Alternative titles; symbols
HGNC Approved Gene Symbol: IFNG
Cytogenetic location: 12q15 Genomic coordinates (GRCh38): 12:68,154,768-68,159,740 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q15 | ?Immunodeficiency 69, mycobacteriosis | 618963 | Autosomal recessive | 3 |
| {AIDS, rapid progression to} | 609423 | 3 | ||
| {Aplastic anemia} | 609135 | 3 | ||
| {Hepatitis C virus, response to therapy of} | 609532 | 3 | ||
| {TSC2 angiomyolipomas, renal, modifier of} | 613254 | Autosomal dominant | 3 | |
| {Tuberculosis, protection against} | 607948 | 3 |
Interferon-gamma (IFNG), or type II interferon, is a cytokine critical for innate and adaptive immunity against viral and intracellular bacterial infections and for tumor control. Aberrant IFNG expression is associated with a number of autoinflammatory and autoimmune diseases. The importance of IFNG in the immune system stems in part from its ability to inhibit viral replication directly, but most importantly derives from its immunostimulatory and immunomodulatory effects. IFNG is produced predominantly by natural killer (NK) and natural killer T (NKT) cells as part of the innate immune response, and by CD4 (186940) and CD8 (see 186910) cytotoxic T lymphocyte (CTL) effector T cells once antigen-specific immunity develops (Schoenborn and Wilson, 2007).
Naylor et al. (1983) determined that the 146-amino acid sequence of mature gamma-interferon, deduced from the nucleotide sequence of cloned cDNA, is unrelated to the sequences of other interferons.
Gray and Goeddel (1982) found that the immune interferon gene contains 4 exons, a repetitive DNA element, and a low order of polymorphism. There appeared to be a single gene; resolution of gamma-interferon into 2 components (Yip et al., 1982) probably reflects posttranslational processing. Naylor et al. (1983) noted that gamma-interferon differs from the alpha- and beta-interferons (which are on 9p and have no introns) by the presence of 3 introns.
Naylor et al. (1983) found that the gamma-interferon gene is on chromosome 12. By in situ hybridization, Trent et al. (1982) assigned the IFI gene to chromosome 12q24.1.
On both the physical and the genetic maps of chromosome 12, Bureau et al. (1995) mapped the IFG gene close to the D12S335 and D12S313 microsatellites. They also physically mapped it close to the locus of the MDM2 oncogene (164875) on 12q15, a localization proximal to that arrived at earlier.
By FISH, Zimonjic et al. (1995) mapped the IFNG gene to chromosome 12q14. This correction of the previous localization resolved the discrepancy between the syntenic maps of human chromosome 12 and mouse 10.
Justice et al. (1990) showed that the mouse Ifng gene is located on chromosome 10. Using RFLVs in multipoint backcrosses, Shimizu et al. (1992) determined the map position of the Ifng gene in relation to other genes on mouse chromosome 10.
Bureau et al. (1995) described the organization of the Ifng, Myf6, Mdm1 (613813), and Mdm2 loci on mouse chromosome 10 in a region with homology of synteny to human 12q15.
Luster et al. (1985) showed that gamma-interferon regulates the INP10 gene (147310), which encodes a protein with amino acid homology to platelet factor-4 (PF4; 173460) and beta-thromboglobulin (see PPBP; 121010).
Tzoneva et al. (1988) found failure of phytohemagglutinin-induced gamma-IFN synthesis in lymphocyte cultures in a Bulgarian brother and sister, aged 18 and 16 years, respectively. Both had had recurrent infections and showed selective IgA deficiency and reduced blast transformation index under PHA stimulation. Recurrent 'flu' was complicated at times in both of them by a painless swelling of the carotid gland on one or both sides. Both had had 'butterfly rubella' in early childhood and an appendectomy. Furthermore, both had oxalate renal stones.
Expression of HLA-DR antigen (see 142860) and intracellular adhesion molecule-1 (ICAM1; 147840) in human conjunctival epithelium is upregulated in patients with dry eyes associated with Sjogren syndrome (270150). Tsubota et al. (1999) reported that this upregulation in Sjogren syndrome patients may be controlled by interferon-gamma through the activation of transcription factor NFKB (nuclear factor kappa-B; see 164011).
Diefenbach et al. (1999) studied the relationship of IL12 (see 161561) and nitric oxide synthase-2 (NOS2A; 163730), also known as inducible NOS (iNOS), to innate immunity to the parasite Leishmania in mice. In the absence of iNOS activity, IL12 was unable to prevent spreading of Leishmania parasites, did not stimulate natural killer cells for cytotoxicity or interferon-gamma release, and failed to activate TYK2 (176941) and to tyrosine-phosphorylate STAT4, the central signal transducer of IL12, in NK cells. Activation of TYK2 in NK cells by IFN-alpha/beta (type I interferon) also required iNOS. Thus, iNOS-derived NO is a prerequisite for cytokine signaling and function in innate immunity.
Takayanagi et al. (2000) demonstrated that T-cell production of IFNG strongly suppresses osteoclastogenesis by interfering with the RANKL (602642)-RANK (603499) signaling pathway. IFNG induces rapid degradation of the RANK adaptor protein, TRAF6 (602355), resulting in strong inhibition of the RANKL-induced activation of the transcription factor NFKB and JNK (601158). This inhibition of osteoclastogenesis could be rescued by overexpressing TRAF6 in precursor cells, indicating that TRAF6 is the target critical for the IFNG action. Furthermore, Takayanagi et al. (2000) provided evidence that the accelerated degradation of TRAF6 requires both its ubiquitination, which is initiated by RANKL, and IFNG-induced activation of the ubiquitin-proteasome system. Takayanagi et al. (2000) concluded that there is crosstalk between the tumor necrosis factor (TNF; 191160) and IFN families of cytokines, through which IFNG provides a negative link between T-cell activation and bone resorption.
Cryptosporidiosis presents as a self-limited diarrhea after infection with the protozoan C. parvum in healthy hosts. In immunocompromised individuals, however, infection leads to a chronic and often fatal illness for which there is no direct treatment. In studies with experimentally infected healthy volunteers, White et al. (2000) detected IFNG expression predominantly in previously exposed individuals, with serum IgG specific for C. parvum in lamina propria lymphocytes after reinfection. IFNG expression was not detected in AIDS patients. IFNG expression in the healthy individuals occurred early after infection, and stronger expression was associated with greater resistance to symptomatic infection and reduced oocyst excretion. White et al. (2000) concluded that IFNG expression in the intestinal mucosa is important in controlling parasite burden and preventing chronic disease.
Zohlnhofer et al. (2001) investigated the expression of 2,435 genes in atherectomy specimens and blood cells of patients with restenosis, normal coronary artery specimens, and cultured human smooth muscle cells (SMCs). Of the 223 differentially expressed genes, 37 genes indicated activation of IFNG signaling in neointimal SMCs. In cultured SMCs, IFNG inhibited apoptosis. Genetic disruption of Ifng signaling in a mouse model of restenosis significantly reduced the vascular proliferative response.
Binder and Griffin (2001) observed that antibody-deficient mice could recover from alphaviral (Sindbis virus) encephalomyelitis by using Ifng, but not Tnfa (191160), secreted by CD4-positive and CD8-positive T cells. They found that Ifng mediated noncytolytic viral clearance from spinal cord and brainstem, and at least reduced the amount of virus in brain, indicating that neurons are heterogeneous in their responses to Ifng.
Tbet is a member of the T-box family of transcription factors that appears to regulate lineage commitment in CD4 T helper cells in part by activating the hallmark T(H)1 cytokine, IFNG. IFNG is also produced by NK cells and most prominently by CD8 cytotoxic T cells, and is vital for the control of microbial pathogens. Although Tbet is expressed in all these cell types, Szabo et al. (2002) demonstrated that it is required for control of IFNG production in CD4 and NK cells, but not in CD8 cells. This difference is also apparent in the function of these cell subsets. Thus, Szabo et al. (2002) concluded that the regulation of a single cytokine, IFNG, is controlled by distinct transcriptional mechanisms within the T cell lineage. Szabo et al. (2002) studied mice deficient in Tbet and established that Tbet is a transcription factor required for T(H)1 lineage commitment.
PKR (176871), an interferon-inducible protein kinase activated by double-stranded RNA, inhibits translation by phosphorylating eIF2-alpha (603907). Ben-Asouli et al. (2002) showed that human IFNG mRNA uses local activation of PKR in the cell to control its own translation yield. IFNG mRNA was found to activate PKR through a pseudoknot in its 5-prime untranslated region. Mutations that impaired pseudoknot stability reduced the ability to activate PKR and strongly increased the translation efficiency of IFNG mRNA. Nonphosphorylatable mutant eIF2-alpha, knockout of PKR, and the PKR inhibitors 2-aminopurine, transdominant-negative PKR, or vaccinia E3L correspondingly enhanced translation of IFNG mRNA. The potential to form the pseudoknot was found to be phylogenetically conserved. Ben-Asouli et al. (2002) proposed that the RNA pseudoknot acts to adjust translation of IFNG mRNA to the PKR level expressed in the cell.
Fields et al. (2002) noted that high levels of histone acetylation at particular loci correlate with transcriptional activity, whereas reduced levels correlate with silencing. Using chromatin immunoprecipitation (ChIP), PCR, and green fluorescent protein analysis, they demonstrated that histones in the cytokine loci (IFNG; IL4, 147780) of naive T cells are unacetylated, but upon TCR stimulation, the loci are rapidly and progressively acetylated on histones H3 and H4. The acetylation at the IL4 locus occurs early, regardless of Th1/Th2 polarizing conditions, correlating with early transcription. The maintenance of acetylation depends on cytokine and STAT4 (600558) and STAT6 (601512) signaling and also on the transactivator activity of TBET (604895) and GATA3 (131320), the putative 'master regulators' of Th lineage determination.
Messi et al. (2003) showed that under conditions priming CD4-positive T cells to become either Th1 cells preferentially expressing a subset of cytokines, particularly IFNG, or Th2 cells expressing a different subset of cytokines, particularly interleukin-4 (IL4; 147780), naive and effector memory T cells acquire polarized cytokine gene acetylation patterns. They stated that commitment of T cells to either the Th1 or Th2 lineage requires upregulation of the fate-determining transcription factors TBET and GATA3, respectively. Whereas histone hyperacetylation of IFNG and IL4 promoters in Th1 and Th2 cells, respectively, was stable, central memory T cells had hypoacetylated cytokine genes that became hyperacetylated upon polarization after appropriate stimulation. However, all Th1 and most Th2 cells tested could express the alternative cytokine when stimulated under opposite Th conditions. Messi et al. (2003) concluded that most human CD4-positive T cells retain both memory and flexibility of cytokine gene expression.
The T helper cell 1 and 2 (T(H)1 and T(H)2) pathways, defined by cytokines IFN-gamma and IL4, respectively, comprise 2 alternative CD4+ T-cell fates, with functional consequences for the host immune system. These cytokine genes are encoded on different chromosomes. The T(H)2 locus control region (LCR) coordinately regulates the T(H)2 cytokine genes by participating in a complex between the LCR and promoters of the cytokine genes IL4, IL5 (147850), and IL13 (147683). Although they are spread over 120 kb, these elements are closely juxtaposed in the nucleus in a poised chromatin conformation. In addition to these intrachromosomal interactions, Spilianakis et al. (2005) described interchromosomal interactions between the promoter region of the IFN-gamma gene on chromosome 10 and the regulatory regions of the T(H)2 cytokine locus on chromosome 11. DNase I hypersensitive sites that comprise the T(H)2 LCR developmentally regulate these interchromosomal interactions. Furthermore, there seems to be a cell type-specific dynamic interaction between interacting chromatin partners whereby interchromosomal interactions are apparently lost in favor of intrachromosomal ones upon gene activation. Thus, Spilianakis et al. (2005) provided an example of eukaryotic genes located on separate chromosomes associating physically in the nucleus via interactions that may have a function in coordinating gene expression.
Chang and Aune (2005) compared long-range histone hyperacetylation patterns across the Ifng gene in mouse T cells and NK cells in the resting state and after induction of Ifng gene transcription by stimulation with Il12 (see 161560) and/or Il18 (600953). In T cells, long-range histone acetylation depended on stimulation that drove both Th1 differentiation and active transcription, and it depended on the presence of Stat4 and Tbet, transcription factors required for Th1 lineage commitment. Binding of these factors was not observed in Th2 cells. In NK cells, similar histone hyperacetylated domains were found in the absence of stimulation and active transcription, and additional proximal domains were hyperacetylated after transcription stimulation. Chang and Aune (2005) proposed that formation of extended histone hyperacetylated domains across the Ifng region marks this gene for cell- or stimulus-specific transcription.
Bai et al. (2008) investigated the effects of IFNG on vascular smooth muscle cells (VSMCs) through interactions involving STAT proteins. They found that IFNG stimulation phosphorylated both STAT1 (600555) and STAT3 (102582) in human VSMCs, but not in mouse VSMCs or human endothelial cells. Activation by IFNG induced STAT3 translocation to the nucleus. Microarray analysis identified signaling candidates that were inducible by IFNG and dependent on STAT3, and RT-PCR and immunoblot analyses verified roles for XAF1 (606717) and NOXA (PMAIP1; 604959). STAT3 activation sensitized VSMCs to apoptosis triggered by both death receptor- and mitochondria-mediated pathways. Knockdown of XAF1 and NOXA expression inhibited priming of VSMCs to apoptotic stimuli by IFNG. Immunodeficient mice with human coronary artery grafts were susceptible to the proapoptotic effects of XAF1 and NOXA induced by IFNG. Bai et al. (2008) concluded that STAT1-independent signaling by IFNG via STAT3 promotes death of VSMCs.
Mukhopadhyay et al. (2008) noted that phosphorylation of ribosomal protein L13A (RPL13A; 619225) is essential for translational repression of inflammatory genes by the IFN-gamma-activated inhibitor of translation (GAIT) complex. They found that IFN-gamma activated a kinase cascade in which DAPK (DAPK1; 600831) activated ZIPK (DAPK3; 603289), which then phosphorylated RPL13A at ser77 in human U937 cells. RPL13A phosphorylation by DAPK-ZIPK was not only required for activation of RPL13A and subsequent release from the ribosome, but also for GAIT-mediated translational silencing. GAIT-mediated translational silencing then targeted and repressed DAPK and ZIPK expression to return RPL13A to the nonphosphorylated, inactive form. This negative-feedback circuit restored cells to the basal state, allowing subsequent renewed induction of GAIT target transcripts by repeated stimulation.
Zaidi et al. (2011) introduced a mouse model permitting fluorescence-aided melanocyte imaging and isolation following in vivo UV irradiation. They used expression profiling to show that activated neonatal skin melanocytes isolated following a melanomagenic UVB dose bear a distinct, persistent interferon response signature, including genes associated with immunoevasion. UVB-induced melanocyte activation, characterized by aberrant growth and migration, was abolished by antibody-mediated systemic blockade of IFN-gamma, but not type I interferons. IFN-gamma was produced by macrophages recruited to neonatal skin by UVB-induced ligands to the chemokine receptor Ccr2 (601267). Admixed recruited skin macrophages enhanced transplanted melanoma growth by inhibiting apoptosis; notably, IFN-gamma blockade abolished macrophage-enhanced melanoma growth and survival. IFN-gamma-producing macrophages were also identified in 70% of human melanomas examined. Zaidi et al. (2011) concluded that their data revealed an unanticipated role for IFN-gamma in promoting melanocytic cell survival/immunoevasion, identifying a novel candidate therapeutic target for a subset of melanoma patients.
Using an approach that combined the in vitro priming of naive T cells with the ex vivo analysis of memory T cells, Zielinski et al. (2012) described 2 types of human TH17 cells with distinct effector function and differentiation requirements. Candida albicans-specific TH17 cells produced IL17 (603149) and IFN-gamma but no IL10 (124092), whereas Staphylococcus aureus-specific TH17 cells produced IL17 and could produce IL10 upon restimulation. IL6 (147620), IL23 (see 605580), and IL1-beta (147720) contributed to TH17 differentiation induced by both pathogens, but IL1-beta was essential in C. albicans-induced TH17 differentiation to counteract the inhibitory activity of IL12 (see 161561) and to prime IL17/IFN-gamma double-producing cells. In addition, IL1-beta inhibited IL10 production in differentiating and in memory TH17 cells, whereas blockade of IL1-beta in vivo led to increased IL10 production by memory TH17 cells. Zielinski et al. (2012) showed that, after restimulation, TH17 cells transiently downregulated IL17 production through a mechanism that involved IL2 (147680)-induced activation of STAT5 (601511) and decreased expression of ROR-gamma-t (see 602943). Zielinski et al. (2012) concluded that, taken together, their findings demonstrated that by eliciting different cytokines, C. albicans and S. aureus prime TH17 cells that produce either IFN-gamma or IL10, and identified IL1-beta and IL2 as pro- and antiinflammatory regulators of TH17 cells both at priming and in the effector phase.
Braumuller et al. (2013) showed that the combined action of the T helper-1-cell cytokines IFNG and tumor necrosis factor (TNF; 191160) directly induces permanent growth arrest in cancers. To safely separate senescence induced by tumor immunity from oncogene-induced senescence, Braumuller et al. (2013) used a mouse model in which the Simian virus-40 large T antigen (Tag) expressed under the control of the rat insulin promoter creates tumors by attenuating p53 (191170)- and Rb (614041)-mediated cell cycle control. When combined, Ifng and Tnf drive Tag-expressing cancers into senescence by inducing permanent growth arrest in G1/G0, activation of p16Ink4a (CDKN2A; 600160), and downstream Rb hypophosphorylation at ser795. This cytokine-induced senescence strictly requires Stat1 and Tnfr1 (TNFRSF1A; 191190) signaling in addition to p16Ink4a. In vivo, Tag-specific T-helper-1 cells permanently arrest Tag-expressing cancers by inducing Ifng- and Tnfr1-dependent senescence. Conversely, Tnfr1-null Tag-expressing cancers resist cytokine-induced senescence and grow aggressively, even in Tnfr1-expressing hosts. Braumuller et al. (2013) concluded that as IFNG and TNF induce senescence in numerous murine and human cancers, this may be a general mechanism for arresting cancer progression.
Using RT-PCR and immunohistochemistry, Teles et al. (2013) demonstrated increased expression of the type I interferon IFNB (IFNB1; 147640) in lesions of lepromatous leprosy (i.e., multibacillary, or L-lep) patients compared with tuberculoid leprosy (i.e., paucibacillary, or T-lep) patients (see 609888). Expression of an IFNB receptor, IFNAR1 (107450), was also increased in L-lep lesions. Increased expression of IFNB was associated with increased expression of IL10, and IFNB alone induced IL10 expression in mononuclear cells in vitro. There was an inverse correlation between IL10 expression and expression of the antimicrobial peptides CAMP (600474) and DEFB4 (DEFB4A; 602215). Measurement of uncultivable Mycobacterium leprae viability based on the ratio of M. leprae 16S rRNA to M. leprae repetitive element DNA indicated that IFNG induced antimicrobial activity against M. leprae in monocytes by about 35%, which was abrogated by the addition of either IFNB or IL10. Teles et al. (2013) concluded that the type I interferon gene expression program prominently expressed in L-lep lesions inhibits the IFNG-induced antimicrobial response against M. leprae through an intermediary, IL10.
Arbore et al. (2016) found that the NLRP3 (606416) inflammasome assembled in human CD4-positive T cells and initiated CASP1 (147678)-dependent IL1B secretion, thereby promoting IFNG production and Th1 differentiation in an autocrine fashion. NLRP3 assembly required intracellular C5 (120900) activation and stimulation of C5AR1 (113995), and this process was negatively regulated by C5AR2 (609949). Aberrant NLRP3 activity in T cells affected inflammatory responses in patients with cryopyrin-associated periodic syndrome (FCAS1; 120100) and in mouse models of inflammation and infection. Arbore et al. (2016) concluded that NLRP3 inflammasome activity is involved in normal adaptive Th1 responses, as well as in innate immunity.
Filiano et al. (2016) demonstrated that meningeal immunity is critical for social behavior; mice deficient in adaptive immunity exhibit social deficits and hyperconnectivity of frontocortical brain regions. Associations between rodent transcriptomes from brain and cellular transcriptomes in response to T cell-derived cytokines suggested a strong interaction between social behavior and IFN-gamma-driven responses. Concordantly, Filiano et al. (2016) demonstrated that inhibitory neurons respond to IFN-gamma and increase GABAergic (gamma-aminobutyric-acid) currents in projection neurons, suggesting that IFN-gamma is a molecular link between meningeal immunity and neural circuits recruited for social behavior. Metaanalysis of the transcriptomes of a range of organisms revealed that rodents, fish, and flies elevate IFN-gamma/JAK-STAT (see 600555)-dependent gene signatures in a social context, suggesting that the IFN-gamma signaling pathway could mediate a coevolutionary link between social/aggregation behavior and an efficient antipathogen response. Filiano et al. (2016) concluded that their study implicated adaptive immune dysfunction, in particular IFN-gamma, in disorders characterized by social dysfunction and suggested a coevolutionary link between social behavior and an antipathogen immune response driven by IFN-gamma signaling.
By treating mouse bone marrow-derived macrophages (BMDMs) with IFN-gamma followed by the TLR4 agonist lipopolysaccharide (LPS), Simpson et al. (2022) found that IFN-gamma activated macrophages and triggered cell death via TLR signaling and Fasl (FASLG; 134638) expression. Knockout analysis revealed that efficient IFN-gamma/LPS-induced cell death required caspase-8 (CASP8; 601763) and the mitochondrial apoptosis effector proteins Bax (600040) and Bak (BAK1; 600516). Activation of Bax and Bak was not triggered by caspase-8 cleavage of its substrate Bid (601997). Instead, caspase-8 mediated transcriptional programming in macrophages to increase proapoptotic Noxa and reduce prosurvival Bcl2 (151430), thereby reducing prosurvival proteins Mcl1 (159552) and A1 to facilitate Bax/Bak activation and subsequent apoptotic cell death upon stimulation with IFN-gamma and LPS. Caspase-8 enzymatic activity was required for IFN-gamma/LPS-mediated activation of Bax/Bak and subsequent apoptotic cell death. Bax/Bak activation resulted in irreversible damage to mitochondria and caused cell death even when the functions of other downstream caspases were eliminated. Treatment with IFN-gamma/LPS induced robust expression of iNos and generation of nitric oxide in macrophages, upstream of Bax/Bak activation and cell death. However, toxicity of nitric oxide was not the direct cause of cell death. Instead, iNos expression played a role in reducing Mcl1 and A1 to sensitize macrophages for Bax/Bak activation and mitochondrial apoptosis. In agreement, both iNos and caspase-8 contributed to disease severity of SARS-CoV-2 infection in mice, as deletion of iNos or caspase-8 limited SARS-CoV-2-induced disease, whereas caspase-8 caused lethality through hemophagocytic lymphohistiocytosis independently of iNos.
Reviews of IFNG Function
Schoenborn and Wilson (2007) reviewed the regulation of IFNG during innate and adaptive immune responses.
The first intron of the IFNG gene contains a CA microsatellite repeat that is highly polymorphic, with up to 6 alleles (variable number of CA dinucleotide repeats at position 1349; VNDR 1349). Allele 2, with 12 CA repeats (147470.0001), is associated with high levels of interferon-gamma production in vitro (Pravica et al., 1999), which may be due to its association with a nearby SNP within a putative NFKB (164011) binding site. This allele has been associated with higher or lower risk of a variety of diseases, including rheumatoid arthritis (RA; 180300) (Khani-Hanjani et al., 2000), allograft fibrosis in lung transplant recipients (Awad et al., 1999), and acute graft-versus-host disease (GVHD; see 614395) (Cavet et al., 2001) in bone marrow transplant recipients.
Dabora et al. (2002) found that the frequency of the intron 1 allele 2, with 12 CA repeats, of the IFNG gene in patients with tuberous sclerosis (613254) with mutations in the TSC2 gene (191092) was significantly higher in those without kidney angiomyolipomas than in those with kidney angiomyolipomas.
Interferon-gamma mediates the final damage of the stem cell compartment in aplastic anemia (609135). Dufour et al. (2004) studied the distribution of the VNDR 1349 polymorphism of IFNG in 67 Caucasian patients with aplastic anemia and in normal controls. Homozygosity for allele 2 (12 repeats on each chromosome) or the 12 repeats on only 1 chromosome were significantly more frequent (p = 0.005 and 0.004, respectively) in patients versus controls. The polymorphism was equally distributed in aplastic anemia patients regardless of their response to immunosuppression. Dufour et al. (2004) concluded that homozygosity for 12 CA repeats at position 1349 of the IFNG gene is strongly associated with the risk of aplastic anemia in Caucasian subjects.
To test the hypothesis that a polymorphism in IFNG is associated with susceptibility to tuberculosis (TB), Rossouw et al. (2003) conducted 2 independent studies. In a case-control study of 313 tuberculosis cases, they noted a significant association between a polymorphism (+874A-T; 147570.0002) in IFNG and protection against tuberculosis (607948) in a South African population (p = 0.0055). This finding was replicated in a family-based study, in which the transmission disequilibrium test was used in 131 families (p = 0.005). The transcription factor NF-kappa-B (NFKB1; 164011) binds preferentially to the +874T allele, which was overrepresented in controls, suggesting that genetically-determined variability in IFNG and expression might be important for the development of tuberculosis.
In a case-control study of 682 TB patients and 619 controls from 3 West African countries (Gambia, Guinea-Bissau, and Guinea-Conakry), Cooke et al. (2006) observed the IFNG +874AA genotype more frequently in TB patients than controls, but the trend was not statistically significant. However, the +874A-T SNP was in strong linkage disequilibrium with 2 other SNPs, -1616G-A and +3234T-C, and both the -1616GG and +3234TT genotypes were significantly associated with TB. Haplotype analysis in a smaller Gambian population sample showed that the 3 alleles putatively associated with TB were all found on the most common West African haplotype, which, although overtransmitted, was not significantly associated with disease in this smaller population. Cooke et al. (2006) concluded that there is a significant role for genetic variation in IFNG in susceptibility to TB.
Huang et al. (2007) genotyped 8 SNPs spanning the entire 5.4-kb IFNG gene in 2 large cohorts of hepatitis C virus (HCV; see 609532)-positive patients, one consisting of IFNA (147660)-treated patients, and the other consisting of intravenous drug users who had spontaneously cleared HCV infection or who had chronic HCV infection. One SNP, a C-to-G change at position -764 (147570.0004; rs2069707) in the proximal promoter region next to the binding motif for HSF1 (140580), was significantly associated with sustained virologic response to IFNA therapy in the first cohort and with spontaneous recovery in the second cohort. Luciferase reporter and EMSA analyses showed that the -764G allele had 2- to 3-fold higher promoter activity and stronger binding affinity for HSF1 than the -764C allele. Huang et al. (2007) concluded that the -764C-G SNP is functionally important in determining viral clearance and treatment response in HCV-infected patients.
Autosomal Recessive Immunodeficiency 69
In 2 patients from a large consanguineous kindred of Lebanese descent with autosomal recessive immunodeficiency-69 (IMD69; 618963) manifest as increased susceptibility to mycobacterial disease, Kerner et al. (2020) identified a homozygous frameshift mutation in the IFNG gene (147570.0005). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression studies of patient cells and cells transfected with the mutation showed that it resulted in a complete loss of function with impaired production of gamma-interferon in patient cells.
Diaz et al. (1993), with the approval of the Nomenclature Committee of the International Society of Interferon Research, tabulated the nomenclature for the human interferon genes.
Badovinac et al. (2000) showed that Ifng knockout mice failed to eliminate Listeria monocytogenes as rapidly as wildtype mice but had a higher number of antigen-specific cytotoxic CD8 cells due to the higher number of cells responding to relatively nonimmunodominant antigens, as measured by intracellular cytokine or MHC class I tetramer staining. In addition, there was little CD8-positive T-cell death after clearance of infection, as seen in wildtype mice. In mice that also had a disruption of the Prf1 gene (170280), there was a greater expansion of cytotoxic T cells, an equivalence of cells responding to dominant antigens, and an attenuated rate of T-cell death compared to wildtype. In contrast to Prf1 knockout mice, Badovinac et al. (2000) found that Ifng knockout mice cleared lymphocytic choriomeningitis virus as well as wildtype mice. Again, there was little CD8-positive T-cell death after clearance of infection. The authors proposed a number of hypotheses to test the basis of altered immunodominance, a poorly understood phenomenon, and reduced T-cell death in animals lacking Ifng. Badovinac et al. (2000) also proposed that their findings may suggest strategies for enhancing T-cell memory in response to vaccination.
In immunodeficient mice inoculated with human peripheral blood mononuclear cells, Koh et al. (2004) examined transplanted human arteries for endothelial cell and vascular smooth muscle cell dysfunction. Within 7 to 9 days, transplanted arteries developed endothelial cell dysfunction but remained sensitive to exogenous nitric oxide. By 2 weeks, the grafts developed signs of vascular smooth muscle cell dysfunction, including impaired contractility and desensitization to NO. These T-cell dependent changes correlated with loss of endothelial nitric oxide synthase (eNOS; 163729) and expression of iNOS. Neutralizing IFN-gamma completely prevented both vascular dysfunction and changes in NOS expression; neutralizing TNF reduced IFN-gamma production and partially prevented dysfunction. Inhibiting iNOS partially preserved responses to NO at 2 weeks and reduced graft intimal expansion after 4 weeks in vivo. Koh et al. (2004) concluded that IFN-gamma is a central mediator of vascular dysfunction through dysregulation of NO production.
Barton et al. (2007) showed that herpesvirus latency, always presumed to be parasitic as it leaves the host at risk for subsequent viral reactivation and disease, actually confers a surprising benefit to the host. Mice latently infected with either murine gammaherpesvirus-68 or murine cytomegalovirus, which are genetically highly similar to the human pathogens Epstein-Barr virus and human cytomegalovirus, respectively, were resistant to infection with the bacterial pathogens Listeria monocytogenes and Yersinia pestis. Latency-induced protection was not antigen-specific but involved prolonged production of the antiviral cytokine interferon-gamma and systemic activation of macrophages. Latency thereby upregulates the basal activation state of innate immunity against subsequent infections. Barton et al. (2007) speculated that herpesvirus latency may also sculpt the immune response to self and environmental antigens through establishment of a polarized cytokine environment. Thus, Barton et al. (2007) concluded that whereas the immune evasion capabilities and lifelong persistence of herpesviruses were commonly viewed as solely pathogenic, their data suggested that latency is a symbiotic relationship with immune benefits for the host.
Kosaka et al. (2008) used cecal cauterization to develop a unique experimental mouse model of intestinal adhesion. Mice developed severe intestinal adhesion after this treatment. Adhesion development depended upon the IFNG and STAT1 system. Natural killer T (NKT) cell-deficient mice developed adhesion poorly, whereas they developed severe adhesion after reconstitution with NKT cells from wildtype mice, suggesting that NKT cell IFNG production is indispensable for adhesion formation. This response does not depend on STAT4 (605989), STAT6 (601512), IL12 (see 161560), IL18 (600953), TNF-alpha, TLR4 (603030), or MYD88 (602170)-mediated signals. Wildtype mice increased the ratio of plasminogen activator inhibitor type-1 (PAI1; 173360) to tPA (173370) after cecal cauterization, whereas Ifng-null or Stat1-null mice did not, suggesting that IFNG has a crucial role in the differential regulation of PAI1 and tPA. Additionally, hepatocyte growth factor (HGF; 142409), a potent mitogenic factor for hepatocytes, strongly inhibited intestinal adhesion by diminishing IFNG production, providing a potential new way to prevent postoperative adhesions.
Using Ifng-deficient mice and Cxcl10-deficient mice, King et al. (2009) showed that the Ifng-Cxcl10 pathway inhibited abdominal aneurysm formation and promoted plaque formation. They proposed that cellular immunity may play different roles in these 2 vascular diseases.
Using mice lacking Ifngr1, Baldridge et al. (2010) showed that Ifng was required for activation of hemopoietic stem cells and restoration of hematopoietic stem cells expressing KSL (i.e., Kit (164920) and Sca1) and Cd150 (SLAMF1; 603492), as well neutrophils and lymphocytes, after infection with the chronic bacterial disease agent Mycobacterium avium. Experiments with Ifng -/- hematopoietic stem cells showed that Ifng stimulated hematopoietic stem cells even in the steady state, and suggested that baseline Ifng tone may influence hematopoietic stem cell turnover. Baldridge et al. (2010) concluded that IFNG is a regulator of hematopoietic stem cells during homeostasis and under conditions of infectious stress.
Barin et al. (2013) reported that mice lacking Ifng developed severe experimental autoimmune myocarditis (EAM) following immunization with cardiac myosin peptide (residues 614 to 629 of MYH6, 160710). In contrast, mice lacking Il17a were protected from progression to dilated cardiomyopathy. Double-knockout (DKO) mice lacking both Il17a and Ifng developed rapidly fatal EAM following immunization. Eosinophils constituted one-third of infiltrating leukocytes, allowing the condition to be characterized as eosinophilic myocarditis. Infection of DKO mice with coxsackie virus B3, which is associated with myocarditis in both humans and mouse models, resulted in a similar form of EAM. Flow cytometric analysis of infiltrating Cd4 T cells demonstrated production of Ccl11 (601156), as well as Th2 deviation. DKO mice that also carried a deletion of the high-affinity double GATA-binding site in the Gata1 (305371) promoter, which ablates eosinophil generation, demonstrated improved survival and were at least partially protected from fatal heart failure. Barin et al. (2013) concluded that eosinophils have the capacity to act as necessary mediators of morbidity in an autoimmune process.
Using bone marrow chimeric mice, Sa et al. (2015) showed that Ifng produced by brain-resident cells was essential for protective innate immune responses to restrict cerebral Toxoplasma gondii growth. Studies with transgenic mice expressing Ifng only in Cd11b (ITGAM; 120980)-positive cells showed that Ifng production by microglia, the only resident cells that express Cd11b in brain, was able to suppress T. gondii growth and recruit T cells to brain to control infection. Sa et al. (2015) proposed that IFNG production by brain-resident cells is crucial for protective innate and T cell-mediated immune responses to control cerebral infection with T. gondii.
Tissues of the nervous system are shielded from plasma proteins, such as antibodies, by the blood-brain and blood-nerve barriers. Iijima and Iwasaki (2016) examined the mechanisms by which circulating antibodies access neuronal tissues in a mouse model of genital herpes (HSV-2) infection. (Converse (2016) noted that others, such as Svensson et al. (2005) (see TBX21, 604895), have explored additional requirements for immune protection against HSV-2.) Iijima and Iwasaki (2016) found that memory Cd4-positive T cells migrated to dorsal root ganglia (DRG) harboring latent HSV-2 and released Ifng, leading to a local increase in vascular permeability that enabled antibody to access the DRG and control the virus. Mice lacking Ifngr1 were also more susceptible to intravaginal HSV-2 challenge. Depletion of Cd4 cells, but not Cd8 or natural killer cells, rendered mice unable to resist HSV-2 challenge or to respond effectively after intranasal vaccination. Iijima and Iwasaki (2016) concluded that the efficacy of circulating antibody-mediated protection requires CD4 T cells and IFNG.
TSC2 Renal Angiomyolipoma Modifier
Because interferon-gamma is a useful mediator of tumor regression in animal models of kidney tumors, and because allele 2 of the IFNG gene is known to be highly expressed in humans, Dabora et al. (2002) examined the influence of this IFNG genotype on the severity of renal disease in patients with tuberous sclerosis-2 (613254) who had mutations in the TSC2 gene (191092). The frequency of allele 2, with 12 CA repeats, was significantly higher in the patients without kidney angiomyolipomas than in those with kidney angiomyolipomas.
Susceptibility to Aplastic Anemia
Dufour et al. (2004) studied the distribution of the VNDR 1349 polymorphism of IFNG in 67 Caucasian aplastic anemia (609135) patients and in normal controls. Homozygosity for allele 2 (12 repeats on each chromosome) or the 12 repeats on only 1 chromosome were significantly more frequent (p = 0.005 and 0.004, respectively) in patients versus controls. The polymorphism was equally distributed in aplastic anemia patients regardless of their response to immunosuppression. Dufour et al. (2004) concluded that homozygosity for 12 CA repeats at position 1349 of the IFNG gene is strongly associated with the risk of aplastic anemia in Caucasian subjects.
A microsatellite polymorphism in the first intron of IFNG (147570.0001) has been associated with several autoimmune and chronic inflammatory conditions (Bream et al., 2000). One particular allele of this microsatellite (the 12 CA repeat) is associated with increased production of IFNG in vitro (Pravica et al., 2000), and with allograft fibrosis in recipients of lung transplant. This association might reflect a functional role in vivo for either the microsatellite itself or, perhaps more probably, a functional polymorphism in linkage disequilibrium with the 12 CA repeat. Directly adjacent to the CA repeat region in the first intron of IFNG is located a single-nucleotide polymorphism (+874A-T). The presence of the +874T allele and the 12 CA repeat allele was absolute (Pravica et al., 2000). The +874A-T polymorphism lies within a binding site for the transcription factor NF-kappa-B (164011) and electrophoretic mobility shift assays showed specific binding of NF-kappa-B to the allelic sequence containing the +874T allele. Since this transcription factor induces IFNG expression, the +874T and +874A alleles probably correlate with high and low interferon gamma expression, respectively. In an association study and in a family study using the transmission disequilibrium test, Rossouw et al. (2003) implicated the +874T allele in protection against tuberculosis (607948).
By meta-analysis of 11 studies using random effects models, Pacheco et al. (2008) determined that the IFNG +874T allele has a significant protective effect against tuberculosis.
An et al. (2003) reported an association between a SNP in the IFNG promoter region, a G-to-T change at position -173, and progression to AIDS (see 609423). In individuals with the rare -179T allele, but not in those with the -179G allele, IFNG is inducible by TNF (191160). An et al. (2003) studied 298 African American HIV-1 seroconverters and found that the -179T allele was associated with accelerated progression to a CD4 (186940) cell count below 200 and to AIDS. They noted that the SNP is present in 4% of African Americans and in only 0.02% of European Americans, and proposed that the increased IFNG production may cause CD4 depletion by apoptosis.
Huang et al. (2007) identified a SNP in the IFNG gene, a C-to-G change at position -764 (rs2069707) in the proximal promoter region next to the binding motif for HSF1 (140580), that was significantly associated with sustained virologic response to IFNA (147660) therapy in one cohort of hepatitis C virus (HCV; see 609532)-positive patients and with spontaneous recovery from HCV infection in another cohort of HCV-positive patients. Luciferase reporter and EMSA analyses showed that the -764G allele had 2- to 3-fold higher promoter activity and stronger binding affinity for HSF1 than the -764C allele. Huang et al. (2007) concluded that the -764C-G SNP is functionally important in determining viral clearance and treatment response in HCV-infected patients.
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