Alternative titles; symbols
HGNC Approved Gene Symbol: IL12B
Cytogenetic location: 5q33.3 Genomic coordinates (GRCh38): 5:159,314,780-159,330,487 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q33.3 | Immunodeficiency 29, mycobacteriosis | 614890 | Autosomal recessive | 3 |
The IL12 p40 subunit, or IL12B, heterodimerizes with the IL12 p35 subunit (IL12A; 161560) to form IL12 and with the IL23 p19 subunit (IL23A; 605580) to form IL23. In addition, IL12 p40 exists as a monomer and as a homodimer (IL12 p80) (Gunsten et al., 2008).
Gubler et al. (1991) cloned and expressed cDNAs for both subunits of IL12 from a lymphoblastoid B-cell line. They showed that their mRNAs are coordinately induced upon activation of these cells and that coexpression of the 2-subunit cDNAs in COS cells is necessary for the secretion of biologically active CLMF.
The generation of cell-mediated immunity against many infectious pathogens involves the production of interleukin-12, a key signal of the innate immune system. Yet, for many pathogens, the molecules that induce IL12 production by macrophages and the mechanisms by which they do so remain undefined. Brightbill et al. (1999) demonstrated that microbial lipoproteins are potent stimulators of IL12 production by human macrophages and that induction is mediated by toll-like receptors (TLRs; see 603030). Several lipoproteins stimulated TLR-dependent transcription of inducible nitric oxide synthase (NOS2; 163730) and the production of nitric oxide, a powerful microbicidal pathway. Activation of TLRs by microbial lipoproteins may initiate innate defense mechanisms against infectious pathogens.
Using immunoprecipitation analysis, Oppmann et al. (2000) determined that IL12B and p19 (605580) form a soluble cytokine/receptor complex, which they termed IL23. Immunoprecipitation and 2-dimensional SDS-PAGE analysis detected expression of high levels of IL23 in activated dendritic cells. Functional analysis determined that IL23 enhanced the secretion of gamma-interferon (IFNG; 147570) by memory (CD45RO) but not naive (CD45RA) T cells in an IL2 (147680)-dependent manner; however, this occurred at lower levels than in IL12-stimulated cells. Receptor-binding analysis established that IL23 and IL12 share IL12RB1 (601604), but that only IL12 binds to IL12RB2 (601642). However, IL23 stimulation does result in STAT4 (600558) activation at lower levels than those observed with IL12/IL12RB2 signaling, suggesting that IL23 has a unique receptor as well. Oppmann et al. (2000) pointed out that anti-IL12B antibodies used to evaluate IL12 in immunity and immunopathology do not discriminate between IL12 and IL23.
Psoriasis (see 177900) is characterized by the presence of IFNG and multiple IFN-related inflammatory genes in lesions. Because IL23 is involved in the recruitment of inflammatory cells in Th1-mediated diseases, Lee et al. (2004) examined psoriatic lesions for IL23 production. Quantitative RT-PCR detected significantly increased levels of IL23A and IL12B, but not IL12A, in psoriatic lesions compared with nonlesional skin. IL23 expression was found mainly in dermal cells of psoriatic lesions, particularly monocytes and mature dendritic cells, suggesting that IL23 plays a more dominant role than IL12 in psoriasis.
Schwarz et al. (2002) showed that preincubation of a variety of human cell lines with IL12 inhibited apoptosis induced by ultraviolet B (UVB) radiation, but not apoptosis induced by gamma irradiation. Immunohistochemistry revealed that intracutaneous injection of IL12 also reduced UVB-induced DNA damage and the number of sunburn cells in mouse skin. The number of apoptotic keratinocytes was higher in Il12a knockout mice than in controls. Because these protective effects of IL12 were not apparent immediately after UVB exposure, Schwarz et al. (2002) reasoned that IL12 might induce DNA repair. This conclusion was supported by comet assays, RNase protection analysis, and by the failure of Xpa (611153)-deficient mice, which are severely deficient in nucleotide excision repair capacity, to be protected by IL12 treatment. Schwarz et al. (2002) concluded that IL12 inhibits sunburn cell formation by reducing UVB-induced DNA damage and promoting DNA repair. They also proposed that overexpression of IL12 may be useful in preventing UV-induced skin cancer.
Ferlazzo et al. (2004) observed that peripheral blood natural killer (NK) cells have a CD56 (NCAM1; 116930)-dim/CD16 (FCGR3A; 146740)-positive phenotype and express perforin (170280), the natural cytotoxicity receptors (NCRs) NKp30 (NCR3; 611550) and NKp46 (NCR1; 604530), and, in part, killer cell Ig-like receptors (KIRs, see 604936). In contrast, lymph node NK cells have mainly a CD56-bright/CD16-negative phenotype and lack perforin, KIRs, and NCRs, except for low levels of NKp46. Tonsilar NK cells also lack perforin, KIRs, NKp30, and CD16, but partially express NKp44 (NCR2; 604531) and NKp46. Ferlazzo et al. (2004) found that IL2 stimulation leads lymph node and tonsilar NK cells to upregulate NCRs, express perforin, and acquire cytolytic activity for NK-sensitive target cells. In addition, they express CD16 and KIRs upon IL2 activation and therefore display a phenotype similar to peripheral blood NK cells. Ferlazzo et al. (2004) hypothesized that IL2 can mobilize NK cells of secondary lymphoid tissues to mediate natural killing during immune responses. They also showed that NK cells isolated from lymphoid tissues produce IFNG after activation by IL2 and IL12. The results suggested that secondary lymphoid organs are possible sites of NK-cell differentiation and self-tolerance acquisition.
Using immunofluorescent microscopy, Ferlazzo et al. (2004) demonstrated that NK cells and DEC205 (LY75; 604524)-positive dendritic cells (DCs) are localized in T- rather than B-cell areas of normal human lymph nodes. They showed that DEC205-positive DCs induce IFNG expression by lymph node NK cells through IL12, whereas IL15 (600554) expressed at the DC surface mediates lymph node NK cell proliferation.
Zheng et al. (2007) showed that IL22 (605330) is preferentially produced by Th17 cells and mediates the acanthosis induced by IL23. Zheng et al. (2007) found that IL23 or IL6 (147620) can directly induce the production of IL22 from both murine and human naive T cells. Moreover, the production of IL22 and IL17 from Th17 cells is differentially regulated. Transforming growth factor-beta (190180), although crucial for IL17 production, actually inhibits IL22 production. Furthermore, IL22 mediates IL23 induced acanthosis and dermal inflammation through the activation of STAT3 (102582) in vivo. Zheng et al. (2007) concluded that Th17 cells, through the production of both IL22 and IL17, might have essential functions in host defense and in the pathogenesis of autoimmune diseases such as psoriasis. IL22, as an effector cytokine produced by T cells, mediates the crosstalk between the immune system and epithelial cells.
Pang et al. (2007) investigated the expression of IL12B, IFNG, and the activational state of STAT4 signaling in mucosal tissues at the site of disease in 30 Chinese patients with active ulcerative colitis (UC; see 266600) compared with 30 healthy controls. They found increased mRNA expression of IL12B, but not IFNG, in the UC patients, and Western blot analysis demonstrated increased levels of STAT4 in the cytoplasm and phosphorylated STAT4 in the nucleus of mucosal cells from UC patients. The authors concluded that a heightened, perhaps persistent, activational state of IL12/STAT4 and/or IL23/STAT4 signaling may be present in active Chinese UC patients and may be involved in the chronic inflammation of UC.
Brain et al. (2013) detected upregulated expression of MIR29A (610782), MIR29B (see 610783), and MIR29C (610784) in human DCs stimulated with NOD2 (605956). They found that MIR29 regulated expression of multiple immune mediators. Notably, MIR29 downregulated IL23 by targeting its IL12p40 component directly and its IL23p19 component indirectly, most likely through a reduction of the transcription factor ATF2 (123811). Dextran sodium sulfate (DSS)-induced colitis was exacerbated in mice lacking Mir29 and was associated with elevated Il23 and Th17 cytokines in intestinal mucosa. DCs from Crohn disease patients expressing NOD2 polymorphisms failed to induce MIR29 after stimulation of pathogen pattern recognition receptors, and these DCs showed enhanced release of IL12p40 on exposure to adherent E. coli. Brain et al. (2013) proposed that loss of MIR29-mediated immune regulation in Crohn disease DCs may contribute to elevated IL23 in patients with the disease.
Huang et al. (2000) determined that the IL12B gene contains 8 exons, the first and last of which are noncoding.
The NKSF2 gene was one of 18 genes incorporated into a radiation hybrid map of the distal region of the long arm of chromosome 5 by Warrington et al. (1992). By PCR analysis of DNA from rodent/human cell hybrids containing intact chromosomes or translocation chromosomes, Sieburth et al. (1992) demonstrated that the IL12B gene maps to 5q31-q33. Warrington and Bengtsson (1994) used 3 physical mapping methods (radiation hybrid mapping, pulsed field gel electrophoresis, and fluorescence in situ hybridization of interphase nuclei) to determine the order and relative distances between 12 loci in the 5q31-q33 region. IL12B was one of those loci.
Gross (2014) mapped the IL12B gene to chromosome 5q33.3 based on an alignment of the IL12B sequence (GenBank AF180563) with the genomic sequence (GRCh38).
Noben-Trauth et al. (1996) mapped the Il12b gene to mouse chromosome 11.
Immunodeficiency 29
In a child they reported with curable BCG and Salmonella enteritidis infection (IMD29; 614890), Altare et al. (1998) found a large homozygous deletion (161561.0001) in the IL12B gene that precluded expression of functional IL12-p70 cytokine by activated dendritic cells and phagocytes. As a result, interferon-gamma production by lymphocytes was markedly impaired. This was said to be the first discovered human disease caused by a cytokine gene defect, suggesting that IL12 is essential to and appears specific for protective immunity to intracellular bacteria such as mycobacteria and salmonella.
In 1 kindred in India, Picard et al. (2002) identified the same large deletion (161561.0001) that was described by Altare et al. (1998) in a Pakistani child. In 4 kindreds in Saudi Arabia, Picard et al. (2002) found a recessive loss-of-function frameshift insertion (161561.0002). A conserved haplotype encompassing the IL12B gene suggested that a founder effect accounted for the recurrence of each mutation. The 2 founder mutational events, the deletion and the insertion, were estimated to have occurred approximately 700 and 1,100 years ago, respectively.
By flow cytometric analysis following mitogen activation of IL17 (603149)-expressing blood T cells from healthy controls or patients with particular genetic traits affecting various cytokine signaling pathways, de Beaucoudrey et al. (2008) found that there was considerable interindividual variability in IL17 expression in controls and most patient groups. However, dominant-negative mutations in STAT3 in patients with autosomal dominant hyper-IgE recurrent infection syndrome (147060) and, to a lesser extent, null mutations in IL12B or IL12RB1 (601604) in patients with mendelian susceptibility to mycobacterial disease impaired development of IL17-producing T cells.
Associations Pending Confirmation
For discussion of a possible association between variation in the IL12B gene and psoriasis, see PSORS11 (612599).
For discussion of a possible association between variation in the IL12B gene and psoriatic arthritis, see PSORAS1 (607507).
For a discussion of a possible association between variation in the IL12B gene and susceptibility to leprosy, see 609888.
Susceptibility to Type I Diabetes
Using linkage analysis with sib pairs in Australia, followed by stratification by sex and HLA status, Morahan et al. (2001) found an association of type 1 diabetes (see IDDM18, 605598) and a single base change in the 3-prime UTR (16974A-C) of IL12B in HLA-identical sibs. The finding was confirmed in an independent cohort of simplex families. Northern blot analysis showed allele-dependent expression of IL12B. Morahan et al. (2001) proposed that variable IL12B production may mediate or protect against type 1 diabetes.
Susceptibility to Asthma
In a cohort study involving 844 children in Australia, Morahan et al. (2002) found that heterozygosity for IL12B promoter polymorphisms contributes to asthma (see 600807) severity. The predisposing genotype is associated with reduced IL12B expression and IL12p70 secretion.
To test the hypothesis that the IL12B gene contains polymorphisms associated with asthma, Randolph et al. (2004) genotyped 6 haplotype-tagging polymorphisms in the IL12B gene in 708 children and in their parents. Using the family-based association test (FBAT) program, they tested each polymorphism and haplotype for association with asthma and asthma-related phenotypes. For replication, they tested positive associations in a case-control study comparing 177 adult moderate to severe asthmatics with 177 nonasthmatic controls. In whites in the initial cohort, the A allele of the IL12B 4237G-A polymorphism (161561.0003) was undertransmitted to asthmatic children, the global test for haplotypes for affection status was positive, and 2 polymorphisms were associated with different atopy phenotypes. Randolph et al. (2004) found a strong association between the 4237G-A and 6402A-C polymorphisms of IL12B and an asthma severity phenotype in white children, which they replicated in the independent population of white adult asthmatics.
Susceptibility to Gastric Carcinogenesis
IL12 favors T helper-1 (Th1) differentiation. Th1 lymphocytes prevail over Th2 in the chronic gastritis associated with H. pylori infection, the first step in H. pylori-associated gastric carcinogenesis. Navaglia et al. (2005) compared 110 patients with noncardia gastric cancer with 251 patients with benign gastroduodenal diseases to see whether there was any correlation between IL12 gene polymorphisms and H. pylori-associated gastric adenocarcinoma. They found that the frequency of noncardia gastric cancer was higher in patients with -504T/T homozygosity of IL12A (OR = 2.38) or with a particular VNTR of IL12B (OR = 1.36). No IL12 gene polymorphisms correlated with intestinal metaplasia. Navaglia et al. (2005) suggested that IL12A and IL12B gene polymorphisms may affect the final steps in gastric carcinogenesis in patients with H. pylori infection.
Susceptibility to Cerebral Malaria
Using a family-based association study with 240 Malian families, Marquet et al. (2008) investigated 21 markers in IL12-related genes for involvement in susceptibility to cerebral malaria (CM; 611162). They found that the IL12B promoter polymorphism rs17860508, in which GC is replaced with CTCTAA, was associated with susceptibility to CM. The CTCTAA allele and the GC/CTCTAA heterozygous genotype were associated with increased risk of CM (P of 0.0002 and 0.00002, respectively). Children with the GC/CTCTAA genotype had a higher risk of CM than children homozygous for either allele (odds ratio of 2.11; P less than 0.0001). Among 134 CM children with a heterozygous parent, a significant number received the CTCTAA allele. Marquet et al. (2008) noted that heterozygosity for rs17860508 is associated with reduced IL12B expression and reduced IL12 secretion, and that low IL12 and IFNG levels are associated with CM. They proposed that Th1 responses may reduce the parasite load and severe malaria risk.
Susceptibility to Crohn Disease
Wang et al. (2009) applied pathway analysis using Affymetrix SNP genotype data from the Wellcome Trust Case Control Consortium and uncovered significant association between Crohn disease (see 266600) and the IL12/IL23 pathway, harboring 20 genes (p = 8 x 10(-5)). Interestingly, the pathway contains multiple genes (IL12B and JAK2, 147796) or homologs of genes (STAT3, 102582 and CCR6, 601835) that had been identified as genuine susceptibility genes only through metaanalysis of several genomewide association studies. In addition, the pathway contains other susceptibility genes for Crohn disease, including IL18R1 (604494), JUN (165160), IL12RB1 (601604), and TYK2 (176941), which do not reach genomewide significance by single marker association tests. The observed pathway-specific association signal was subsequently replicated in 3 additional genomewide association studies of European and African American ancestry generated on the Illumina HumanHap550 platform. Wang et al. (2009) concluded that their study suggested that examination beyond individual SNP hits, by focusing on genetic networks and pathways, is important to realizing the true power of genomewide association studies. It was notable, however, that examination of this pathway failed to detect the well-known association between Crohn disease and NOD2 (605956).
Diefenbach et al. (1999) studied the relationship of IL12 and NOS2 to innate immunity to the parasite Leishmania in mice. In the absence of NOS2 activity, IL12 was unable to prevent spreading of Leishmania parasites, did not stimulate natural killer cells for cytotoxicity or interferon-gamma (147570) 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; see 107470) also required NOS2. Thus, NOS2-derived NO is a prerequisite for cytokine signaling and function in innate immunity.
Using female mice lacking either the Il12a or Il12b gene, Cooper et al. (2002) determined that both types of mice were more susceptible than wildtype mice to aerosol infection with virulent M. tuberculosis, but mice lacking Il12b were most susceptible and had increased mortality. This greater susceptibility for Il12b-deficient mice correlated with a reduced capacity to mount a delayed-type hypersensitivity response and a reduced ability to produce Ifng and to recruit activated lymphocytes (i.e., highly CD44 (107269)-positive) and Ifng-producing cells to the site of infection. RT-PCR analysis showed that the lungs of infected mice expressed increased levels of p19, a protein complexed with IL12B to form IL23. Expression of p19 was maintained longer in both types of knockout mice than in controls. Cooper et al. (2002) proposed that p19 may be produced by dendritic cells after ligation of TLR2 (603028) with a 19-kd lipoprotein of M. tuberculosis.
Using nonlethal microbial stimuli on Il12b-deficient mice, Jankovic et al. (2002) showed that although Th1-type cytokine production was diminished in the absence of Il12b, the pathogen-specific Cd4 (186940)-positive T cells that emerged nevertheless displayed an Ifng-dominated lymphokine profile and failed to default to a Th2 phenotype. In mice lacking both Il12b and Il10 (124092), these Th1 cells were protective. In contrast, in mice lacking Myd88 (602170), not only was a normal Th2-type response to Schistosoma mansoni antigens developed, but, in response to Toxoplasma gondii antigens, no Ifng was detected and the mice defaulted to a Th2-type response. Jankovic et al. (2002) proposed that microbial-induced Th1 polarization is determined during the initial encounter of pathogens with pattern recognition receptors (e.g., TLRs) on antigen-presenting cells. They concluded that IL12, however, does not determine Th1 versus Th2 phenotype.
Becher et al. (2002) found that p40 (IL12B) -/- mice showed no clinical evidence of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis, after immunization with myelin oligodendrocyte glycoprotein 35-55 (MOG). In contrast, p35 (IL12A) -/- mice were highly susceptible to EAE, with manifestations more severe than in wildtype mice, including severe central nervous system (CNS) inflammation. RT-PCR analysis of CNS-infiltrating cells showed reduced Tnf (191160) and markedly increased Il4 (147780) and Il10 expression in p35 -/- mice compared with wildtype mice. Becher et al. (2002) concluded that p40 is critical for the development of EAE, but the IL12 p70 heterodimer is completely dispensable. They suggested that another molecule using p40, such as IL23, is likely to be involved in EAE pathogenesis.
IL12 is composed of p35 (IL12A) and p40 (IL12B) subunits, while IL23 is composed of a p19 (IL23A) subunit and the IL12 p40 subunit. Cua et al. (2003) generated mice lacking only IL23 (p19 -/-), only IL12 (p35 -/-), or both IL23 and IL12 (p40 -/-) and immunized them with MOG in an EAE model of multiple sclerosis. The p19 -/- mice were generated by completely removing the p19 locus. Mice lacking p19 or p40 were resistant to development of EAE, whereas mice lacking only p35 were at least as susceptible as wildtype mice. Exogenous IL23 delivered into the CNS, but not intravenously, 2 days before expected onset of disease reconstituted EAE in both p19 -/- and p40 -/- mice, although onset in the latter was delayed and disease was less severe. Administration of recombinant IL12 for 7 days, followed by IL23 gene transfer on day 8, also induced intense EAE, suggesting that IL12 promotes the development of Th1 cells, while IL23 is required for subsequent inflammatory events. MOG immunization induced Th1 cells and proinflammatory cytokines in p19 -/- mice, whereas in p35 -/- and p40 -/- mice, a Th2 phenotype was observed. Flow cytometric and real-time PCR analyses demonstrated the entry of Th1 cells into the CNS in the absence of IL23, without the recruitment of additional T cells or macrophages or the activation of resident microglia. During EAE, IL23R (607562) and IL12RB1 were coexpressed by inflammatory macrophages, whereas resident microglia expressed only IL12RB1. Although resident microglia and inflammatory macrophages produced IL23, only inflammatory macrophages responded to IL23. In contrast, IL12 was produced primarily by inflammatory macrophages, and both macrophages and microglia had the potential to respond to IL12. Cua et al. (2003) concluded that IL12 promotes the development of naive T cells, while IL23 mediates late-stage inflammation and seems to be necessary for chronic inflammation. In a commentary, Watford and O'Shea (2003) noted that IL12 now has an 'alibi' in the development of autoimmune disease and that previous studies attributing these deleterious effects to IL12 may need reevaluation, including precise determination of the role of each subunit in this family of dimeric cytokines.
Using irradiation bone chimeras, Becher et al. (2003) generated mice in which p40 was deleted from the CNS parenchyma but not from the systemic immune system. They found that p40 expressed by CNS endogenous cells was critical for the development of EAE. Although clinical disease was reduced, inflammation, accompanied by increased Th2 and reduced Th1 cytokines, was not reduced in the p40 -/- chimeras. Becher et al. (2003) concluded that p40 expression by CNS-resident cells is the basis of the Th1 bias in the CNS in EAE disease.
Sugimoto et al. (2004) demonstrated that peritoneal macrophages and bone marrow-derived dendritic cells from Tpl2 (MAP3K8; 191195)- null mice produced significantly more IL12 in response to CG-rich bacterial DNA than those from wildtype mice. Enhanced IL12 production in Tpl2 -/- macrophages was regulated in part at the transcriptional level, and the elevated IL12 mRNA level in Tpl2 -/- macrophages was accompanied by decreased amounts of IL12 repressors. Tpl2-null mice consistently showed Th1-skewed antigen-specific immune responses upon OVA immunization and Leishmania major infection in vivo. Sugimoto et al. (2004) concluded that TPL2 is an important negative regulator of Th1-type adaptive immunity and that it achieves this regulation by inhibiting IL12 production from accessory cells.
Grabie et al. (2003) studied transgenic mice expressing cardiac myocyte-restricted membrane-bound OVA, which are tolerant to OVA. They found that adoptively transferred OVA peptide-specific CD8 (see 186910)-positive T cells could infiltrate the hearts of transgenic mice and induce lethal myocarditis only in the presence of vesicular stomatitis virus infection or when the T cells were first stimulated with OVA peptide in vitro in the presence of recombinant IL12.
Gunsten et al. (2008) noted that IL12 p80 is present in inflamed lung tissue and is associated with airway macrophage accumulation. They generated mice selectively overexpressing Il12 p40 in airway epithelial cells and observed increased Il12 p80 and macrophage numbers in lung. Viral infection of these mice resulted in reduced mortality, possibly due to the prior establishment of increased numbers of resident airway macrophages.
Vom Berg et al. (2013) used a syngeneic mouse model for glioblastoma (GB; see 137800) and administered cytokines in the tumor area to overcome the immunosuppressive GB microenvironment. The authors found that Il12, but not Il23, reversed GB-induced immunosuppression and led to tumor clearance in a T cell-dependent manner. To better replicate the human clinical situation, vom Berg et al. (2013) delayed therapy until after GB progression. They found that intratumoral application of Il12 combined with systemic anti-Ctla4 (123890), but not monotherapy with either Il12 or anti-Ctla4, led to tumor eradication even at advanced disease stages. The Il12 and anti-Ctla4 combination treatment acted predominantly on Cd4-positive T cells, causing a drastic reduction in Foxp3 (300292)-positive regulator T cells and an increase in effector T cells. Vom Berg et al. (2013) proposed that the combination of intratumoral IL12 and anti-CTLA4 should be tested in clinical trials for treatment of GB and, possibly, other solid tumors.
In a Pakistani child of consanguineous parents, Altare et al. (1998) demonstrated that disseminated infection with BCG and Salmonella enteritidis (IMD29; 614890) was due to homozygosity for a deletion within the IL12-p40 subunit gene. One sib had died at age 1 year with fever of unknown cause. The father suffered in childhood from severe and recurrent non-typhi salmonella (Salmonella bareilly) infection, requiring several prolonged courses of antibiotic therapy over 4 years. The gene encoding the p40 subunit was shown to consist of at least 7 exons, and a deletion of 4.4 kb encompassing 2 coding exons was found in the patient. Three nucleotides adjacent to the 2 recombination breakpoints were identical and may have contributed to the recombination process. The parents and a healthy sib were heterozygous for the deletion.
In 4 kindreds in Saudi Arabia with disseminated infection with BCG and Salmonella enteritidis (IMD29; 614890), Picard et al. (2002) found a recessive loss-of-function frameshift mutation (g.315-316insA). A conserved haplotype encompassing the IL12B gene suggested founder effect. The founder mutational event was estimated to have occurred approximately 1,100 years ago. In all 4 families the parents were first cousins. The immune defect in most was revealed by development of disseminated BCG infection at a few months of age, with BCG vaccination having occurred at birth.
This variant, formerly titled ASTHMA, SEVERE, SUSCEPTIBILITY TO, has been reclassified because its contribution to this phenotype has not been confirmed.
Randolph et al. (2004) found a strong association between the intronic 4237G-A polymorphism of the IL12B gene and an asthma severity phenotype (see 600807) in white children and in an independent population of white adult asthmatics. In a family-based association study, they found that the A allele of the 4237G-A variant was undertransmitted to asthmatic white children, but this finding could not be replicated in their independent population of white adult asthmatics.
In 4 male and 2 female patients with mycobacterial disease (IMD29; 614890) from 4 families from a central Tunisian town with fewer than 25,000 inhabitants, Ben-Mustapha et al. (2014) identified an 8-bp deletion (c.298_305del) in exon 3 of the IL12B gene. The mutation led to a premature stop codon at nucleotide 342. Parents and unaffected sibs were heterozygous for the mutation. Two families were consanguineous, and consanguinity could not be ruled out in the other 2 families. Of the 5 patients who received neonatal BCG vaccination, 4 developed disseminated BCG disease and 1 developed localized BCG disease. None of the BCG-vaccinated patients developed environmental mycobacterial disease. Stimulation of patient cells with BCG or BCG plus IFNG (147570) produced no IL12B, in contrast with control cells. Production of IFNG in response to BCG plus IL12B was enhanced in patient cells, but the level of IFNG was lower than that in control cells. Using Estiage likelihood analysis, Ben-Mustapha et al. (2014) estimated the founder event to have occurred 44 generations previously, or approximately 1,100 years ago. The authors noted that identifying the mutation in a resource-limited setting helped to establish a preventive approach to genetic counseling and prenatal diagnosis in affected families.
Altare, F., Lammas, D., Revy, P., Jouanguy, E., Doffinger, R., Lamhamedi, S., Drysdale, P., Scheel-Toellner, D., Girdlestone, J., Darbyshire, P., Wadhwa, M., Dockrell, H., Salmon, M., Fischer, A., Durandy, A., Casanova, J.-L., Kumararatne, D. S. Inherited interleukin 12 deficiency in a child with bacille Calmette-Guerin and Salmonella enteritidis disseminated infection. J. Clin. Invest. 102: 2035-2040, 1998. [PubMed: 9854038] [Full Text: https://doi.org/10.1172/JCI4950]
Becher, B., Durell, B. G., Noelle, R. J. Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. J. Clin. Invest. 110: 493-497, 2002. [PubMed: 12189243] [Full Text: https://doi.org/10.1172/JCI15751]
Becher, B., Durell, B. G., Noelle, R. J. IL-23 produced by CNS-resident cells controls T cell encephalitogenicity during the effector phase of experimental autoimmune encephalomyelitis. J. Clin. Invest. 112: 1186-1191, 2003. [PubMed: 14561703] [Full Text: https://doi.org/10.1172/JCI19079]
Ben-Mustapha, I., Ben-Ali, M., Mekki, N., Patin, E., Harmant, C., Bouguila, J., Elloumi-Zghal, H., Harbi, A., Bejaoui, M., Boughammoura, L., Chemli, J., Barbouche, M.-R. A 1,100-year-old founder effect mutation in IL12B gene is responsible for mendelian susceptibility to mycobacterial disease in Tunisian patients. Immunogenetics 66: 67-71, 2014. [PubMed: 24127073] [Full Text: https://doi.org/10.1007/s00251-013-0739-0]
Brain, O., Owens, B. M. J., Pichulik, T., Allan, P., Khatamzas, E., Leslie, A., Steevels, T., Sharma, S., Mayer, A., Catuneanu, A. M., Morton, V., Sun, M.-Y., Jewell, D., Coccia, M., Harrison, O., Maloy, K., Schonefeldt, S., Bornschein, S., Liston, A., Simmons, A. The intracellular sensor NOD2 induces microRNA-29 expression in human dendritic cells to limit IL-23 release. Immunity 39: 521-536, 2013. [PubMed: 24054330] [Full Text: https://doi.org/10.1016/j.immuni.2013.08.035]
Brightbill, H. D., Libraty, D. H., Krutzik, S. R., Yang, R.-B., Bellsie, J. T., Bieharski, J. R., Maitland, M., Norgard, M. V., Plevy, S. E., Smale, S. T., Brennan, P. J., Bloom, B. R., Godowski, P. J., Modlin, R. L. Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. Science 285: 732-736, 1999. [PubMed: 10426995] [Full Text: https://doi.org/10.1126/science.285.5428.732]
Cooper, A. M., Kipnis, A., Turner, J., Magram, J., Ferrante, J., Orme, I. M. Mice lacking bioactive IL-12 can generate protective, antigen-specific cellular responses to mycobacterial infection only if the IL-12 p40 subunit is present. J. Immun. 168: 1322-1327, 2002. [PubMed: 11801672] [Full Text: https://doi.org/10.4049/jimmunol.168.3.1322]
Cua, D. J., Sherlock, J., Chen, Y., Murphy, C. A., Joyce, B., Seymour, B., Lucian, L., To, W., Kwan, S., Churakova, T., Zurawski, S., Wiekowski, M., Lira, S. A., Gorman, D., Kastelein, R. A., Sedgwick, J. D. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421: 744-748, 2003. [PubMed: 12610626] [Full Text: https://doi.org/10.1038/nature01355]
de Beaucoudrey, L., Puel, A., Filipe-Santos, O., Cobat, A., Ghandil, P., Chrabieh, M., Feinberg, J., von Bernuth, H., Samarina, A., Janniere, L., Fieschi, C., Stephan, J.-L., Boileau, C., and 33 others. Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells. J. Exp. Med. 205: 1543-1550, 2008. [PubMed: 18591412] [Full Text: https://doi.org/10.1084/jem.20080321]
Diefenbach, A., Schindler, H., Rollinghoff, M., Yokoyama, W. M., Bogdan, C. Requirement for type 2 NO synthase for IL-12 signaling in innate immunity. Science 284: 951-955, 1999. Note: Erratum: Science 284: 1776 only, 1999. [PubMed: 10320373] [Full Text: https://doi.org/10.1126/science.284.5416.951]
Ferlazzo, G., Pack, M., Thomas, D., Paludan, C., Schmid, D., Strowig, T., Bougras, G., Muller, W. A., Moretta, L., Munz, C. Distinct roles of IL-12 and IL-15 in human natural killer cell activation by dendritic cells from secondary lymphoid organs. Proc. Nat. Acad. Sci. 101: 16606-16611, 2004. [PubMed: 15536127] [Full Text: https://doi.org/10.1073/pnas.0407522101]
Ferlazzo, G., Thomas, D., Lin, S. L., Goodman, K., Morandi, B., Muller, W. A., Moretta, A., Munz, C. The abundant NK cells in human secondary lymphoid tissues require activation to express killer cell Ig-like receptors and become cytolytic. J. Immun. 172: 1455-1462, 2004. [PubMed: 14734722] [Full Text: https://doi.org/10.4049/jimmunol.172.3.1455]
Grabie, N., Delfs, M. W., Westrich, J. R., Love, V. A., Stavrakis, G., Ahmad, F., Seidman, C. E., Seidman, J. G., Lichtman, A. H. IL-12 is required for differentiation of pathogenic CD8-positive T cell effectors that cause myocarditis. J. Clin. Invest. 111: 671-680, 2003. [PubMed: 12618521] [Full Text: https://doi.org/10.1172/JCI16867]
Gross, M. B. Personal Communication. Baltimore, Md. 9/4/2014.
Gubler, U., Chua, A. O., Schoenhaut, D. S., Dwyer, C. M., McComas, W., Motyka, R., Nabavi, N., Wolitzky, A. G., Quinn, P. M., Familletti, P. C., Gately, M. K. Coexpression of two distinct genes is required to generate secreted bioactive cytotoxic lymphocyte maturation factor. Proc. Nat. Acad. Sci. 88: 4143-4147, 1991. [PubMed: 1674604] [Full Text: https://doi.org/10.1073/pnas.88.10.4143]
Gunsten, S., Mikols, C. L., Grayson, M. H., Schwendener, R. A., Agapov, E., Tidwell, R. M., Cannon, C. L., Brody, S. L., Walter, M. J. IL-12 p80-dependent macrophage recruitment primes the host for increased survival following a lethal respiratory viral infection. Immunology 126: 500-513, 2008. [PubMed: 18783467] [Full Text: https://doi.org/10.1111/j.1365-2567.2008.02923.x]
Huang, D., Cancilla, M. R., Morahan, G. Complete primary structure, chromosomal localisation, and definition of polymorphisms of the gene encoding the human interleukin-12 p40 subunit. Genes Immun. 1: 515-520, 2000. [PubMed: 11197695] [Full Text: https://doi.org/10.1038/sj.gene.6363720]
Jankovic, D., Kullberg, M. C., Hieny, S., Caspar, P., Collazo, C. M., Sher, A. In the absence of IL-12, CD4+ T cell responses to intracellular pathogens fail to default to a Th2 pattern and are host protective in an IL-10-/- setting. Immunity 16: 429-439, 2002. [PubMed: 11911827] [Full Text: https://doi.org/10.1016/s1074-7613(02)00278-9]
Lee, E., Trepicchio, W. L., Oestreicher, J. L., Pittman, D., Wang, F., Chamian, F., Dhodapkar, M., Krueger, J. G. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J. Exp. Med. 199: 125-130, 2004. [PubMed: 14707118] [Full Text: https://doi.org/10.1084/jem.20030451]
Marquet, S., Doumbo, O., Cabantous, S., Poudiougou, B., Argiro, L., Safeukui, I., Konate, S., Sissoko, S., Chevereau, E., Traore, A., Keita, M. M., Chevillard, C., Abel, L., Dessein, A. J. A functional promoter variant in IL12B predisposes to cerebral malaria. Hum. Molec. Genet. 17: 2190-2195, 2008. [PubMed: 18413324] [Full Text: https://doi.org/10.1093/hmg/ddn118]
Morahan, G,, Huang, D., Wu, M., Holt, B. J., White, G. P., Kendall, G. E., Sly, P. D., Holt, P. G. Association of IL12B promoter polymorphism with severity of atopic and non-atopic asthma in children. Lancet 360: 455-459, 2002. Note: Erratum 360: 1892 only, 2002. [PubMed: 12241719] [Full Text: https://doi.org/10.1016/S0140-6736(02)09676-9]
Morahan, G., Huang, D., Ymer, S. I., Cancilla, M. R., Stephen, K., Dabadghao, P., Werther, G., Tait, B. D., Harrison, L. C., Colman, P. G. Linkage disequilibrium of a type 1 diabetes susceptibility locus with a regulatory IL12B allele. Nature Genet. 27: 218-221, 2001. Note: Erratum: Nature Genet. 27: 346 only, 2001. [PubMed: 11175794] [Full Text: https://doi.org/10.1038/84872]
Navaglia, F., Basso, D., Zambon, C.-F., Ponzano, E., Caenazzo, L., Gallo, N., Falda, A., Belluco, C., Fogar, P., Greco, E., Di Mario, F., Rugge, M., Plebani, M. Interleukin 12 gene polymorphisms enhance gastric cancer risk in H pylori infected individuals. (Letter) J. Med. Genet. 42: 503-510, 2005. [PubMed: 15937086] [Full Text: https://doi.org/10.1136/jmg.2004.022723]
Noben-Trauth, N., Schweitzer, P. A., Johnson, K. R., Wolf, S. F., Knowles, B. B., Shultz, L. D. The interleukin-12 beta subunit (p40) maps to mouse chromosome 11. Mammalian Genome 7: 392 only, 1996. [PubMed: 8661733] [Full Text: https://doi.org/10.1007/s003359900113]
Oppmann, B., Lesley, R., Blom, B., Timans, J. C., Xu, Y., Hunte, B., Vega, F., Yu, N., Wang, J., Singh, K., Zonin, F., Vaisberg, E., and 13 others. 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: 715-725, 2000. [PubMed: 11114383] [Full Text: https://doi.org/10.1016/s1074-7613(00)00070-4]
Pang, Y. H., Zheng, C. Q., Yang, X. Z., Zhang, W. J. Increased expression and activation of IL-12-induced Stat4 signaling in the mucosa of ulcerative colitis patients. Cell. Immun. 248: 115-120, 2007. [PubMed: 18048021] [Full Text: https://doi.org/10.1016/j.cellimm.2007.10.003]
Picard, C., Fieschi, C., Altare, F., Al-Jumaah, S., Al-Hajjar, S., Feinberg, J., Dupuis, S., Soudais, C., Al-Mohsen, I. Z., Genin, E., Lammas, D., Kumararatne, D. S., and 12 others. Inherited interleukin-12 deficiency: IL12B genotype and clinical phenotype of 13 patients from six kindreds. Am. J. Hum. Genet. 70: 336-348, 2002. [PubMed: 11753820] [Full Text: https://doi.org/10.1086/338625]
Randolph, A. G., Lange, C., Silverman, E. K., Lazarus, R., Silverman, E. S., Raby, B., Brown, A., Ozonoff, A., Richter, B., Weiss, S. T. The IL12B gene is associated with asthma. Am. J. Hum. Genet. 75: 709-715, 2004. [PubMed: 15322986] [Full Text: https://doi.org/10.1086/424886]
Schwarz, A., Stander, S., Berneburg, M., Bshm, M., Kulms, D., van Steeg, H., Grosse-Heitmeyer, K., Krutmann, J., Schwarz, T. Interleukin-12 suppresses ultraviolet radiation-induced apoptosis by inducing DNA repair. Nature Cell Biol. 4: 26-31, 2002. [PubMed: 11780128] [Full Text: https://doi.org/10.1038/ncb717]
Sieburth, D., Jabs, E. W., Warrington, J. A., Li, X., Lasota, J., LaForgia, S., Kelleher, K., Huebner, K., Wasmuth, J. J., Wolf, S. F. Assignment of genes encoding a unique cytokine (IL12) composed of two unrelated subunits to chromosomes 3 and 5. Genomics 14: 59-62, 1992. [PubMed: 1358798] [Full Text: https://doi.org/10.1016/s0888-7543(05)80283-6]
Sugimoto, K., Ohata, M., Miyoshi, J., Ishizaki, H., Tsuboi, N., Masuda, A., Yoshikai, Y., Takamoto, M., Sugane, K., Matsuo, S., Shimada, Y., Matsuguchi, T. A serine/threonine kinase, Cot/Tpl2, modulates bacterial DNA-induced IL-12 production and Th cell differentiation. J. Clin. Invest. 114: 857-866, 2004. [PubMed: 15372110] [Full Text: https://doi.org/10.1172/JCI20014]
vom Berg, J., Vrohlings, M., Haller, S., Haimovici, A., Kulig, P., Sledzinska, A., Weller, M., Becher, B. Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell-mediated glioma rejection. J. Exp. Med. 210: 2803-2811, 2013. [PubMed: 24277150] [Full Text: https://doi.org/10.1084/jem.20130678]
Wang, K., Zhang, H., Kugathasan, S., Annese, V., Bradfield, J. P., Russell, R. K., Sleiman, P. M. A., Imielinski, M., Glessner, J., Hou, C., Wilson, D. C., Walters, T., and 16 others. Diverse genome-wide association studies associate the IL1/IL23 pathway with Crohn disease. Am. J. Hum. Genet. 84: 399-405, 2009. [PubMed: 19249008] [Full Text: https://doi.org/10.1016/j.ajhg.2009.01.026]
Warrington, J. A., Bailey, S. K., Armstrong, E., Aprelikova, O., Alitalo, K., Dolganov, G. M., Wilcox, A. S., Sikela, J. M., Wolfe, S. F., Lovett, M., Wasmuth, J. J. A radiation hybrid map of 18 growth factor, growth factor receptor, hormone receptor, or neurotransmitter receptor genes on the distal region of the long arm of chromosome 5. Genomics 13: 803-808, 1992. [PubMed: 1322355] [Full Text: https://doi.org/10.1016/0888-7543(92)90156-m]
Warrington, J. A., Bengtsson, U. High-resolution physical mapping of human 5q31-q33 using three methods: radiation hybrid mapping, interphase fluorescence in situ hybridization, and pulsed-field gel electrophoresis. Genomics 24: 395-398, 1994. [PubMed: 7698768] [Full Text: https://doi.org/10.1006/geno.1994.1636]
Watford, W. T., O'Shea, J. J. A case of mistaken identity. Nature 421: 706-707, 2003. [PubMed: 12610607] [Full Text: https://doi.org/10.1038/421706a]
Zheng, Y., Danilenko, D. M., Valdez, P., Kasman, I., Eastham-Anderson, J., Wu, J., Ouyang, W. Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 445: 648-651, 2007. [PubMed: 17187052] [Full Text: https://doi.org/10.1038/nature05505]