Disease relevance of TNFRSF21

• Despite the ability of exogenous DR6 expression to induce apoptosis, DR6 mRNA and protein were found to be elevated in prostate tumor cell lines and in advanced stages of prostate cancer [1].
• In autoimmune chronic active hepatitis patients without extrahepatic manifestations, a weak association with human leukocyte antigen DR6 was found.(ABSTRACT TRUNCATED AT 250 WORDS)[2]
• Pemphigus vulgaris is reported to be associated with human leukocyte antigen DR4 and/or DR6 whereas no data are available on pemphigus foliaceus, except for the endemic Brazilian form (fogo selvagem), which is reported to be associated with DR1 and DR4 [3].
• Univariate analysis revealed higher frequencies of DR2 (odds ratio [OR], 4.8; 95% confidence interval [CI], 1.2-18.8) and DR5 (OR, 7.5; 95% CI, 1.5-37.5) but lower frequencies of DR4 (OR, 2.3; 95% CI, 1.1-4.9) and DR6 (OR, 2.8; 95% CI, 1.4-5.8), in rubella vaccinees compared with placebo recipients with arthropathy [4].
• T cells recognizing tetanus toxin peptide 'p2' (sequence 830-844) raised in HLA DR6 individuals preferentially express V beta 2 in the TCR [5].

High impact information on TNFRSF21

• However, DR6(-/-) CD4(+) T cells hyperproliferated in response to TCR-mediated stimulation and protein antigen challenge [6].
• The phenotype seen in the DR6(-/)- mice is not due to the apoptotic pathway [7].
• The disease is associated with two kinds of HLA-DR4, DQ8 haplotypes dominantly distributed among Jewish patients, and these plus DR6, DQ5 haplotypes in non-Jewish patients [8].
• The inheritance of these low levels of antibody in asymptomatic relatives was linked to the major histocompatibility complex with a highly significant logarithm of the odds score of 9.07, almost always to a DR4 or DR6 haplotype of the patient [8].
• Incubation of the oligonucleotide containing the DR6 with keratinocyte nuclear extracts produced a specific protein-DNA complex that shifted to a higher molecular weight form upon the addition of an antibody specific to the 1,25-(OH)2D3 receptor [9].

Chemical compound and disease context of TNFRSF21

• HLA-A33/B44/DR6 is highly related to intrahepatic cholestasis induced by tiopronin [10].

Biological context of TNFRSF21

• Deletion and mutation studies of the fragment +135 to -877 demonstrated a vitamin D-responsive element that contains a motif arranged as two direct repeats separated by 6 bases (DR6), AGGTCAgaccacTGGACA, located between -786 and -803 base pairs [9].
• The affected girl from this family was shown to have human leukocyte antigen DR2 and DR6 alleles and random X-chromosome inactivation in peripheral blood mononuclear cells [11].
• We were unable to confirm that the HLA-DR6 specificity or the DR6-split DRB1*1302 are associated with poor graft survival [12].
• Previous analyses using transient transfection assays indicated that the promoter for the gene encoding the herpes simplex virus type 1 (HSV-1) neurovirulence protein ICP34.5 can be divided into an essential core region of approximately 80 bp and two potent upstream silencer domains corresponding to the DR2 and DR6 repeat arrays [13].
• A significant decrease in the frequency of TAP2*0201 was found among the patients negative for DR5, DR6, and DR8 as compared to the DR-matched controls (p < 0.05), but this could be explained by its linkage disequilibrium to the negatively associated allele DR1 [14].

Anatomical context of TNFRSF21

• DR6 is expressed in most human tissues and abundant transcript was detected in heart, brain, placenta, pancreas, thymus, lymph node and several non-lymphoid cancer cell lines [15].
• Therefore, the 5'-flanking region of the human phospholipase C-gamma1 gene confers promoter activity and contains a DR6-type vitamin D-responsive element that mediates, at least in part, the enhanced expression of this gene in human keratinocytes by 1, 25-(OH)2D3 [9].
• Among the DR specificities, DR6 was associated with a weak protective effect against thyroid autoimmunity in IDDM patients [16].
• One of the most recently identified members of the tumor necrosis factor receptor family, death receptor-6 (DR6), has been shown to mediate apoptosis following overexpression in HeLa cells [17].
• Supernatants from these cell lines reacted with lymphocytes from all DR5 positive donors and a minority of DR6 positive donors but were negative on lymphocytes of other phenotypes [18].

Associations of TNFRSF21 with chemical compounds

• Tumor necrosis factor-alpha induces the expression of DR6, a member of the TNF receptor family, through activation of NF-kappaB [1].
• Similarly, treatment of cells expressing high levels of DR6 with indomethacin and ibuprofen, compounds also known to perturb NF-kappaB function, resulted in a dose-dependent decrease in DR6 protein and mRNA levels [1].
• Our finding implied that androgen signaling pathway might cross talk with apoptosis signaling pathway through the interaction between ARA267-alpha and DR6 [19].
• Although cloned B8 recognized a DR6-specific determinant, clone C6 appeared to recognize a supratypic determinant that may be common to some DR molecules (e.g., MT2) or possibly another human Ia-like antigen (e.g., SB) [20].
• To identify the DR6 allelic frequencies in this population, PCR-positive samples were further analyzed by dot-blot hybridization using digoxigenin-labeled SSOPs [21].

Physical interactions of TNFRSF21

• Androgen receptor coregulator ARA267-alpha interacts with death receptor-6 revealed by the yeast two-hybrid [19].

Other interactions of TNFRSF21

• Treatment of LnCAP cells with TNF-alpha resulted in increases in both DR6 mRNA and protein levels, and this induction was suppressed by inhibitors of NF-kappaB [1].
• Coregulation of known apoptotic mediators (caspase-3 and death receptor 6) raises the possibility that NARC 1 might be involved in the propagation of apoptotic signaling in neurons [22].

Analytical, diagnostic and therapeutic context of TNFRSF21

• Age at onset and body mass index were unrelated to HLA antigens, but the Type 2 diabetic patients with HLA-Cw4, DR5 and DR6 showed a strong family history for Type 2 diabetes [23].
• The HLA-DR alloantigens were determined on FB II cells after IFN-gamma treatment, by immunofluorescence and by cytotoxicity assays, and were shown to be DR4, DR6, Drw52, DRw53 and DQwl [24].
• Sequence analysis of the DQ beta gene from the DRw6 haplotype revealed a new allele that differed from the DQ beta allele from a control DR6 allele at two residues [25].
• There were no significant differences between the three groups in the distribution of HLA mismatching (A, B and DR), time interval between the last BT and transplantation, DR6 recipient phenotype, or nonimmunological failures [26].
• Allele HLA DR6 was demonstrated in a similar proportion (26%) among control group and group B, while HLA DR14 (6) was less frequent among controls (18% vs 1.4%) [27].

References