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M Labrador

Publications and source records attributed to M Labrador.

18 recordsLinked to original sources
PubMed2006

Multiplex family-based study in systemic lupus erythematosus: association between the R620W polymorphism of PTPN22 and the FcgammaRIIa (CD32A) R131 allele.

A functional polymorphism in PTPN22, a gene encoding a phosphatase involved in T-cell signaling, has been associated with autoimmunity. We checked for the prevalence of the PTPN22 R620W polymorphism in multiplex families affected with systemic lupus erythematosus (SLE) and other autoimmune diseases. Its association with other polymorphisms in mannose binding lectin (MBL) and FcgammaRIIa (CD32A) genes was also studied. Deoxyribonucleic acid samples were obtained from 233 Spanish individuals who belonged to 21 families in which at least two members had been diagnosed with some autoimmune disease, mainly SLE. A healthy control population was also included (n= 129). Genotyping for the R620W single-nucleotide polymorphism (SNP) was performed by restriction fragment length polymorphism analysis of polymerase chain reaction products. Allele frequency for the T allele was slightly higher in the families with autoimmune disease, especially when considering the affected individuals (0.094 vs 0.062). Actually, 18.8% affected family members vs 11.6% controls had the polymorphism (P= 0.179). Nineteen percent of affected individuals had both the PTPN22 T and the CD32A R131 alleles, whereas only 8.5% unaffected relatives had both susceptibility alleles simultaneously [P= 0.031, odds ratios 2.508 (95% confidence interval 1.066-5.896)]. The tendency toward finding the T allele more frequently in members affected with some particular autoimmune disorder suggests that this SNP may confer susceptibility to autoimmunity. The fact that more affected than unaffected relatives carried both the T and the R131 alleles simultaneously leads us to think about the existence of a combinatorial effect between genes that could help define individuals prone to autoimmune diseases.

Alleles↗
PubMed2003

Predictors of poor renal outcome in patients with lupus nephritis treated with combined pulses of cyclophosphamide and methylprednisolone.

Lupus nephritis remains a major cause of morbidity and mortality in patients with systemic lupus erythematosus. Although the renal prognosis has improved, the optimal therapeutic regime has not been definitively established, and significant challenges remain in the management of disease progression and recurrent renal relapse. We performed a prospective study to evaluate the outcome of 38 patients with severe lupus nephritis treated with standard cyclophosphamide and methylprednisolone pulse therapy, and to determine the variables associated with poor outcome. Five patients developed end-stage renal disease (ESRD) (13%), 10 (26%) developed persistent proteinuria (> 1 g/24h) and 15 (39%) suffered at least one relapse after 8 years of follow-up. A high chronicity index, interstitial fibrosis (P = 0.04), persistent hypertension (P < 0.0001) and hypocomplementaemia (P = 0.002) after treatment were the major variables associated with ESRD. Tubular atrophy (P = 0.01), persistent hypertension (P = 0.0001) and hypocomplementaemia after treatment (P = 0.0281) were associated with persistent proteinuria. Persistence of anti-dsDNA antibodies and hypocomplementaemia after treatment (P = 0.0118) were associated with renal relapse. Our data suggest that the group of patients with persistence of hypocomplementaemia and raised anti-dsDNA antibodies titres are at high risk of renal relapse and may be candidates for continuation of immunosuppressive treatment. Patients with persistent proteinuria alone or a high chronicity index are less likely to respond to immunosuppression, and strict control of the hypertension may be the best approach.

Adolescent↗
PubMed2001

Protein determinants of insertional specificity for the Drosophila gypsy retrovirus.

The gypsy retrovirus invades the germ line of Drosophila females, inserting with a high frequency into the ovo locus. Gypsy insertion sites in ovo are clustered within a region in the promoter of the ovo gene that contains multiple binding sites for the OvoA and OvoB proteins. We found that a 1.3-kb DNA fragment containing this region is able to confer gypsy insertional specificity independent of its genomic location. The frequency of gypsy insertions into the ovo gene is significantly lower in wild-type females than in ovoD1 females. In addition, gypsy insertions in ovoD1 females occur during most stages of germ-line development whereas insertions in wild-type females occur only in late stages. This pattern of temporally specific insertions, as well as the higher frequency of insertion in ovoD1 females, correlates with the presence of the OvoA or OvoD1 proteins. The results suggest that gypsy insertional specificity might be determined by the binding of the OvoA repressor isoform to the promoter region of the gene.

Animals↗
PubMed2001

Familial CD8 deficiency due to a mutation in the CD8 alpha gene.

CD8 glycoproteins play an important role in both the maturation and function of MHC class I-restricted T lymphocytes. A 25-year-old man, from a consanguineous family, with recurrent bacterial infections and total absence of CD8(+) cells, was studied. Ab deficiencies and ZAP-70 and TAP defects were ruled out. A missense mutation (gly90-->ser) in both alleles of the immunoglobulin domain of the CD8 alpha gene was shown to correlate with the absence of CD8 expression found in the patient and two sisters. Conversely, high percentages of CD4(-)CD8(-)TCR alpha beta(+) T cells were found in the three siblings. A novel autosomal recessive immunologic defect characterized by absence of CD8(+) cells is described. These findings may help to further understanding of the role of CD8 molecules in human immune response.

Adult↗
PubMed1999

The retrotransposon Osvaldo from Drosophila buzzatii displays all structural features of a functional retrovirus.

The Osvaldo retrotransposon has shown a high transposition rate in some strains of Drosophila buzzatii and in hybrids between D. buzzatii and its sibling D. koepferae. In order to understand the molecular basis of this phenomenon, we developed a procedure to clone a recently transposed copy with the aim of characterizing an active, full- length Osvaldo element. The complete nucleotide sequence of Osvaldo, obtained from a recent insertion site, was determined. Osvaldo is 9,045 bp long and is composed of a central coding region flanked by identical long terminal repeats (LTRs) of 1,196 bp each. Sequences homologous to the polypurine tract and tRNA-primer-binding site of retroviruses are located adjacent to the 3' and 5' LTRs, respectively. The internal region of Osvaldo contains three long open reading frames (ORFs 1, 2, and 3), comparable in size and location to gag, pol, and env retroviral genes. The conceptual translation of Osvaldo ORF1 exhibits sequence homology to HIV1 and SIV capsid (p24) and nucleocapsid (p7) mature proteins. ORF2 encodes the putative protease (PR), reverse transcriptase/ribonuclease H (RT/RH), integrase (IN), and a significant portion of the surface envelope (ENV) protein that is interrupted by a putative intron. A third ORF encodes the remaining part of the ENV protein. The predicted 62-kDa ENV protein shares several general features with membrane glycoproteins, including a potential signal peptide, a transmembrane domain near the C-terminus that could function as a membrane anchor, four consensus N-linked glycosylation motifs, and, finally, a potential protease cleavage site. The phylogenetic relationships of Osvaldo are explored, and they suggest that Osvaldo may constitute a new family of retroviruses in insects, distantly related to the previously described group of gypsy retroviruses.

Amino Acid Sequence↗
PubMed1999

Interspecific hybridization increases transposition rates of Osvaldo.

Several authors have postulated that genetic divergence between populations could result in genomic incompatibilities that would cause an increase in transposition in their hybrids, producing secondary effects such as sterility and therefore starting a speciation process. It has been demonstrated that transposition largely depends on intraspecific hybridization for P, hobo, and I elements in Drosophila melanogaster and for several elements, including long terminal repeat (LTR) and non-LTR retrotransposons, in D. virilis. However, in order to demonstrate the putative effect of transposable elements on speciation, high levels of transposition should also be induced in hybrids between species that could have been originated by this process and that are still able to interbreed. To test this hypothesis, we studied the transposition of the LTR retrotransposon Osvaldo in Drosophila buzzatii-Drosophila koepferae hybrids. We used a simple and robust experimental design, analyzing large samples of single-pair mate offspring, which allowed us to detect new insertions by in situ hybridization to polytene chromosomes. In order to compare transposition rates, we also used a stock recently obtained from the field and a highly inbred D. buzzatii strain. Our results show that the transposition rate of Osvaldo is 10(-3) transpositions per element per generation in all nonhybrid samples, very high when compared with those of other transposable elements. In hybrids, the transposition rate was always 10(-2), significantly higher than in nonhybrids. We show that inbreeding has no effect on transposition in the strains used, concluding that hybridization significantly increases the Osvaldo transposition rate.

Animals↗
PubMed1998

Antibodies against a novel nucleolar and cytoplasmic antigen (p105-p42) present in the sera of patients with a subset of rheumatoid arthritis (RA) with signs of scleroderma.

We identified three patients (two of them relatives) with RA and signs of scleroderma whose sera contained a high titre of IgG class antibodies against the nucleoli and the nucleoplasm of cells of different mammalian origins. Sera from these patients uniformly immunoprecipitated four polypeptides, from a 35S-methionine-labelled HeLa cell extract, whose mol. wts were 120, 105, 95 and 42 kD. Of these, the 95-kD protein was highly phosphorylated. By immunoblotting, these sera reacted with 105-, 95- and 42-kD proteins and affinity-purified antibodies from these, demonstrating that 105- and 95-kD proteins shared cross-reactive epitopes. Moreover, affinity-purified antibodies from each of these proteins immunoprecipitated the whole complex. Localization studies using immunoelectron microscopy and in vivo actinomycin-D-treated cells demonstrated that the 105-, 95- and 42-kD proteins were present in the granular component of the nucleolus and the nucleoplasm. In addition, the 105- and 95-kD were present in free polyribosomes as well as ribosomes attached to endoplasmic reticulum. Pulse/chase experiments strongly suggested that the complex was accomplished shortly after a 10-min pulse. It was preferentially present in the nucleus after a 2 h chase and in both nucleus and cytoplasm after a 5 h chase. We conclude that a protein complex with a main nucleolar distribution is a new autoantigen (p105-p42) recognized by autoantibodies present in the serum of a subgroup of patients with RA and scleroderma signs. These antibodies could be useful as diagnostic markers and as tools for further studies involving the biology of the nucleolus.

Antibodies, Antinuclear↗
PubMed1998

Evolutionary relationships among the members of an ancient class of non-LTR retrotransposons found in the nematode Caenorhabditis elegans.

We took advantage of the massive amount of sequence information generated by the Caenorhabditis elegans genome project to perform a comprehensive analysis of a group of over 100 related sequences that has allowed us to describe two new C. elegans non-LTR retrotransposons. We named them Sam and Frodo. We also determined that several highly divergent subfamilies of both elements exist in C. elegans. It is likely that several master copies have been active at the same time in C. elegans, although only a few copies of both Sam and Frodo have characteristics that are compatible with them being active today. We discuss whether it is more appropriate under these circumstances to define only 2 elements corresponding to the most divergent groups of sequences or up to 16, considering each subfamily a different element. The C. elegans elements are related to other previously described non-LTR retrotransposons (CR1, found in different vertebrates; SR1, from the trematode Schistosoma; Q and T1, from the mosquito Anopheles). All of these elements, according to the analysis of their reverse transcriptases, form a monophyletic cluster that we call the "T1/CR1 subgroup." Elements of this subgroup are thus ancient components of the genome of animal species. However, we discuss the possibility that these elements may occasionally be horizontally transmitted.

Amino Acid Sequence↗
PubMed1998

The evolutionary history of Drosophila buzzatii. XXXIV. The distribution of the retrotransposon Osvaldo in original and colonizing populations.

The frequency distribution of the retrotransposon Osvaldo in the haploid genome of Drosophila buzzatii has been studied in five natural populations from the Iberian Peninsula and six natural populations from Argentina. In Iberian populations, Osvaldo insertion sites do not follow a Poisson distribution, most probably due to eight euchromatic sites with high occupancy, found in all populations. The estimated alpha and beta parameters, which measure the relative importance of drift and negative selection in shaping frequency distributions, indicate that drift is the main force acting upon the distribution of Osvaldo in natural populations of D. buzzatii in the Iberian Peninsula. On the other hand, Osvaldo distribution in populations from Argentina is similar to the distribution of elements with low copy numbers, such as those described for Drosophila melanogaster and Drosophila simulans: there are no indications for deviation from a Poisson distribution, there is a low occupancy per insertion site, and genetic drift has no apparent effect on the frequency distribution. We propose that the unusual distribution found in the populations from the Iberian Peninsula is a consequence of the colonization process. Iberian Peninsula populations suffered a genomic redistribution of Osvaldo, most probably after a founder effect. Consequently, certain copies that arrived at high frequencies are showing a high occupancies today, and the mean copy number of Osvaldo is higher in Iberian Peninsula populations than in populations from Argentina. All other copies are the result of recent (after colonization) transposition events.

Animals↗
PubMed1998

Host H-2 haplotype modulates the induction of host-versus-graft disease after the induction of neonatal tolerance to H-2 alloantigens.

Mice injected at birth with semiallogeneic spleen cells develop a host-versus-graft disease (HVGD) characterized by the polyclonal activation of donor B cells by alloreactive host CD4+ T cells, the production of autoantibodies (autoAb) and the development of an inmmunocomplex-mediated glomerulonephritis. It has been demonstrated that the recognition of MHC class II, but not class I or non MHC, alloantigens triggers the development of the autoimmune syndrome (AIS). The finding of different expression patterns of Ia molecules in different mouse strains, and a closed restriction of some immune responses to particular H-2 haplotypes, prompted us to analyze whether variations in the expressed MHC class II molecules modify the HVGD. First, newborn BALB/c mice received spleen cells from F1 hybrid mice obtained by mating BALB/c mice with several mouse strains differing in the H-2 haplotype. Second, spleen cells from different F1 mice were neonatally injected in mice of both parental strains. All groups of BALB/c mice injected with different combinations of F1 mice showed an HVGD with a very similar serological course. However, in some instances, duration was different when comparing both parental strains injected with spleen cells from the mutual F1 hybrids. These results suggest that host MHC, but not donor MHC haplotype may modulate the AIS associated with the induction of neonatal tolerance.

Animals↗
PubMed1997

Transposable element-host interactions: regulation of insertion and excision.

Transposable elements propagate by inserting into new locations in the genomes of the hosts they inhabit. Their transposition might thus negatively affect the fitness of the host, suggesting the requirement for a tight control in the regulation of transposable element mobilization. The nature of this control depends on the structure of the transposable element. DNA elements encode a transposase that is necessary, and in most cases sufficient, for mobilization. In general, regulation of these elements depends on intrinsic factors with little direct input from the host. Retrotransposons require an RNA intermediate for transposition, and their frequency of mobilization is controlled at multiple steps by the host genome by regulating both their expression levels and their insertional specificity. As a result, a symbiotic relationship has developed between transposable elements and their host. Examples are now emerging showing that transposons can contribute significantly to the well being of the organisms they populate.

Animals↗
PubMed1996

The role of BALB/c donor CD8+ lymphocytes in graft-versus-host disease in (BALB/c x A/J)F1 (CAF1) mice.

To investigate the role of donor T lymphocyte subsets in the development of chronic graft-vs-host disease (GVHD) induced in (BALB/c x A/J)F1 (CAF1) mice by injecting BALB/c lymphoid cells, we analyzed the effect that CD8+ cell removal from donor inoculum has on the manifestation of the disease. Compared with age- and sex-matched CAF1 mice injected with whole lymphocyte inoculum, CAF1 mice injected with CD8(+)-depleted inoculum exhibited: 1) a higher incidence and exacerbation of nephritis by immunocomplexes; 2) higher (five- to sevenfold) spontaneous IL-4 production; 3) higher frequency titer and precocity of anti-dsDNA, anti-histone, and IgM and IgG rheumatoid factors; 4) a dramatic change in the frequency and titer of anti-U1 small nuclear ribonucleoprotein Abs; and 5) a markedly decreased engraftment (10- to 15-fold) on BALB/c donor lymphocytes. In contrast, rheumatoid arthritis-like disease, a later clinical manifestation of the GVHD in CAF1 + BALB/c model, is not present in the CD8(+)-depleted model (CAF1 + CD8-BALB/c). Considered together, these data suggest that CD8+ donor T lymphocytes play an important role in the degree of chimerism, modulation of the response to autoantigens, and clinical aspects developed in the GVHD model presented here.

Animals↗
PubMed1994

High transposition rates of Osvaldo, a new Drosophila buzzatii retrotransposon.

Transposition of a new Drosophila retrotransposon was investigated. Total genomic Southern analysis and polytene in situ hybridizations in D. buzzatii strains and other related species using a 6 kb D. buzzatii clone (cDb314) showed a dispersed, repetitive DNA pattern, suggesting that this clone contains a transposable element (TE). We have sequenced the cDb314 clone and demonstrated that it contains all the conserved protein sequences and motifs typical of retrovirus-related sequences. Although cDb314 does not include the complete TE, the protein sequence alignment demonstrates that it includes a defective copy of a new long terminal repeat (LTR) retrotransposon, related to the gypsy family, which we have named Osvaldo. Using a D. buzzatii inbred line in which all insertion sites are known, we have measured Osvaldo transposition rates in hybrids between this D. buzzatii line and its sibling species D. koepferae. The results show that Osvaldo transposes in bursts at high rate, both in the D. buzzatii inbred line and in species hybrids.

Amino Acid Sequence↗
PubMed1992

The evolutionary history of Drosophila buzzatii. XXIII. High content of nonsatellite repetitive DNA in D. buzzatii and in its sibling D. koepferae.

The frequency and types of repetitive nonsatellite DNA of two sibling species of the repleta group of Drosophila, D. buzzatii, and D. koepferae have been determined. For each species, the analysis is based on a sample of more than 100 clones (400 kb) obtained from genomic DNA. A theoretical model has been developed to correct for the presence of a mixture of repetitive and unique DNA in these clones. After correction, a high content of repetitive DNA has been demonstrated for both species (D. buzzatii, 19-26%; D. koepferae, 27-32%). The repetitive sequences have been classified according to their hybridization pattern when used as probes against genomic DNA and by their in situ hybridization signals on polytene chromosomes. Data suggest that the main nonsatellite component of these species is simpler and more repetitive than that of D. melanogaster, pointing to a wide variability in content and class size distribution of repetitive DNA among Drosophila species.

Animals↗
PubMedDate not supplied

Genetic mapping of the Adh locus in the repleta group of Drosophila by in situ hybridization.

A biotinylated probe of the Adh (alcohol dehydrogenase) gene of Drosophila melanogaster was used for in situ hybridization on polytene chromosomes of D. mojavensis and D. buzzatii, two species of the repleta group of the genus Drosophila. Hybridization showed that the Adh gene maps at the G1a band of the third chromosome. This is in accordance with a previous result obtained through the use of interspecific hybrid asynapsis as a cytological marker and establishes the limits of the precision of this method.

Alcohol Dehydrogenase↗