HGNC Approved Gene Symbol: IL12RB2
Cytogenetic location: 1p31.3 Genomic coordinates (GRCh38): 1:67,307,364-67,398,724 (from NCBI)
Chua et al. (1994) and Presky et al. (1996) identified 2 subunits of the interleukin-12 (IL12; 161560) receptor complex designated beta-1 (601604) and beta-2, respectively. Presky et al. (1996) identified IL12RB2 cDNA from a human phytohemagglutinin-activated lymphoblast library. It is an 862-amino acid type I transmembrane protein with a 595-amino acid-long extracellular domain and a cytoplasmic tail of 216 amino acids that contains 3 tyrosine residues. A cDNA encoding the mouse homolog was also isolated. The human and mouse proteins show 68% amino acid sequence identity. When expressed in COS-7 cells, IL12RB2 exists as a disulfide-linked oligomer with an apparent monomeric molecular mass of 130 kD. Functional studies indicated that high affinity IL12R is composed of at least 2 beta-type cytokine receptor subunits, each independently exhibiting low affinity for IL12.
By fluorescence in situ hybridization, Yamamoto et al. (1997) mapped the IL12RB2 gene to 1p31.2. By PCR analysis of genomic DNA from a panel of rodent/human somatic cell hybrids containing single human chromosomes, Morton et al. (1997) assigned the IL12RB2 gene to chromosome 1. With PCR analysis of a radiation hybrid panel and by fluorescence in situ hybridization, they localized the gene to 1p31.3-p31.2.
IL12RB1 is constitutively expressed on both Th1 and Th2 lymphocytes. IL12RB2 is expressed more strongly on Th1 cells, however, and can be induced by antigen receptor triggering or by IL12 and alpha-interferon (IFNA; 147660). Using RT-PCR analysis, Kim et al. (2001) showed that IL12RB2 expression was high in lesions of tuberculoid (i.e., M. leprae-resistant) leprosy (see 246300) patients but not in lesions of lepromatous (i.e., low-resistance) patients. IL12RB1 expression was similar in both groups. Flow cytometric analysis demonstrated that tuberculoid patient T cells responded with increased expression of IL12RB1 and IL12RB2 to M. leprae antigen stimulation, whereas lepromatous patients upregulated expression of IL12RB1 but not IL12RB2. EMSA, supershift, and Western blot analyses indicated that IL12 stimulation induced STAT4 phosphorylation and STAT4-DNA binding in tuberculoid but not lepromatous patients. The defect in lepromatous patients was specific to M. leprae in that they upregulated both IL12RB1 and IL12RB2 in response to M. tuberculosis and activated the STAT4 pathway. ELISA analysis showed that production of IFNG (147570) correlated with IL12RB2 expression in the leprosy patients. Kim et al. (2001) proposed that the Th response to antigen determines IL12RB2 expression and function in the generation of cell-mediated immunity to microbial infection.
Minimal change nephrotic syndrome (MCNS), also known as lipoid nephrosis, is a glomerular disease characterized by heavy proteinuria that remits with abatement of cell-mediated immunity. Shalhoub (1974) postulated that MCNS results from abnormal T-cell activation. By subtractive cloning and differential screening analyses using MCNS patient T lymphocytes, Sahali et al. (2002) identified a number of genes differentially regulated in MCNS. The findings suggested that MCNS relapse might be associated with a Th2 response, in part due to downregulation of IL12RB2, a Th1-associated cytokine receptor, and selective recruitment of MAF (177075), which promotes Th2 responses.
Associations Pending Confirmation
For discussion of a possible association between variation in the IL12RB2 gene and primary biliary cirrhosis, see PBC3 (613008).
For discussion of a possible association between a primary immunodeficiency with susceptibility to mycobacterial infection (see, e.g., 607948) and variation in the IL12RB2 gene, see 601642.0001.
The article by Airoldi et al. (2004) discussing the function of IL12RB2 as a tumor suppressor in human B-cell malignancies was retracted.
This variant is classified as a variant of unknown significance because its contribution to a primary immunodeficiency with susceptibility to mycobacterial infection (see, e.g., 607948) has not been confirmed.
In a girl (P1), born in a consanguineous Turkish family (kindred A), who developed a mycobacterial infection after BCG vaccination, Martinez-Barricarte et al. (2018) identified a homozygous c.412C-T transition in exon 4 of the IL12RB2 gene, resulting in a gln138-to-ter (Q138X) substitution upstream from the segment encoding the transmembrane domain. The variant, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family, although there was evidence of incomplete penetrance. The variant was found twice in the heterozygous state in the gnomAD database. Patient-derived cells and B cells expressing the variant failed to enhance STAT4 (600558) phosphorylation or CXCL10 (147310) production in response to IL12 stimulation, consistent with a loss-of-function effect. Expression of wildtype IL12RB2 restored these defects. Computational predictions based on population exome data suggested that there is a lower clinical penetrance of mycobacterial disease in patients with IL12RB2 deficiency compared to patients with IL12RB1 deficiency (IMD30; 614891). The numbers of many subsets of lymphoid cells in the patient were similar to controls, but there was a lower frequency of MAIT cells, higher numbers of naive cells in the CD4+ and CD8+ T-cell populations, and lower numbers of memory cells, particularly memory Th1 cells. There was also impaired differentiation of CD4+ Th1 cells in response to IL12 stimulation, and lack of generation of Mycobacterium-specific IFNG in Th cells. The proband was a girl who was vaccinated with BCG at age 3 months and developed left axillary lymphadenitis at age 17 months. Lymph node biopsy showed caseating granulomatous inflammation with acid-fast bacilli. She was diagnosed with BCG-osis and treated with multiple antituberculosis medications. She made a full recovery. She never had Salmonella or candidal infections. Two paternal uncles were found to be homozygous for the variant; 1 had pulmonary tuberculosis at 5 years of age and recovered with treatment, and the other was asymptomatic. The authors concluded that the isolated absence of IL12 signaling was partially compensated by other cytokines for the production of IFNG, including the IL23 (see 605580) signaling pathway, which could explain the lower clinical penetrance.
Airoldi, I., Di Carlo, E., Banelli, B., Moserle, L., Cocco, C., Pezzolo, A., Sorrentino, C., Rossi, E., Romani, M., Amadori, A., Pistoia, V. The IL-12R-beta-2 gene functions as a tumor suppressor in human B cell malignancies. J. Clin. Invest. 113: 1651-1659, 2004. Note: Retraction: J. Clin. Invest. 124: 2807 only, 2014. [PubMed: 15173892] [Full Text: https://doi.org/10.1172/JCI20303]
Chua, A. O., Chizzonite, R., Desai, B. B., Truitt, T. P., Nunes, P., Minetti, L. J., Warrier, R. R., Presky, D. H., Levine, J. F., Gately, M. K., Gubler, U. Expression cloning of a human IL-12 receptor component: a new member of the cytokine receptor superfamily with strong homology to gp130. J. Immun. 153: 128-136, 1994. [PubMed: 7911493]
Kim, J., Uyemura, K., Van Dyke, M. K., Legaspi, A. J., Rea, T. H., Shuai, K., Modlin, R. L. A role for IL-12 receptor expression and signal transduction in host defense in leprosy. J. Immun. 167: 779-786, 2001. [PubMed: 11441083] [Full Text: https://doi.org/10.4049/jimmunol.167.2.779]
Martinez-Barricarte, R., Markle, J. G., Ma, C. S., Deenick, E. K., Ramirez-Alejo, N., Mele, F., Latorre, D., Mahdaviani, S. A., Aytekin, C., Mansouri, D., Bryant, V. L., Jabot-Hanin, F., and 41 others. Human IFN-gamma immunity to mycobacteria is governed by both IL-12 and IL-23. Sci. Immun. 3: eaau6759, 2018. Note: Electronic Article. [PubMed: 30578351] [Full Text: https://doi.org/10.1126/sciimmunol.aau6759]
Morton, S. M., Bocaccio, I., Depetris, D., Mattei, M., Dessein, A. Assignment of IL12RB2 to human chromosome 1p31.3-p31.2 between D1S230 and D1S198. Cytogenet. Cell Genet. 79: 282-283, 1997. [PubMed: 9605872] [Full Text: https://doi.org/10.1159/000134743]
Presky, D. H., Yang, H., Minetti, L. J., Chua, A. O., Nabavi, N., Wu, C.-Y., Gately, M. K., Gubler, U. A functional interleukin 12 receptor complex is composed of two beta-type cytokine receptor subunits. Proc. Nat. Acad. Sci. 93: 14002-14007, 1996. [PubMed: 8943050] [Full Text: https://doi.org/10.1073/pnas.93.24.14002]
Sahali, D., Pawlak, A., Valanciute, A., Grimbert, P., Lang, P., Remy, P., Bensman, A., Guellaen, G. A novel approach to investigation of the pathogenesis of active minimal-change nephrotic syndrome using subtracted cDNA library screening. J. Am. Soc. Nephrol. 13: 1238-1247, 2002. [PubMed: 11961011] [Full Text: https://doi.org/10.1681/ASN.V1351238]
Shalhoub, R. J. Pathogenesis of lipoid nephrosis: a disorder of T-cell function. Lancet 304: 556-560, 1974. Note: Originally Volume 2. [PubMed: 4140273] [Full Text: https://doi.org/10.1016/s0140-6736(74)91880-7]
Yamamoto, K., Kobayashi, H., Miura, O., Hirosawa, S., Miyasaka, N. Assignment of IL12RB1 and IL12RB2, interleukin-12 receptor beta-1 and beta-2 chains, to human chromosome 19 band p13.1 and chromosome 1 band p31.2, respectively, by in situ hybridization. Cytogenet. Cell Genet. 77: 257-258, 1997. [PubMed: 9284929] [Full Text: https://doi.org/10.1159/000134589]