS  Google Scholar 

  80. Dorman SE, Holland SM (1998) Mutation in the signal-transducing chain of the interferon-gamma receptor and susceptibility to mycobacterial infection. J Clin Invest 101(11):2364–2369

    Article  CAS  Google Scholar 

  81. Rosenzweig SD et al (2004) Characterization of a dipeptide motif regulating IFN-gamma receptor 2 plasma membrane accumulation and IFN-gamma responsiveness. J Immunol 173(6):3991–3999

    Article  CAS  Google Scholar 

  82. Martinez-Barricarte R et al (2014) Mycobacterium simiae infection in two unrelated patients with different forms of inherited IFN-gammaR2 deficiency. J Clin Immunol 34(8):904–909

    Article  CAS  Google Scholar 

  83. Vogt G et al (2005) Gains of glycosylation comprise an unexpectedly large group of pathogenic mutations. Nat Genet 37(7):692–700

    Article  CAS  Google Scholar 

  84. Vogt G et al (2008) Complementation of a pathogenic IFNGR2 misfolding mutation with modifiers of N-glycosylation. J Exp Med 205(8):1729–1737

    Article  CAS  Google Scholar 

  85. Bandari AK et al (2019) A novel splice site mutation in IFNGR2 in patients with primary immunodeficiency exhibiting susceptibility to mycobacterial diseases. Front Immunol 10:1964

    Article  CAS  Google Scholar 

  86. Moncada-Velez M et al (2013) Partial IFN-gammaR2 deficiency is due to protein misfolding and can be rescued by inhibitors of glycosylation. Blood 122(14):2390–2401

    Article  CAS  Google Scholar 

  87. Doffinger R et al (2000) Partial interferon-gamma receptor signaling chain deficiency in a patient with bacille Calmette-Guerin and Mycobacterium abscessus infection. J Infect Dis 181(1):379–384

    Article  CAS  Google Scholar 

  88. Oleaga-Quintas C et al (2018) A purely quantitative form of partial recessive IFN-gammaR2 deficiency caused by mutations of the initiation or second codon. Hum Mol Genet 27(22):3919–3935

    CAS  Google Scholar 

  89. Kong XF et al (2013) Haploinsufficiency at the human IFNGR2 locus contributes to mycobacterial disease. Hum Mol Genet 22(4):769–781

    Article  CAS  Google Scholar 

  90. Rieux-Laucat F, Casanova JL (2014) Immunology. Auto immunity Haplo Insufficiency Sci 345(6204):1560–1561

    CAS  Google Scholar 

  91. Kerner G et al (2020) Inherited human IFN-gamma deficiency underlies mycobacterial disease. J Clin Invest 130(6):3158–3171

    Article  CAS  Google Scholar 

  92. de Weerd NA, Nguyen T (2012) The interferons and their receptors–distribution and regulation. Immunol Cell Biol 90(5):483–491

    Article  Google Scholar 

  93. Eletto D et al (2016) Biallelic JAK1 mutations in immunodeficient patient with mycobacterial infection. Nat Commun 7:13992

    Article  CAS  Google Scholar 

  94. Daza-Cajigal V et al (2019) Loss of janus associated kinase 1 alters urothelial cell function and facilitates the development of bladder cancer. Front Immunol. https://doi.org/10.3389/fimmu.2019.02065

    Article  Google Scholar 

  95. Boisson-Dupuis S et al (2012) Inborn errors of human STAT1: allelic heterogeneity governs the diversity of immunological and infectious phenotypes. Curr Opin Immunol 24(4):364–378

    Article  CAS  Google Scholar 

  96. Mizoguchi Y, Okada S (2021) Inborn errors of STAT1 immunity. Curr Opin Immunol 72:59–64

    Article  CAS  Google Scholar 

  97. Chapgier A et al (2009) A partial form of recessive STAT1 deficiency in humans. J Clin Invest 119(6):1502–1514

    Article  CAS  Google Scholar 

  98. Dupuis S et al (2003) Impaired response to interferon-alpha/beta and lethal viral disease in human STAT1 deficiency. Nat Genet 33(3):388–391

    Article  CAS  Google Scholar 

  99. Vairo D et al (2011) Severe impairment of IFN-gamma and IFN-alpha responses in cells of a patient with a novel STAT1 splicing mutation. Blood 118(7):1806–1817

    Article  CAS  Google Scholar 

  100. Le Voyer T et al (2021) Genetic, immunological, and clinical features of 32 patients with autosomal recessive STAT1 deficiency. J Immunol 207(1):133–152

    Article  Google Scholar 

  101. Karakawa S et al (2021) Successful hematopoietic stem cell transplantation for autosomal recessive STAT1 complete deficiency. J Clin Immunol 41(3):684–687

    Article  Google Scholar 

  102. Dupuis S et al (2001) Impairment of mycobacterial but not viral immunity by a germline human STAT1 mutation. Science 293(5528):300–303

    Article  CAS  Google Scholar 

  103. Hirata O et al (2013) Heterozygosity for the Y701C STAT1 mutation in a multiplex kindred with multifocal osteomyelitis. Haematologica 98(10):1641–1649

    Article  CAS  Google Scholar 

  104. Sampaio EP et al (2012) A novel STAT1 mutation associated with disseminated mycobacterial disease. J Clin Immunol 32(4):681–689

    Article  CAS  Google Scholar 

  105. Tsumura M et al (2012) Dominant-negative STAT1 SH2 domain mutations in unrelated patients with Mendelian susceptibility to mycobacterial disease. Hum Mutat 33(9):1377–1387

    Article  CAS  Google Scholar 

  106. Chapgier A et al (2006) Novel STAT1 alleles in otherwise healthy patients with mycobacterial disease. PLoS Genet 2(8):e131

    Article  Google Scholar 

  107. Holtschke T et al (1996) Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene. Cell 87(2):307–317

    Article  CAS  Google Scholar 

  108. Marquis JF et al (2011) Interferon regulatory factor 8 regulates pathways for antigen presentation in myeloid cells and during tuberculosis. PLoS Genet 7(6):e1002097

    Article  CAS  Google Scholar 

  109. Hambleton S et al (2011) IRF8 mutations and human dendritic-cell immunodeficiency. N Engl J Med 365(2):127–138

    Article  CAS  Google Scholar 

  110. Salem S, Gros P (2013) Genetic determinants of susceptibility to Mycobacterial infections: IRF8, a new kid on the block. Adv Exp Med Biol 783:45–80

    Article  CAS  Google Scholar 

  111. Mace EM et al (2017) Biallelic mutations in IRF8 impair human NK cell maturation and function. J Clin Invest 127(1):306–320

    Article  Google Scholar 

  112. Rosain J et al (2022) Pulmonary alveolar proteinosis and multiple infectious diseases in a child with autosomal recessive complete IRF8 deficiency. J Clin Immunol. https://doi.org/10.1007/s10875-022-01250-4

    Article  Google Scholar 

  113. Voss M, Schroder B, Fluhrer R (2013) Mechanism, specificity, and physiology of signal peptide peptidase (SPP) and SPP-like proteases. Biochim Biophys Acta 1828(12):2828–2839

    Article  CAS  Google Scholar 

  114. Kong XF et al (2018) Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency. Nat Immunol 19(9):973–985

    Article  CAS  Google Scholar 

  115. Bustamante J et al (2007) A novel X-linked recessive form of Mendelian susceptibility to mycobaterial disease. J Med Genet 44(2):e65

    Article  Google Scholar 

  116. Bustamante J et al (2011) Germline CYBB mutations that selectively affect macrophages in kindreds with X-linked predisposition to tuberculous mycobacterial disease. Nat Immunol 12(3):213–221

    Article  CAS  Google Scholar 

  117. Oeckinghaus A, Hayden MS, Ghosh S (2011) Crosstalk in NF-kappaB signaling pathways. Nat Immunol 12(8):695–708

    Article  CAS  Google Scholar 

  118. Zhang Q, Lenardo MJ, Baltimore D (2017) 30 Years of NF-kappaB: a blossoming of relevance to human pathobiology. Cell 168(1–2):37–57

    Article  CAS  Google Scholar 

  119. Zonana J et al (2000) A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO). Am J Hum Genet 67(6):1555–1562

    Article  CAS  Google Scholar 

  120. Filipe-Santos O et al (2006) X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production. J Exp Med 203(7):1745–1759

    Article  CAS  Google Scholar 

  121. Bogunovic D et al (2012) Mycobacterial disease and impaired IFN-gamma immunity in humans with inherited ISG15 deficiency. Science 337(6102):1684–1688

    Article  CAS  Google Scholar 

  122. Zhang X et al (2015) Human intracellular ISG15 prevents interferon-alpha/beta over-amplification and auto-inflammation. Nature 517(7532):89–93

    Article  CAS  Google Scholar 

  123. Martin-Fernandez M et al (2020) Systemic type I IFN inflammation in human ISG15 deficiency leads to necrotizing skin lesions. Cell Rep 31(6):107633

    Article  CAS  Google Scholar 

  124. Buda G et al (2020) Inflammatory cutaneous lesions and pulmonary manifestations in a new patient with autosomal recessive ISG15 deficiency case report. Allergy Asthma Clin Immunol 16:77

    Article  CAS  Google Scholar 

  125. Malakhova OA et al (2006) UBP43 is a novel regulator of interferon signaling independent of its ISG15 isopeptidase activity. EMBO J 25(11):2358-2367

    Article  CAS  Google Scholar 

  126. Alsohime F et al (2020) JAK inhibitor therapy in a child with inherited USP18 deficiency. N Engl J Med 382(3):256–265

    Article  CAS  Google Scholar 

  127. Meuwissen ME et al (2016) Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome. J Exp Med 213(7):1163–1174

    Article  Google Scholar 

  128. Vavassori S et al (2021) Multisystem inflammation and susceptibility to viral infections in human ZNFX1 deficiency. J Allergy Clin Immunol 148(2):381–393

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

Not applicable.

Author information

Authors and Affiliations

Authors

Contributions

AER conceptualized and wrote the manuscript. JE did the initial review and corrected the manuscript. LA did a second review and give his opinion. JB and SBD revised and corrected the text and completed references. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Abderrahmane Errami.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Errami, A., El Baghdadi, J., Ailal, F. et al. Mendelian susceptibility to mycobacterial disease: an overview. Egypt J Med Hum Genet 24, 7 (2023). https://doi.org/10.1186/s43042-022-00358-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s43042-022-00358-x

Keywords

  • Mycobacterial diseases
  • Monogenic
  • Inborn errors of immunity
  • Mendelian susceptibility
  • IFN-γ