Impact of Endogenous Intronic Retroviruses on Major Histocompatibility Complex Class II Diversity and Stability

Doxiadis, Gaby G. M.; Groot, Nanine de; Bontrop, Ronald E.

doi:10.1128/jvi.00097-08

Cited by 38 publications

(37 citation statements)

References 75 publications

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“…At present, based on the analysis of introns 1 to 4, it is believed that DRB3 and DRB1*03 appeared via gene duplication from a specific ancestral DRB1 gene, which was similar to DRB1*01/15 [3, 13]. On basis of exon 2 analysis, DRB3*0101 shows a higher similarity to DRB1*0301, so the generation of DRB3*0101 by gene conversion from DRB1*03 and an ancestral DRB3 appears feasible [14, 15].…”

Section: Introductionmentioning

confidence: 99%

Reassessing the role of HLA‐DRB3 T‐cell responses: Evidence for significant expression and complementary antigen presentation

et al. 2009

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In humans, several HLA-DRB loci (DRB1/3/4/5) encode diverse b-chains that pair with a-chains to form DR molecules on the surface of APC. While DRB1 and DRB5 have been extensively studied, the role of DRB3/4 products of DR52/DR53 haplotypes has been largely neglected. To clarify the relative expression of DRB3, we quantified DRB3 mRNA levels in comparison with DRB1 mRNA from the same haplotype in both B cells and monocytes, observing quantitatively significant DRB3 synthesis. In CD19 1 cells, DRB1*03/11/13 was 3.5-fold more abundant than DRB3, but in CD14 1 this difference was only two-fold. Monocytes also had lower overall levels of DR mRNA compared with B cells, which was confirmed by cell surface staining of DRB1 and DRB3. To evaluate the functional role of DRB3, tetramerguided epitope mapping was used to detect T cells against tetanus toxin and several influenza antigens presented by DRB3*0101/0202 or DRB1*03/11/13. None of the epitopes discovered were shared among any of the DR molecules. Quantitative assessment of DRB3-tetanus toxin specific T cells revealed that they are present at similar frequencies as those observed for DRB1. These results suggest that DRB3 plays a significant role in antigen presentation with different epitopic preferences to DRB1. Therefore, DRB3, like DRB5, serves to extend and complement the peptide repertoire of DRB1 in antigen presentation. polymorphisms that influence the peptide binding properties of each variant. In addition to this diversity, certain DRB clusters contain a second ''duplicate'' DR b chain [3]. These duplications can be considered copy number polymorphisms, a re-discovered mechanism of gene variation [4]. In humans, next to DRB1, there are three functional secondary DRB chains: DRB3, DRB4 and DRB5. These secondary b chains can also combine with the common DRa chain to form additional DR molecules on the cell surface [5]. Although the polymorphisms in all DRB loci are analogous, DRB1 is clearly the most polymorphic with over 500 alleles described. The other DRB loci are less polymorphic: DRB3 has 45 alleles, DRB4 has 14 alleles and DRB5 has 18 alleles [6]. While DRB1 is present in all haplotypes, the secondary DRB loci are not found simultaneously in every individual. Rather, for any given HLA-DRB1 haplotype, only one secondary DRB gene such as DRB3, DRB4 or DRB5 may be present. This means that a maximum of four DRB products can be found in an individual. Furthermore, secondary DRB loci are in linkage disequilibrium with the DRB1, and therefore three main DRB haplotypes are defined: DR51, DR52 and DR53 [7]. These names originate from the serological classification of DR specificities created in the 1980s. The human HLA-DR52 haplotype comprises a single DRB1/DRB3 locus. However, several DRB1 alleles comprise this haplogroup: DRB1 Ã 03, DRB1 Ã 11, DRB1 Ã 12, DRB1 Ã 13, DRB1 Ã 14 (all of them named in this article HLA-DRB1-52). The role of DRB5 Ã 0101 in antigen presentation has been extensively studied due to the linkage disequilibrium with DRB1 Ã 15 and its associ...

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Section: Introductionmentioning

confidence: 99%

Reassessing the role of HLA‐DRB3 T‐cell responses: Evidence for significant expression and complementary antigen presentation

et al. 2009

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“…For instance, region configuration IV is completely identical between humans and chimpanzees, indicating that it was present in a common ancestor and inherited ‘untouched’ during primate evolution. The stability of this region configuration may be due to an antisense integration of a retroviral insert within the DRB7 pseudogene (Doxiadis et al, 2008a). Moreover, all p.t.v.…”

Section: Resultsmentioning

confidence: 99%

“…No transcripts were detected for the Patr-DRB4 * 0104 and -DRB7 * 0101 alleles, present on region configuration IVa/b (Table 1A/B). Patr-DRB4 * 0104 was deemed to represent a non-functional allele because of the presence of a premature stopcodon at the end of exon 2, whereas the -DRB7 * 0101 allele is considered to be a pseudogene because of the presence of deletions and a premature stopcodon (Doxiadis et al, 2008a; Kenter et al, 1992). However, the Patr-DRB4 * 0201 allele, representing the other lineage within the Patr-DRB4 locus, produces a transcript.…”

Section: Resultsmentioning

confidence: 99%

The chimpanzee Mhc-DRB region revisited: Gene content, polymorphism, pseudogenes, and transcripts

Groot

Heijmans

Groot

et al. 2009

Molecular Immunology

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In humans, great apes, and different monkey species, the major histocompatibility complex (MHC) class II DRB region is known to display considerable copy number variation. The microsatellite D6S2878 has been shown to be a valuable marker for haplotyping the DR region in humans and macaque species. The present report illustrates that chimpanzee haplotypes also can be discriminated with this marker. The analyses resulted in the description of nine different region configurations, of which seven are present within the West African chimpanzee population studied. The region configurations vary in gene content from two up to five DRB genes. Subsequent cDNA sequencing increased the number of known full-length Patr-DRB sequences from 3 to 32, and shows that one to three Patr-DRB genes per haplotype apparently produce functional transcripts. This is more or less comparable to humans and rhesus macaques. Moreover, microsatellite analysis in concert with full-length DRB gene sequencing showed that the Patr-DRB*W9 and -DRB3*01/02 lineages most likely arose from a common ancestral lineage: hence, the Patr-DRB*W9 lineage was renamed to Patr-DRB3*07. Overall, the data demonstrate that the D6S2878 microsatellite marker allows fast and accurate haplotyping of the Patr-DRB region. In addition, the limited amount of allelic variation observed at the various Patr-DRB genes is in agreement with the fact that chimpanzees experienced a selective sweep that may have been caused by an ancient retroviral infection.

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“…Retrotransposon-mediated sequence transduction and gene duplication lead to the creation of novel genes (Brandt et al 2005;Xing et al 2006) and fosters the diversity of multigene families such as MHC-or T-cell receptor genes (Agrawal et al 1998;Doxiadis et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Different transcription activity of HERV-K LTR-containing and LTR-lacking genes of the KIAA1245/NBPF gene subfamily

Abrarova¹,

Simonova²,

Виноградова³

2011

Genetica

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Long terminal repeats (LTRs) of human endogenous retroviruses (HERVs) located near or within genes might affect their expression. We used the KIAA1245/NBPF human gene subfamily in an attempt to assess the regulatory potential of HERV LTRs. The subfamily includes five closely related paralogous genes: three of them contain an LTR in the second intron, and two genes lack it. Earlier we reported that the second and third exons of only LTR-containing genes of this subfamily could be detected in mature mRNAs of various cell lines and human tissues. The corresponding parts of mRNA of LTR-lacking genes analyzed in our study were absent from EST libraries, but other fragments of their mRNAs were available in EST databases. For a more unbiased view on the correlation between gene transcription and the intronic LTRs, in the present work we analyzed non-spliced pre-mRNA thus avoiding splicing effects. Based on RT-PCR analysis, we demonstrated that the KIAA1245/NBPF LTR-lacking gene AL592309/NBPF3 was transcriptionally active, but the LTR-containing genes showed significantly higher transcription levels. The data are in agreement with the suggestion that HERV-K LTRs within the second intron of the KIAA1245/NBPF subfamily genes might affect their transcriptional activity. However, it still remains to be investigated whether the revealed effect is due just to the LTR insertion or other factors are responsible for the difference.

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Impact of Endogenous Intronic Retroviruses on Major Histocompatibility Complex Class II Diversity and Stability

Cited by 38 publications

References 75 publications

Reassessing the role of HLA‐DRB3 T‐cell responses: Evidence for significant expression and complementary antigen presentation

Reassessing the role of HLA‐DRB3 T‐cell responses: Evidence for significant expression and complementary antigen presentation

The chimpanzee Mhc-DRB region revisited: Gene content, polymorphism, pseudogenes, and transcripts

Different transcription activity of HERV-K LTR-containing and LTR-lacking genes of the KIAA1245/NBPF gene subfamily

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