Alternative titles; symbols
HGNC Approved Gene Symbol: TNFRSF1B
Cytogenetic location: 1p36.22 Genomic coordinates (GRCh38): 1:12,166,991-12,209,220 (from NCBI)
Schall et al. (1990) isolated a cDNA corresponding to TNFR2 using oligomer probes based on amino acid sequence from the purified protein. The receptor encodes a predicted 415-amino acid polypeptide with a single membrane-spanning domain and has an extracellular domain with sequence similarity to nerve growth factor receptor (162010) and B-cell activation protein Bp50 (164011). Recombinantly expressed receptor was shown by Schall et al. (1990) to bind TNF-alpha (191160). Northern blots showed expression in a variety of cell types.
In their review, Faustman and Davis (2010) noted that there are marked differences in expression of TNFR1 (TNFRSF1A; 191190) and TNFR2. TNFR1 shows near ubiquitous expression, whereas TNFR2 is restricted to certain T-cell populations, endothelial cells, microglia and specific neuron subtypes, oligodendrocytes, cardiac myocytes, thymocytes, and mesenchymal stem cells. Thus, all cells expressing TNFR2 also express TNFR1. Erythrocytes do not express either receptor.
Beltinger et al. (1996) showed that TNFR2 contains 10 exons and spans about 26 kb of genomic DNA. Most of the functional domains, including the extracellular cysteine-rich motifs, occur in separate exons. Overall, the gene structure is similar to that of TNFR1 (191190). On the basis of a YAC contig for the region, they mapped TNFR2 to within 400 kb of the marker D1S434 on 1p36.
Santee and Owen-Schaub (1996) characterized the complete gene structure for human TNFR p75, which spans nearly 43 kb. The gene consists of 10 exons (ranging from 34 bp to 2.5 kb) and 9 introns (343 bp to 19 kb). Consensus elements for transcription factors involved in T-cell development and activation were noted in the putative promoter region.
TNFBR (TNFR75) is the larger of the 2 TNF receptors; see 191190. It is present on many cell types, especially those of myeloid origin, and is strongly expressed on stimulated T and B lymphocytes. Beltinger et al. (1996) noted that TNFR2 is the main TNF receptor found on circulating T cells and is the major mediator of autoregulatory apoptosis in CD8+ cells. TNFR2 may act with TNFR1 to kill nonlymphoid cells.
Preassembly or self-association of cytokine receptor dimers (e.g., IL1R, see 147810; IL2R, 147730; and EPOR, 133171) occurs via the same amino acid contacts that are critical for ligand binding. Chan et al. (2000) found that, in contrast, the p60 (TNFRSF1A) and p80 (TNFRSF1B) TNFA receptors self-assemble through a distinct functional domain in the TNFR extracellular domain, termed the pre-ligand assembly domain (PLAD), in the absence of ligand. Deletion of the PLAD results in monomeric presentation of p60 or p80. Flow cytometric analysis showed that efficient TNFA binding depends on receptor self-assembly. They also found that other members of the TNF receptor superfamily, including the extracellular domains of TRAIL (TNFRSF10A; 603611), CD40 (109535), and FAS (TNFRSF6; 134637), all self-associate but do not interact with heterologous receptors.
Using Jurkat T cells, which express TNFR1 but little TNFR2, and Jurkat cells stably transfected with TNFR2, Li et al. (2002) confirmed that TNF stimulation, or stimulation with a TNFR2, but not TNFR1, agonist, causes a loss of TRAF2 (601895) in the TNFR2-expressing cells, but not the parental cell line, through a ubiquitination- and proteasome-dependent process. Binding analysis indicated that TRAF2 interacts with CIAP1 (601712) and CIAP2 (601721), which possess E3 ubiquitin ligase (e.g. UBE3A, 601623) activity. Ubiquitination assays and SDS-PAGE analysis showed that in the presence of an E2-conjugating enzyme (e.g., UBCH7, 603721), CIAP1, but not CIAP2, induces TRAF2 ubiquitination outside of its RING domain. Both CIAPs bind but neither ubiquitinates TRAF1 (601711). CIAP1 expression fails to protect TNFR2-expressing cells from TNF-induced apoptosis, whereas an E3-inactive CIAP1 mutant and wildtype CIAP2 do protect cells from TRAF2 downregulation and cause a delay in cell death. Li et al. (2002) concluded that TNFR2 stimulation causes the ubiquitination of TRAF2 by CIAP1, which can play a proapoptotic role in TNF signaling.
Tang et al. (2011) reported that PGRN (138945) bound directly to tumor necrosis factor receptors (TNFR1 and TNRF2) and disturbed the TNFA-TNFR interaction. Pgrn-deficient mice were susceptible to collagen-induced arthritis, and administration of PGRN reversed inflammatory arthritis. Atsttrin, an engineered protein composed of 3 PGRN fragments, exhibited selective TNFR binding. PGRN and Atsttrin prevented inflammation in multiple arthritis mouse models and inhibited TNFA-activated intracellular signaling. Tang et al. (2011) concluded that PGRN is a ligand of TNFR, an antagonist of TNFA signaling, and plays a critical role in the pathogenesis of inflammatory arthritis in mice.
By Southern blot analysis of human/Chinese hamster somatic cell hybrid DNA, Milatovich et al. (1991) mapped the TNFR2 gene to 1pter-p32. By in situ hybridization and Southern blot analysis of a series of human/mouse hybrid cell lines, Baker et al. (1991) refined the assignment of TNFR2 to 1p36. By nonradioactive in situ hybridization, Kemper et al. (1991) assigned the gene to 1p36.3-p36.2. Using an SSCP polymorphism of the TNFR2 gene, Kaufman et al. (1994) demonstrated that TNFR2 is very closely linked to the pronatriodilatin gene (108780).
White et al. (1995) showed that TNFR2 maps outside the region of 1p36.3-p36.2 thought by loss of heterozygosity (LOH) studies to contain the neuroblastoma tumor suppressor locus (256700).
By linkage analysis, Santee and Owen-Schaub (1996) confirmed the mapping of the TNFR2 gene to 1p36.3-p36.2.
Glenn et al. (2000) tested markers in and near the TNFR2 gene for linkage and association with hypertension (145500) as well as hypercholesterolemia and plasma levels of the shed soluble receptor (sTNF-R2). Using sib pair analysis, they reported a sharp, significant linkage peak centered at TNFRSF1B (multipoint maximum lod score = 2.6 and 3.1 by weighted and unweighted MAPMAKER/SIBS, respectively). In a case-control study, they demonstrated a possible association of TNFRSF1B with hypertension by haplotype analysis. Plasma sTNF-R2 was significantly elevated in hypertensives and showed a correlation with systolic and diastolic blood pressure. A genotypic effect of TNFRSF1B on plasma sTNF-R2, as well as total, low, and high density lipoprotein cholesterol, and diastolic blood pressure was also observed. The authors proposed a scheme for involvement of TNF and its receptors in hypertension and hypercholesterolemia.
Geurts et al. (2000) conducted a genomic scan in 18 Dutch familial combined hyperlipidemia (FCHL; 144250) families and identified several loci with evidence for linkage. Linear regression analysis using 79 independent sib pairs showed linkage with a quantitative FCHL discriminant function and the intron 4 (CA)n polymorphism of TNFRSF1B (P = 0.032), and a case-control study demonstrated an association as well (P = 0.029). Mutation analysis of exon 6 in 73 FCHL family members delineated 2 TNFRSF1B alleles, coding for methionine (196M) and arginine (196R). Complete linkage disequilibrium between CA267, CA271, and CA273 and this polymorphism was detected. In 85 hyperlipidemic FCHL subjects, an association was demonstrated between soluble TNFRSF1B plasma concentrations and the CA271-196M haplotype. The authors concluded that TNFRSF1B is associated with susceptibility to FCHL.
In Japan, Sashio et al. (2002) examined polymorphisms of the tumor necrosis factor gene (TNFA; 191160) and the TNFRSF1B gene in patients with inflammatory bowel disease (see IBD1, 266600), including 124 with Crohn disease and 106 with ulcerative colitis, and 111 unrelated healthy controls. They studied 2 SNPs: 1466A-G and 1493C-T. They found a significant difference in carrier frequency for haplotype AT (1466A, 1493T) of the TNFRSF1B gene between Crohn disease patients and the controls (odds ratio = 2.13). Significance proved to be greater in Crohn disease patients with both internal and external fistula, and in those who were poor responders to treatment, which consisted of nutritional, medical, and surgical therapy.
Peral et al. (2002) evaluated serum soluble TNF receptor-2 levels, and several common polymorphisms in the TNFRSF1B gene, in women presenting with polycystic ovary syndrome (PCOS; 184700) or hyperandrogenic disorders. The 196R alleles of the M196R (676T-G) variant in exon 6 of TNFRSF1B, which is in linkage disequilibrium with a CA repeat microsatellite polymorphism in intron 4 of TNFRSF1B, tended to be more frequent in hyperandrogenic patients than in controls (P = 0.056), reaching statistical significance when the analysis was restricted to include only PCOS patients (P less than 0.03). Extended analysis including another 11 hyperandrogenic patients from Spain and 64 patients and 29 controls from Italy confirmed the association between 196R alleles of the M196R variant and hyperandrogenic disorders (P less than 0.05), which was maintained when restricting the analysis to PCOS patients (P less than 0.02). On the contrary, the 3-prime-untranslated region (exon 10) variants 1663G-A, 1668T-G, and 1690T-C were not associated with hyperandrogenism. The authors concluded that the M196R variant in exon 6 of TNFRSF1B is associated with hyperandrogenism and PCOS, further suggesting a role for inflammatory cytokines in the pathogenesis of these disorders.
One of the candidate loci for regulation of hip bone mineral density (BMD) is on chromosome 1p36 (BMND3; 606928). Albagha et al. (2002) studied several TNFRSF1B polymorphisms in a population-based cohort study of 1,240 perimenopausal women from the UK. The authors found no association between 676T-G (met196-to-arg) alleles and BMD at the spine or hip. However, subjects homozygous for the A593-T598-C620 haplotype in the 3-prime UTR region had femoral neck BMD values 5.7% lower than those who did not carry the haplotype (P less than 0.0001). Regression analysis showed that the ATC haplotype accounted for 1.2% of the population variance in hip BMD and was the second strongest predictor after body weight.
Xu et al. (2005) analyzed the (CA)n polymorphism in intron 4 of the TNFRSF1B gene and BMD in 1,263 Chinese individuals from 402 nuclear families composed of both parents and at least 1 daughter. Significant within-family association was detected between the CA16 allele and BMD at the lumbar spine (p = 0.005); about 3.14% of lumbar spine BMD variation could be explained by the CA16 allele.
Fairfax et al. (2011) identified a haplotype marked by a SNP (rs522807) in the TNFR2 promoter that was strongly associated with reduced tolerance to lipopolysaccharide (LPS). The haplotype was associated with increased expression of TNFR2, and basal TNFR2 expression was associated with secondary TNF release. Fairfax et al. (2011) reported that the tolerance-associated ancestral allele of rs522807 is present at a frequency of 8% in northern Europeans, is absent in Asians, and is present at a frequency of approximately 50% in equatorial Africans.
Bruce et al. (1996) used targeted gene disruption to generate mice lacking either the p55 (TNFR1) or the p75 (TNFR2) TNF receptor; mice lacking both p55 and p75 were generated from crosses of the singly deficient mice. The TNFR-deficient (TNFR-KO) mice exhibited no overt phenotype under unchallenged conditions. Bruce et al. (1996) reported that damage to neurons caused by focal cerebral ischemia and epileptic seizures was exacerbated in the TNFR-KO mice, indicating that TNF serves a neuroprotective function. Their studies indicated that TNF protects neurons by stimulating antioxidative pathways. Injury-induced microglial activation was suppressed in TNFR-KO mice. They concluded that drugs which target TNF signaling pathways may prove beneficial in treating stroke or traumatic brain injury.
Vielhauer et al. (2005) studied immune complex-mediated glomerulonephritis in Tnfr1- and Tnfr2-deficient mice. Proteinuria and renal pathology were initially milder in Tnfr1-deficient mice, but at later time points were similar to those in wildtype controls, with excessive renal T-cell accumulation and reduced T-cell apoptosis. In contrast, Tnfr2-deficient mice were completely protected from glomerulonephritis at all time points, despite an intact immune system response. Tnfr2 expression on intrinsic renal cells, but not leukocytes, was essential for glomerulonephritis and glomerular complement deposition. Vielhauer et al. (2005) concluded that the proinflammatory and immunosuppressive properties of TNF segregate at the level of its receptors, with TNFR1 promoting systemic immune responses and renal T-cell death and intrinsic renal cell TNFR2 playing a critical role in complement-dependent tissue injury.
Absence of TNF, like that of IL1B (147720), IL12B (161561), or IFNG (147570), is lethal to organisms confronting Mycobacterium tuberculosis (see 607948) challenge. The membrane-bound form of TNF preferentially signals through p75, whereas soluble TNF, generated through cleavage by TACE (ADAM17; 603639), primarily uses p55. The p55 and p75 receptors have similar extracellular regions but distinct cytoplasmic domains, and both receptors can also be soluble. Mice lacking p55 succumb to M. tuberculosis challenge. Using mice deficient in p75, Keeton et al. (2014) evaluated the role of p75 following aerosol M. tuberculosis infection. Unlike mice lacking p55 or both p55 and p75, mice lacking p75 did not succumb to infection or lose weight. Compared with wildtype mice, p75-null mice better controlled lung bacillary numbers and had fewer lesions. Both wildtype and p75-null mice, but not p55-null mice, had clearly demarcated granulomas. Recruitment of dendritic cells to lungs was increased in p75-null mice. Dendritic cells from p75-null mice exposed in vitro to M. tuberculosis produced more Il12b than wildtype cells, and lymph nodes of M. tuberculosis-infected p75-null mice had higher numbers of dendritic cells and activated dendritic and T cells. Following infection, increased levels of both soluble p55 and p75 were found in lung homogenates of wildtype mice. Keeton et al. (2014) concluded that mice lacking p75 have enhanced protective immunity against M. tuberculosis infection, that soluble p75 inhibits specific Th1 responses, and that Tnf-mediated dendritic cell activation is a critical factor in disease outcome.
TNFA antagonists are beneficial to patients with inflammatory autoimmune diseases, such as IBD and rheumatoid arthritis (RA; 180300), but these treatments exacerbate central nervous system (CNS) autoimmunity, including multiple sclerosis (MS; 126200) and neuromyelitis optica, conditions that are more common in women. Using mice lacking Tnfr2 with myelin oligodendrocyte glycoprotein-specific T cells (2D2 mice), Miller et al. (2015) demonstrated a female-biased susceptibility to spontaneous autoimmune CNS demyelination, with infiltration of T and B cells and increased production of Il17 (603149), Ifng, and IgG2b. Disease was attenuated in mice with Tnf deficiency compared with mice lacking Tnfr2, implicating distinct roles for Tnfr1 and Tnfr2. Oral antibiotic treatment eliminated spontaneous autoimmunity in Tnfr2 -/- 2D2 mice, suggesting a role for gut microbiota. Sequencing of fecal 16S rRNA identified a protective microbiota profile in male Tnfr2 -/- 2D2 mice, and an abundance of other commensal bacterial species in affected female Tnfr2 -/- 2D2 mice. Miller et al. (2015) concluded that Tnfr2 blockade appears to disrupt commensal bacteria-host immune symbiosis, allowing onset of autoimmune deymyelination in genetically susceptible mice.
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