Structure, Sequence and Polymorphism in the HLA‐D Region

Trowsdale, John; Young, John A. T.; Kelly, Adrian; Austin, Penelope; Carson, Susan; Meunter, Helene; So, Alex; Erlich, Henry A.; Spielman, Richard S.; Bodmer, Julia G.; Bodmer, Walter F.

doi:10.1111/j.1600-065x.1985.tb01129.x

Cited by 279 publications

(98 citation statements)

References 51 publications

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“…The functional expression of a DP antigen after transfection into mouse L cells has already been described (8 (20). The Mann 3.6 cosmid used to produce L3.6.2 is derived from the homozygous cell line MANN, which in the primed lymphocyte typing reaction was shown to be DPw2 (3). The cloned genes were introduced into L cells as described (8).…”

Section: Resultsmentioning

confidence: 99%

“…DNA was introduced into mouse Ltk-cells as described (8). The transfectant L11.3 contains cosmid LC11 (DPw4) (19,20), the transfectant L3.6.2 contains cosmid Mann 3.6 (DPw2) (3), and the transfectant LDQ4-3e contains cosmids encoding DQa and -,B genes (D. Wilkinson and J.T., unpublished data). Transfectant L14, used as a control, was produced by cosmid LC14, which contains a truncated DQa gene and so does not allow expression of the DQ gene product (8 …”

Section: Methodsmentioning

confidence: 99%

“…In contrast, DQa is the only markedly polymorphic a chain. DRa is constant between individuals, while DPa shows a low level of variation and only two alleles have so far been identified (2,3). Alloantisera, mainly produced by fetal maternal stimulation, were the original basis for the definition of the HLA-DR and -DQ region products and their polymorphism.…”

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confidence: 99%

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Monoclonal antibodies to HLA-DP-transfected mouse L cells.

Heyes¹,

Austin²,

Bodmer³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

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Mouse L cells transfected with human HLA-DP (DPw4) a and f3 genes were used to make monoclonal antibodies in C3H mice. A polymorphic antibody, DPl1. Alloantisera, mainly produced by fetal maternal stimulation, were the original basis for the definition of the HLA-DR and -DQ region products and their polymorphism. It is clear that most of the serologically detected variation is in the DR and DQ 83 chains. The DP specificities were identified by cellular typing techniques and there is, so far, no corresponding serological identification. One monoclonal antibody, IRL1, has been identified, which appears to react preferentially to DPw2 and DPw3 (4). Monoclonal antibodies that are monomorphic have made a major contribution to the biochemical analysis of the HLA-D region products (5, 6), but useful polymorphic antibodies have been harder to obtain (7). A wider range of polymorphic HLA-D monoclonal antibodies, particularly for the definition of HLA-DP types, would be extremely useful both for serological typing and for biochemical and functional studies.The production by transfection of mouse L cells expressing a single human HLA-D region product, in this case HLA-DP (8), provides the basis for a novel approach to making anti-HLA class II monoclonal antibodies. If an HLA-DPexpressing L-cell transfectant is used to immunize C3H mice, the strain from which L cells were derived, then the only product the mice should react to, apart from L-cell-specific determinants, is HLA-DP. This principle is an extension of that used to make human-specific antisera (9) and monoclonal antibodies (10) by immunizing mice with human-mouse somatic cell hybrids containing a single human chromosome. In this paper, we describe the recognition of polymorphic specificities on L-cell DP transfectants and the use of these transfectants to make a polymorphic monoclonal anti-DP antibody with, surprisingly, specificity for the a chain of DPw4 and to an apparently lesser extent, DPw2.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Monoclonal antibodies to HLA-DP-transfected mouse L cells.

Heyes¹,

Austin²,

Bodmer³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

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“…These cell-surface glycoproteins consist of an a chain (;32 kDa) and a, 3 chain (=29 kDa) encoded by loci on the short arm of chromosome 6. Three related class II antigens have been identified and are designated HLA-DR, HLA-DQ, and HLA-DP.…”

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confidence: 99%

HLA class II allelic variation and susceptibility to pemphigus vulgaris.

Scharf¹,

Friedmann²,

Brautbar³

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

184

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The autoimmune dermatologic disease pemphigus vulgaris (PV) is associated with the HLA serotypes DR4and DRw6. Susceptibility to PV could be conferred either by sequences shared between the DR4 and DRw6 haplotypes or by different sequences in these haplotypes. We have examined the distribution of DR and DQ fl-chain and DQ a-chain alleles in PV patients and in control subjects by hybridization with oligonucleotide probes and sequence analysis of in vitro ampli- (8). In population studies, PV is strongly associated with the serotypes HLA-DR4 and HLADRw6 (9, 10), with <5% of the patients possessing neither marker. Disease associations with two different HLA haplotypes could mean either that these two haplotypes share a common allele or epitope or that different alleles in the two haplotypes can confer disease susceptibility.As noted above, molecular analysis of serologically defined class II haplotypes (e.g., DR4 and DRw6) has revealed significant variation at the DR and DQ loci. Sequence analysis of class II genes from various haplotypes demonstrated that a DR/I epitope at amino acid positions 67-71 (termed here "IDE", based on one-letter symbols for Ile-67, Asp-70, and Glu-71) was shared between a subset of DR4 haplotypes ("DwlO") (11) and a subset of DRw6 haplotypes (DRw13) (ref. 12 and unpublished data). This observation suggests that these shared polymorphic residues of the DR,8I chain, which determines the DR specificity, may contribute to PV autoimmunity and account for both the DR4-and the DRw6-associated susceptibility. However, Szafer et al. (10) reported that specific restriction-fragment length polymorphisms (RFLPs) detected with a DQP cDNA probe subdivided the DR4 and DRw6 haplotypes and showed significantly higher associations with PV than did the serologic markers. Analysis of allelic coding-sequence variation in patients and in controls is needed to identify the putative class II alleles or epitopes that contribute to PV.Sequence analysis of DR,3I, DRfIII, and DQB alleles from three U.S. DR4+ PV patients (DR4/4, -4/5, and -4/5) revealed that all the patients had the Dw1O DRf3I allele (13) found in only 10o of U.S. DR4+ controls (14). Further, three of the four DQP alleles from the DR4 haplotypes were the DQB3.2 allele present in 60-80% of control DR4 haplotypes. These sequence data, although obtained from only three patients, suggest that, for the DR4 susceptibility to PV, the Dw1O DR,6I allele may contribute to autoimmunity but that the DQ, allele does not. These data were obtained by using the polymerase chain-reaction (PCR) method for the in vitro amplification of specific genomic sequences (15)(16)(17).We report here the use of sequence-specific oligonucleotide (SSO) probes to determine the distribution of DR4 DRBI and DQB alleles in a panel of PV patients and controls. The frequency of the IDE sequence in patient and control DRw6 haplotypes was also determined, to test the "shared epitope" model of PV susceptibility. In addition, we describe the Abbreviations: PV, pemphigus vulgaris; ...

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“…The following probes were employed: pDAc~13b (specific for HLA-DP~; Trowsdale et al 1985); pll-13 (specific for HLADPcx; Trowsdale et al 1984); p6 (3" flanking sequence, specific for HLA-B; Ragoussis et al 1989); LG2-E2 (3" untranslated sequence, specific for HLA-E; Ulbrecht et al 1992); p259 (SalI-PstI fragment, contains the 5" untranslated sequence and the first exon of HLA-H; unpublished); HLA-A2 (3" flanking sequence, specific for HLA-A; Ragoussis et al 1989); 21133" UT specific for TUBB; Lee et al 1983). …”

Section: Dna Probesmentioning

confidence: 99%

Presence of an expressed ?-tubulin gene (TUBB) in the HLA class I region may provide the genetic basis for HLA-linked microtubule dysfunction

Volz

Weiß²,

Trowsdale³

et al. 1994

Hum Genet

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Abstract. An expressed I]-tubulin gene (TUBB) has previously been localized to chromosome region 6pter-p21 in man. By using a panel of deletion mutant cell lines and radiation-reduced hybrids containing fragments of chromosome 6, the TUBB locus could be mapped to the HLA class I region at 6p21.3. A long range restriction map including TUBB and several HLA class I genes was then generated by rotating field gel electrophoresis. The results show that TUBB maps to a segment 170-370 kb telomeric of HLA-C. This location suggests that a mutation at the TUBB locus could be the cause for certain forms of HLAlinked microtubule dysfunction, including immotile cilia syndrome.

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Structure, Sequence and Polymorphism in the HLA‐D Region

Cited by 279 publications

References 51 publications

Monoclonal antibodies to HLA-DP-transfected mouse L cells.

Monoclonal antibodies to HLA-DP-transfected mouse L cells.

HLA class II allelic variation and susceptibility to pemphigus vulgaris.

Presence of an expressed ?-tubulin gene (TUBB) in the HLA class I region may provide the genetic basis for HLA-linked microtubule dysfunction

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