Disease relevance of DR1

• In three independent studies, using serological tissue typing techniques, an increase of the HLA class II specificity DR1 has been found in patients with multiple basal cell carcinomas [1].
• Hypoxia actively represses transcription by inducing negative cofactor 2 (Dr1/DrAP1) and blocking preinitiation complex assembly [2].
• Rheumatoid arthritis (RA) is an autoimmune disease associated with the HLA-DR4 and DR1 alleles [3].
• A hexamer sequence of proteus haemolysin spanning residues 32-37 (ESRRAL) has been identified which resembles biochemically, and discriminates by charge, between HLA types associated with RA (DR1, Dw4, Dw14, Dw15), and those not linked with the disease (Dw10, Dw13) [4].
• Rheumatoid arthritis (RA) is a chronic inflammatory joint disease associated with HLA-DR genes that share amino acid sequence motif QKRAA/QRRAA from position 70 to 74 in the third hypervariable region of DR1 molecule [5].

High impact information on DR1

• Dr1 is phosphorylated in vivo and phosphorylation of Dr1 affected its interaction with TBP [6].
• Our results suggest a regulatory role for Dr1 in repression of transcription mediated via phosphorylation [6].
• Dr1, a TATA-binding protein-associated phosphoprotein and inhibitor of class II gene transcription [6].
• Thus, the most likely mechanism for this effect is engagement of antigen-specific T cell receptors by DR1-peptide analog complexes, which results in antigen-specific competitive blocking of T cell responses by virtue of their capacity to compete with DR1-antigen complexes for binding to the T cell receptor [7].
• RARE1 and RARE2 are direct repeats (DR) of two motifs separated by 2 bp (DR2) and 1 bp (DR1), respectively, and bind RAR-RXR heterodimers more efficiently than homodimers [8].

Chemical compound and disease context of DR1

• Association of class II sequences encoding DR1 and DQ5 specificities with hypersensitivity to chironomid allergen Chi t I [9].
• DNA ribonucleases directed against direct repeat 1 (DR1) and polyadenylation signal regions of hepatitis B virus (HBV) messages were prepared with phosphorothioate modifications and varying arm lengths [10].

Biological context of DR1

• Evidence for cobinding of self- and allopeptides to human class II major histocompatibility antigen DR1 by energy transfer [11].
• Since each energy transfer affords close proximity of two fluorophors, the following picture emerges: self- or foreign peptides bind to the DR1 binding cleft by occupation of previously described specificity pockets [11].
• Serologic analysis of two families identified an HLA-DR haplotype in which DR1 and DR2 cosegregated [12].
• We postulate that the DR1/DR2 haplotype represents a recombinant between those of DR1-Dw1 and DR15-Dw2, and that the crossing-over may have been between the DRB1*0101 gene and the DR2 pseudogene [12].
• By somatic cell genetics and fluorescence in situ hybridization, we have localized the gene (DR1), present in the genome of higher eukaryotes as a single copy, to human chromosome region 1p21-->p13 [13].

Anatomical context of DR1

• Human fibroblast cell lines (M1) coexpressing DR1 were transfected with these cDNAs and used in mixed lymphocyte reactions and flow cytometric studies in vitro [14].
• The target autoantigen(s) in RA is unknown, but type II collagen (CII) is a candidate, and the DR4- and DR1-restricted immunodominant T cell epitope in this protein corresponds to amino acids 261-273 (CII 261-273) [3].
• The development of the autoimmune arthritis was accompanied by strong DR1-restricted T and B cell responses to hCII [15].
• Gold recognition did not require active antigen processing since specific proliferation was not affected by glutaraldehyde fixation of the DR1 homozygous antigen presenting cells [16].
• The frequency of HLA antigens was studied in 28 patients with knee joint arthritis; this group was characterized by elevated frequencies of HLA-A2 and DR1 [17].

Associations of DR1 with chemical compounds

• Potential anchor residues at P6 and P9 of the CII peptide are both Gly, and the lack of side chains at these positions appears to result in both a narrower binding groove with the peptide protruding out of the groove at this end of the DR1 molecule [18].
• The association of DR4 with more severe disease and DR1 and DR2 with mild disease was confirmed but no associations were found between the presence of DQw7, Dw14, C4A or C4B null alleles and articular disease severity [19].
• Variants of DR1 (DR1.2) or DR4 (Dw13.1, Dw14.1) with valine at position 86 appeared less able to confer risk for RA [20].
• Relative risk was also associated with DR1.1, the common white DR1 (Dw1) type, which has a third hypervariable region amino acid sequence similar to some forms of DR4 and has glycine at position 86 [20].
• No differences were seen in testosterone levels between DR1 or DR4 RA patients compared to those without these antigens [21].

Physical interactions of DR1

• Negative co-factor 2 (NC2) regulates transcription of the class II genes through binding to TFIID and inhibition of pre-initiation complex formation [22].
• In the absence of the tethering domain, Dr1 interacts with its corepressor DRAP1, but this interaction is not functional [23].
• Mutants that affect the ability of E4BP4 to bring about transcriptional repression are also deficient in their binding of Dr1 [24].
• The NC2 subunits dimerize and bind to TATA binding protein (TBP)-promoter complexes via histone fold domains of the H2A-H2B type [22].
• HLA-DRB6 is one of the human major histocompatibility complex (MHC) genes present in DR1, DR2, and DR10 haplotypes (approximately 26% of individuals) [25].

Regulatory relationships of DR1

• All DR1-positive patients and controls carried the DQA1*0101 and DQB1*0501 alleles [1].
• Binding of NC2 inhibits association of TFIIB with TBP-promoter complexes [22].
• Our data suggest that NC2 controls TBP binding and maintenance on DNA that is largely independent of a canonical TATA sequence [26].
• Irradiated SUM159PT/DR1/CD80 vaccines stimulate proliferation of non-HLA-DRB0101 peripheral blood mononuclear cells and present an exogenous DR1-restricted tetanus toxoid (TT) peptide, indicating that the transduced DRB0101 is functional [27].
• METHODS--PBL from 25 patients with RA and 12 healthy controls were cultured with DR1/4 restricted peptides of the influenza haemagglutinin, amino acids 307-319 (HA) and matrix proteins, amino acids 17-29 (IM) [28].

Other interactions of DR1

• The association of Dr1 with TBP results in repression of both basal and activated levels of transcription [6].
• The enhancement of Dr1-mediated repression of transcription by DRAP1 requires the tethering domain [23].
• An important argument in favor of this shared-epitope hypothesis has been the reported association between DR1 and RA in Israeli Jews [29].
• From the molecular analysis of the other DRB1 polymorphic variants, we find a trend of positive association of DRB1*0101 in DR4-negative patients versus DR4-negative healthy controls and, in the group of DR4-negative and/or DR1-negative patients, a similar increase of DRB1*06 [30].
• In all 20 DR1 haplotypes, the DRB1*0101 or 0102 allele was associated with DQA1*0101 and DQB1*0501, being identical to the Caucasian DR1 haplotypes [29].

Analytical, diagnostic and therapeutic context of DR1

• Functional dissection of a human Dr1-DRAP1 repressor complex [23].
• Japanese patients with schizophrenia (n = 266, DSM-III-R criteria) and Japanese controls (n = 283) were genotyped for DR1 and DR4 alleles using a combination of group-specific polymerase chain reaction (PCR) amplification and PCR-restriction fragment length polymorphism [31].
• In chromatin immunoprecipitations, NC2 is found on a variety of human TATA-containing and TATA-less promoters [26].
• The corresponding serotyping subclassification, however, showed a significantly lower frequency only for DRB1-DR1 (P = 0.01, RR = 0.3) [32].
• With polymerase chain reaction amplification and sequence analysis to characterize the class II alleles, we identified a novel DQB1 allele on the DR1 haplotype and an unusual DQB1 allele on the DR2 haplotype [33].

References