All T lymphocytes and some B lymphocytes express CD5. This coreceptor is encoded by one gene that consists of 11 exons. We have previously described a B cell-specific alternative exon 1, leading to the synthesis of a protein, devoid of leader peptide, and, therefore, retained in the cytoplasm. The novel exon 1 originates from a human endogenous retrovirus (HERV) at a time interval between the divergence of New World monkeys from Old World monkeys, and prior to the divergence of humans from Old World monkeys. Based on sequence similarity to γ-retroviruses, it was categorized as class I: based on the specificity of its primer binding site, it was allotted to the subclass E, and based on its location within the cd5 gene, named HERV-E.CD5. Alternative transcripts were detected in lymphoid organs including fetal liver (not adult liver), more particularly in CD5-negative cell surface B-1b than in CD5-positive cell surface B-1a, and not at all in B-2 cells. By alignment of 5′ long terminal repeats, HERV-E.CD5 was distinguished from similar proviruses. This could be central to the regulation of membrane expression of CD5 in human B lymphocytes, and, thereby, to the strength of the B-cell antigen receptor signaling.
The coreceptor CD5 is encoded by one gene mapping to chromosome 11q12.2, and comprised of 11 exons.1 These are identical in humans and mice with respect to their size, number, and regulatory sequences.2 The protein product is expressed in T lymphocytes and some B lymphocytes.3 Based on this criterion, B cells are divided into two populations, B-2 cells encompassing the conventional B lymphocytes, and B-1 cells comprising of B-1a cells that possess CD5 at cell surface, and B-1b cells that do not, but share the functional attributes of B-1a cells. That is, in particular, the transcription of messenger RNAs (mRNAs) for CD5.4, 5 Such cells are unique in that they make polyreactive antibodies (Ab), and display an increased propensity for malignant transformation.
Phenotypic differences between B-1a, B-1b, and B-2 subsets may be related to differential use of the conventional exon E1A, or the alternative exon E1B of the cd5 gene in B lymphocytes.5 The additional exon 1 originates from the contribution of a human endogenous retrovirus (HERV). This insert generates another promoter for the cd5 gene, and enables the transcription of a new mRNA. Since E1B splices in exon 2, the initiation, shift from exon E1A to exon E3, leads to a functional intracellular variant of CD5.5
HERVs are believed to represent degenerate footprints of exogenous retroviruses. Together with the retroviral long terminal repeats (LTRs), they make up 8% of the human genome.6 They were inserted into the human genome 45 millions of years ago. Thus, the majority of integration events occurred after the divergence of the Old World from the New World monkeys.7 HERVs have been grouped into three classes based on pol gene homologies to exogenous animal retroviruses, such as class I HERVs that are related to γ-retroviruses. In addition, their genes carry a primer-binding site (pbs) complementary to the 3′ 18 nucleotides (nt) of a distinct transfer RNA (tRNA). In their former classification, the genes are named according to which tRNA they bind. Thus, the pbs of HERV-E are specific for tRNAGlu.
Throughout time, most of retroviral open reading frames (ORFs) have been disrupted by point mutations, frameshifts, or deletions. Other proviruses impact on the expression of nearby genes by promotion, enhancement, splice, or polyadenylation. HERVs, in particular those of the type-E family, give rise to protein products with various degrees of tissue specificity. The expression of a given retrovirus in such tissue should impart a benefit to the progeny of those individuals in which integration into their germ lineage occurred. Such are the cases,8 for the gene encoding an enzyme that enhances lipolysis in hibernating mammal and for that encoding one of the two receptors that mediate the effects of endothelin. On the contrary, aberrant expression of the same retroviruses in other tissues would be detrimental. Such are the cases of an alternative promoter for the Opitz syndrome gene Mid 1,9 the pleiotrophin gene in choriocarcinoma cells,10 and various HERVs in autoimmune diseases, such as systemic lupus erythematosus (SLE).
We focus on the alternative exon E1B for cd5 in B lymphocytes due to the integration of an HERV. The structural, phylogenetic, and functional characteristics of this HERV-E.CD5 insert have been analyzed. Based on its structure, this provirus warrants its separation from other HERV-Es. Intriguingly, the related transcripts are specific for B lymphocytes, and never detected in T lymphocytes. There is also evidence for integration of these elements within the human cd5 locus, after the divergence of New World from Old World monkey lineages, and prior to that of humans from Old World monkey lineages.
HERV-E on CD5 locus
We have recently established the integration of a 5254 base pairs (bp) retroviral sequence into the human chromosome 11q12.2.5 It was inserted in the CD5 gene-containing clone pDJ632c8 (Genbank No AC003678) between the cd5 gene enhancer at position 53 809 and the promoter of its first exon E1A at position 59 062 (Figure 1a). A 468-nt ORF is likely to represent the putative gag p15. The 5′LTR embraces the first 463 bp, and, downstream, includes 5 nt and IndexTermTGGTTCCCTGA-CCAGGAA as a 18-bp complementary tRNAglu pbs. Based on this specificity, the HERV may be categorized as subclass E, and, based on sequence similarity to γ-retroviruses distributed into class I.
The IndexTermTGgtaaga splice donor sequence takes up the position 727, and a IndexTermttcctctctcagGC potential splice acceptor site (Figure 1b) appears close to the env region in the position 3334. One may assume that HERV-E splices with the 5′LTR within the viral sequence itself. Since pre-B lymphocyte 697 cell line cells express exclusively E1B-containing transcripts for CD5,5 they were suitable to test this prediction. We used one sens primer (CD5-E1B) located upstream of the splice donor, and several antisense primers overlapping exon 5 and exon 6 primer CD5, or located in the gag, the pro, or the env sequences. A single splice was encountered between the 5′LTRs splice donor and CD5 exon 2 splice acceptor5 (lane 4 in Figure 1c). This suggests that viral proteins were not synthesized.
Other HERV-Es having an alternative splicing
From the alternative HERV-E.E1B-containing CD5, we searched human ESTs in the BLAST GenBank™ database. Transcript HERV-E elements with retroviral or non-retroviral sequences, including HERV-E chimeric transcripts, were selected. Of 145 informative sequences, 77 accounted for 20 distinct retroviral elements. The location of retroviral sequences, and associated splice elements, was then determined (Figure 2). This method revealed that a minimum of 12 genes recombined with an HERV-E provirus element. Recombinations were ascribed to EDNRB, ApoC1, MID1, PTN, E2 ubiquitin ligase 2 (UB2D2), PC326/Hom-Tes 95, to the putative genes FLJ22374, FLJ16052 and FLJ31301, to other endogenous retroviral sequences (HERV-L reverse transcriptase (RT) and LTR7 repetitive element from FLJ36232 on the BRCA1 locus), and to unknown elements (CB16654 on 2p22.3 and BX951758 on 19q13.43). Finally, classification of the retroviral insert as HERV-E was confirmed, and its LTRs belong to LTR2, LTR2B, and LTR2C families. Thus, HERV-E.CD5 is a member of LTR2 family.
Similarity to HERV-Es from different subclasses
A stepwise analysis compared this provirus with HERVs containing similar LTRs, and producting transcripts (Table 1). Examination of complete sequences from HERV-E 4-1,11 and from the provirus inserted into the 13q14.11 loci, revealed a 3621-bp deletion from position 3350 through position 6971 in clone 4-1. Analyses revealed that pol, in full, and env, in part, were lacking in HERV-E.CD5 (Figure 3). Percentages of identity in the HERV-E.CD5 gag, pro, and env regions to HERV-E 4-1 reached 70, 69, and 72%, respectively.
The 5′ and the 3′ ends of the HERV-E.CD5 provirus are homologous to HERV-E 7q33 that was inserted into the pleiotrophin locus.10 Thus, this recombinant HERV-E 7q33 structure emerges as the prototype of a large HERV-E-containing provirus family. Its members occupy 12 loci: 1q24.1, 1q24.3, 2p24.3, 5q31.2, 6p21.31, 6p21.33, 7p22.1, 7q33, 13q22.3, 17q21.31, Xp22.22, plus 7p14.3 which is more deleted.
Next, the HERV-E members were classified according to the combination of their four components (Figure 3): we arrived at two complete proviruses, one deleted provirus (HERV-E.CD5), 12 recombinant proviruses, and four solitary LTRs reported in Table 1.
HERV-E fusion transcripts expression profiles
As indicated by expressed sequence tag (EST) database, HERV-E fusion transcripts were detected in numerous tissues (Table 1). HERV-E.CD5, HERV-E 4-1, HERV-E.Apo C1, HERV-E.FLJ36232 LTR7, and HERV-E.HERV-L RT were even expressed in circulating leukocytes, and resident leukocytes of lymphoid organs. Prompted by our finding of the expression of HERV-E.CD5 in cell sorted B-1 lymphocytes (Figure 4b), we compared CD5-expressing B-1 lymphocytes from chronic lymphocytic leukemia (CLL) patients to CD5-nonexpressing B-2 Daudi cells, as well as to Jurkat, U937, Hep-G2, and placenta cells. HERV-E.CD5 was restricted to B-1 lymphocytes (Figure 4c). In contrast, HERV-E.FLJ32232 LTR7 and HERV-E 7p22.1 were detected in B-1, and also in B-2 and T lymphocytes, and in liver, where HERV-E 4.1 was shared by B-1, B-2, T, and monocytic cells (Figure 4c).
This RT-polymerase chain reaction (PCR) pattern of expression was confirmed by quantitative RT-PCR (Figure 5). It appeared that the level of transcription of E1A-containing transcripts was higher compared to E1B-containing transcripts. The latter were found in lymphoid organs, as well as the fetal liver. In adult liver, heart, pancreas, kidney, and lung, there was little CD5 transcription from the E1A promoter, and no transcription from the E1B promoter.
Evolutionary age of the HERV-E.CD5
In an attempt to determine the date of integration of HERV-E into the cd5 locus, genomic DNAs from the New World Redhowler monkeys were amplified with those from the gorillas, and other Old World monkeys. This amplification is based on the enhancer of cd5 upstream the HERV-E integration site, and downstream the promoter of its E1A. We obtained an HERV element of the expected size in apes and other Old World monkeys, but not in New World monkeys (Figure 6). These results indicate that the sequence was integrated prior to the divergence of apes from other Old World monkeys, some 25 millions years ago.
Sequence comparison of the 5′ and the 3′ LTRs of the HERV-E.CD5 revealed that they were 92.2% identical, and that differences were restricted to five insertions, 12 deletions, and 19 substitutions. Divergences between 5′ and 3′ LTR sequences may serve as ‘molecular clocks’.12 It can indeed be inferred from a divergent rate of 0.15–0.21% per million years7 and an LTR divergent average of 4% integration that HERV-E was integrated into the cd5 locus at a time between 19 and 27 millions years. This result fits with the integration time calculated from the genomic PCR studies.
LTR phylogenetic analysis and expression
Alignment of 5′LTR regions of 18 HERV-E sequences, including HERV-E.CD5, was subjected to phylogenetic analysis using the neighbor-joining method and the maximum-parsimony method. Both strategies converged on similar trees. Three clusters were supported by high bootstrap values (Figure 7). The first cluster is composed of viruses from LTR2 family, HERV-E.CD5 belongs to this cluster. The LTR2B family cluster comprised of two different subclusters, according to the HERV-E transcript cellular expression, and the nondeleted proviruses HERV-E 4.1 and HERV-E 13q14.11 were separate within the LTR2C family.
These proviruses were similar, with respect to their tissue expression, but HERV-E.CD5 was restricted to B lymphocytes. Other LTR2 proviruses were found in lymphoid cells. HERV-E.ApoC1 is also highly expressed in adult liver, and far less in lymphoid organs.13 This is consistent with our failure to detect transcripts either in lymphocytes or monocytes. Their absence may be explained by the sensitivity of our technique, and/or by differences between in vitro cell line cells on the one hand, and in vivo lymphoid tissue cells on the other. In the LTR2 family, the presence of HERV-E.EDNRB and HERV-E 7p14.3 in placenta samples, and their absence in lymphoid organs may help to distinguish them from other members of the cluster.
The HERV-E 4.1 provirus, the product of which is also present in lymphoid organs, differs from these groups LTR2, in that it is included into the LTR2C family. This suggests that HERV-E 4.1 has a large pattern of expression (ie lymphocyte, monocyte, epithelial cells).
We describe structural, phylogenetic, and functional characteristics of a member of the HERV-E family that is associated with the cd5 gene. Sequence analyses indicate that an HERV sequence underpins the new promoter within an intron of this gene, upstream of the coding region, where a new promoter is created. Transcripts fusing HERV-derived 5′ untranslated exon with the intact ORF of cd5 are not expressed in T and B-2 lymphocytes, but confined to B-1b and B-1a cells. The new transcripts were found in lymphoid tissues, including the fetal liver, a primary lymphoid tissue.14 It is interesting that, like all other organs, adult liver (no longer a lymphoid tissue) was devoid of those alternative transcripts.
Since HERV-Es have gained access to the primate lineage,15 unfavorable members have been either not maintained or removed in the long term. Those integrated have been appropriated in the time interval after the first divergence of New World from Old World monkeys, 40 millions years ago, and prior to the second divergence of humans from the apes and Old World monkey lineage, 25 millions years ago. Integration of HERV-E 4-1, HERV-E.PTN, and HERV-E.EDNRB preceded the second divergence, whereas HERV-E.ApoC1, which was present only in humans and apes, inserted later into the human genome.
In view of the increased transcription and translation of members of the HERV-E family in patients with autoimmune diseases, there has been much speculation that some HERVs contribute to the development of SLE. There are several mechanisms that could explain its role in autoimmunity. Firstly, retroviral proteins may mimic components of small ribonucleoproteins. Some patients with SLE mount an Ab response to retroviral antigens, in relation with the detection of the related mRNA in their peripheral blood mononuclear cells (PBMCs). Another example is PC326, a β-transducine protein found in plasmocytomas, but not in normal plasma cells.16 This leads to an increase in the production of Abs, as established by serological analysis of recombinant complementary DNA (cDNA) expression library in the cerebrospinal fluid of patients with moyamoya disease. There is little evidence to involve this protein in autoimmunity. Secondly, the proposed pathogenic role for HERV may be based on the correlation of superantigen (Ag) expression from proviruses, such as a novel HERV, termed ‘IDDMK (1, 2) 22’ in IDDMK and MSRV/HERV-W in multiple sclerosis.17, 18 Thirdly, the effect of HERVs may instead be at the level of cellular gene transcription. CD5 negatively regulates B-cell Ag receptor (BCR)-mediated signaling through its constitutive association19 with SH2-containing phosphatase-1 (SHP-1). If E1B is substituted for E1A, the conventional exon 1 is spliced out, and the initiation site shifts from the first ATG in exon 1, to the next ATG, that is, 171 nt downstream in exon 3.5 Therefore, the transcripts lack the nt encoding the leader peptide, and the truncated protein end product is not translocated to the plasma membrane, but holds SHP-1 in the endoplasmic reticulum. Although B-1a and B-1b lymphocytes express both species of transcripts, the E1A-encoded full-length molecule predominates over its E1B-encoded truncated counterpart in B-1a cells, whereas it is the short molecule that predominates over its long variant in B-1b cells. In the latter case, the strength of the BCR-mediated signaling would be increased, and autoreactive B lymphocytes expanded. Furthermore, this truncated CD5 protein diminishes the expression of full-length CD5 in Jurkat T cells transfected with E1B-type cDNA.5
B-cell-specific transcription factors (TFs) for cd5 could be important in the regulation of CD5 expression in B lymphocytes. In the promoter region of the new E1B motif, there are numerous potential TF binding sites, such as PU.1, SRY, Oct-1, E2A, and AP-1. Ideally, to restrict activation to these lymphocytes, TFs for the E1B-type transcripts should be specific for B cells.
Levels of expression of a given gene may also be encouraged by relaxation of chromatin structures associated with an improved accessibility of TFs.20 This phenomenon is consistent with the hypomethylation status of the autoimmune patients.21 Importantly, provirus sequences, which are transcriptionally silenced by methylated nt, have been suspected to be potential targets for hypomethylation.22 For example, HERV-K gag is overexpressed in response to demethylation in certain cells,23 and CpG methylation directly regulates transcriptional activity of the HERV-K family.
Our preliminary results are indeed indicative of a reduced methylation of nt within the promoter region of cd5 in B cells from patients with SLE. These showed an increased substitution of HERV-E.CD5 for the conventional transcript in their B lymphocytes, which reduces the level of the BCR for transduction, and thereby, enables the production of autoAbs. Our in vivo finding was confirmed by the in vitro induction with procainamide, which is a DNA methyltransferase inhibitor, of E1B-containing transcripts in B cells (data not shown).
To conclude, this new HERV has integrated into a gene that is critical in the control of immunity. The balance between these two exons 1 might control the regulation of membrane expression of CD5 in human B lymphocytes.
Materials and methods
Human CD5-expressing Jurkat T cells and CD5-nonexpressing Daudi B cells, Hep-G2 hepatocytes, myelomonocytic U937 cells, and African green monkey COS-1 cells were all purchased from ATCC. Human pre-B 697 cell line cells were kindly donated by Paul Guglielmi (Montpellier, France).
After informed consent, PBMCs were isolated from healthy volunteers, from patients with CLL, and from tonsil single-cell preparations on Ficoll-Hypaque density gradients, with the approval of our Ethical Committee. These suspensions were enriched in B lymphocytes by removing T lymphocytes with two rounds of rosetting with sheep erythrocytes, and depleting T lymphocytes with anti-CD3 Ab-coated microbeads (Miltenyi).
To sort B-1a (CD5+CD45RAinterm), B-1b (CD5−CD45RAdim), and B-2 (CD5−CD45RAbright) subpopulations, 108 tonsillar B cells were stained with phycoerythrin-anti-CD5 and fluorescein-anti-CD45RA monoclonal Abs (both from Beckman-Coulter) at 4°C for 30 min, flow cytometry sorted, and reanalyzed to confirm 95% purity.
Lymphocytes and monocytes were cultured in RPMI-1640 medium (BioWhittaker) supplemented with 10% fetal calf serum, 2 mM L-glutamine, 200 U/ml penicillin, and 100 μg/ml streptomycin. For other cell types, Dulbecco's modified Eagle's medium was substituted for RPMI-1640.
RT-PCR for fusion transcripts
Total mRNA (1 μg) was extracted by the RNAble method (Eurobio), reverse-transcribed with Moloney murine leukemia virus RT and oligo-dT, according to the manufacturer's instructions (Life Technologies), and applied to RT-PCR with specific primers (Table 2). Two human multiple tissue cDNA panels, ‘Human I’ and ‘Human immune’, were purchased from Clontech (Palo Alto).
RT-PCR was carried out as follows: denaturation at 94°C for 5 min, starting with five cycles (94°C for 30 s, 62°C for 40 s, and 72°C for 1 min), followed by 40 cycles (94°C for 30 s, 58°C for 40 s, and 72°C for 1 min), and completed with extension at 72°C for 20 min. Amplified cDNA was separated on 2% agarose gel (BioWhittaker), and bands were visualized with 0.5 μg/ml ethidium bromide. The CD5 products were verified by digestion with KpnI (restriction site in exon 5), and direct sequencing. By giving the expected patterns, restriction digestion confirmed the specificity of the other RT-PCR products.
Quantitative RT-PCR was performed in 10 μl mixtures containing 50 ng template cDNA, 500 nM of each primer, 1 × SYBR® Green PCR Master mix (Applied Biosystems). Amplification consisted of one cycle at 50°C for 2 min and one at 95°C for 10 min, followed by 50 cycles at 95°C for 15 s, and 60°C for 1 min. Each assay included the reaction mixture with no template, as a negative control.
The CD5 expression was determined by coupling one antisense primer located in exon 3, with sense primers located either in E1A for the conventional cd5, or in E1B for the alternative cd5 (Table 2). All expression levels were normalized to that of hypoxanthine phosphoribosyl-transferase (HPRT). The final results were expressed relative to the level of HERV-E.CD5 transcripts in fetal liver, which was assigned an arbitrary value of 1, because, among the tissues tested, it was that with the lowest quantity of HERV-E.CD5 mRNA.
Genomic extraction and PCRs
Human DNA was extracted from normal PBMCs. DNA from healthy baboons was donated by Gilles Blancho (Nantes, France). African green monkey DNA was isolated from COS-1 cells. A phenol–chloroform standard protocol was used to extract genomic DNA from gorilla cells (gift from Pierre Tivillon, La Plaine, France), macaque cells (gift from Emmanuel Le Grelle, Romagne, France), and redhowler monkey cells (gift from Antoine Gessain, Paris, France).
The PCRs required 0.5 μg genomic DNA, and consisted of denaturation at 94°C for 5 min, starting with five cycles (94°C for 30 s, 58°C for 40 s and 72°C for 3 min), continuing with 40 cycles (94°C for 30 s, 54°C for 40 s, and 72°C for 3 min), and ending with extension at 72°C for 20 min. Amplified DNA was separated on 1% agarose gel, and its bands visualized as above.
Database searches and sequence analyses
Human ESTs were screened by BLAST version 2.2.9,24 using R-U3-leader sequences from HERV-E 11q12.2 on cd5 locus as the query to discern novel chimeric mRNAs. These transcripts were analyzed by Ensembl project (http://www.ensembl.org), which explored both retroviral and nonretroviral sequences. Analyses of retroviruses were performed through HERV database (http://herv.img.cas.cz), blast 2 sequences alignment (http://www.ncbi.nlm.nih.gov), and RepeatMasker (http://www.repeatmasker.org). To determine the nature of the nonrepetitive sequences, potential hybrids were further characterized by Ensembl and BLAST searches.
Sequence alignment and phylogenetic analyses
In all, 19 HERV-E 5′LTR nucleotide sequences were aligned using the CLUSTAL W software, version 1.8 supported by the EBI server (http://www.ebi.ac.uk). This first sketch was manually refined through the alignment editor GENEDOC version 2.6.002.25 Repetitive insertions and deletions in LTRs dictated the exclusion from analysis of an HERV-E sequence located in 8p23.1 locus. The NJM was applied using DNADIST26 and NEIGHBOR of PHYLIP Package,27 version 3.572, with pairwise distances estimated using Kimura 2-parameter distances.28 The robustness of different branches was weighted by bootstrapping 1000 replicates, using SEQBOOT, DNADIST, NEIGHBOR, and CONSENSE modules supplied with the PHYLIP Package. The MPM was also applied using PAUP 4.0b10 program. All trees were constructed through a heuristic tree-search. All characters were weighted equally and left unordered. Program was run on 1000 bootstrap replicates. All trees were visualized using tree view 1.6.6 (swofford DL, Sinaver Associates, Sunderlan, MA, USA).
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We thank S Forest and C Séné for secretarial assistance.
Financial interests: none
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Renaudineau, Y., Vallet, S., Le Dantec, C. et al. Characterization of the human CD5 endogenous retrovirus-E in B lymphocytes. Genes Immun 6, 663–671 (2005). https://doi.org/10.1038/sj.gene.6364253
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