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ABSTRACT: In this work, we proposed to determine the association of the PTPN22*R620W SNP with primary antiphospholipid syndrome (PAPS) in a case-control association study of Spanish Caucasian individuals. A total of 81 PAPS patients were compared with 81 blood-donor healthy control subjects. PTPN22 SNP (R620W) genotyping was performed by using a polymerase chain reaction-restricted fragment length polymorphism assay. No statistically significant differences were found between control subjects and PAPS patients for the PTPN22*R620W genotypes (P = 0.214). No statistically significant differences were found according to either the presence or absence of antiphospholipid antibodies or the clinical manifestations associated to PAPS. Our results indicate that this functional PTPN22*R620W polymorphism is not associated to PAPS; it seems not to be a risk factor in our Spanish population. The effect of the PTPN22 SNP on clinical manifestations and presence of antiphospholipid antibodies in APS warrants further investigations.
International Journal of Immunogenetics 09/2011; 38(6):529-31. · 1.29 Impact Factor
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ABSTRACT: The significance of beta2-glycoprotein I (β2GPI) polymorphisms in the production of anti-β2GPI and other antiphospholipid autoantibodies (aPL) and in the pathogenesis of primary antiphospholipid syndrome (PAPS) is not well understood. We performed a study comparing the distribution of polymorphisms at codons 247 (Val247Leu) and 316 (Trp316Ser) of the β2GPI gene in a Caucasian Spanish population of PAPS patients and healthy controls, and then making correlations with the development of anti-β2GPI antibodies and other aPL and associated clinical manifestations. A total of 57 PAPS patients and 100 control subjects were included. In the analysis of Val247Leu polymorphism, alleles (V and L) and genotypes (V/V, V/L, L/L) were similarly distributed in PAPS patients and controls (P = 0.66 and P = 0.22, respectively). Regarding Trp316Ser polymorphism, we found a higher percentage of patients with respect to controls expressing S allele (11.4 vs. 5%, P = 0.02) and T/S genotype (22.8 vs. 10%, P = 0.02). However, when we compared T/T and T/S genotypes in PAPS patients, we found no differences regarding generation of anti-β2GPI, other aPL and clinical manifestations favoring any genotype. Our findings suggest that among Spanish Caucasians, polymorphisms at codon 247 (Val247Leu) do not seem to influence PAPS pathogenesis. On the contrary, polymorphisms at codon 316 (Trp316Ser), by means of an increased S allele and T/S genotype presence in Spanish Caucasian patients, might play a role in the pathogenic development of PAPS, although mechanism would not involve an increased production of anti-β2GPI and other aPL.
Rheumatology International 01/2011; 32(4):927-32. · 1.88 Impact Factor
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ABSTRACT: The evolution of valvular disease in antiphospholipid syndrome (APS) is barely known. In order to evaluate whether the presence or absence of valvular disease at the time of diagnosis of APS, assessed by an initial echocardiogram, predicts its subsequent evolution, we performed a prospective cohort study. We included 53 patients with APS. An initial transthoracic echocardiogram was performed on patients at the time of diagnosis of APS. Serial echocardiograms were conducted along a 12-year follow-up. Final echocardiograms were used for comparative purposes. We started with 29 patients (54%) with and 24 (45%) without valvulopathy at initial echo. At the final echocardiogram, 27 of 29 patients with initial valvulopathy continued to have valvular disease (a 93% observed likelihood), and 22 of 24 patients without initial valvulopathy demonstrated an absence of valvular disease (a 91% observed likelihood). Patients with valvulopathy in comparison with those without presented more arterial thrombotic events (69% vs. 20%, P < 0.001), atherosclerotic risk factors (62% vs. 29%, P = 0.01), livedo (48% vs. 16%, P = 0.01) and migraine (41% vs. 12%, P = 0.02). We have identified two subtypes of APS patients with and without valvulopathy by defining differential clinical features and with little crossover in valvular involvement over a long follow-up period, giving a high prognostic value to the initial echocardiographic assessment.
Lupus 04/2010; 19(5):575-82. · 2.34 Impact Factor
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ABSTRACT: The main objective of this study is to determine the relationship between the activity of DNase1 and the clinical and immunological features in patients with systemic lupus erythematosus (SLE). A total of 66 patients (8 men and 58 women) diagnosed with SLE according to the American College of Rheumatology (ACR) SLE classification criteria were included in the study. Sixty-two sera from healthy blood donors were also included as controls. Epidemiological, clinical, immunological and therapeutical features for each patient were obtained. Disease activity was assessed using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). DNase1 activity was determined by using a radial enzyme diffusion method. Statistical analysis was performed using SPSS 12.0 software, with significant P value <0.05. Dnase1 activity was lower in patients with SLE than in the control group: 13.69 +/- 8.52 mug/mL vs 24.75 +/- 12.32 mug/mL, respectively (P < 0.005). No statistical relationship was found between DNase1 activity and disease evolution time, hypertension, presence of absolute or relative proteinuria, SLEDAI, new clinical manifestations, anti-Ro antibodies, anti-La antibodies, anti-RNP antibodies, anti-DNA antibodies, anti-cardiolipin antibodies, lupus anticoagulant, or with the treatment pattern received by the patients. Although important differences in DNase1 activity were found between patients with or without anti-Sm antibodies, they did not reach statistical significance. DNase1 activity was significantly lower in patients with SLE. Nevertheless, we did not find further relationships with any other of the epidemiological, clinical, immunological or therapeutical variables considered.
Lupus 02/2009; 18(5):418-23. · 2.34 Impact Factor
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ABSTRACT: To evaluate the presence of anti-PDGFR-alpha antibodies by immunological methods in patients with systemic sclerosis (SSc).
Fifty-eight women diagnosed with SSc and 36 healthy women controls were included. IgG anti-PDGFR-alpha were measured by ELISA and immunoblot. Associations with clinical and immunological findings were also studied.
Non-significant differences were detected between patients with SSc and controls: median value 0.287 (range 0-2.06) versus median value 0.226 (range 0-2.94), respectively (p = 0.583). No correlation between the presence of anti-PDGFR-alpha antibodies and clinical and serological features was found. Serum samples from patients with SSc and healthy people who had high titres of anti-PDGFR-alpha antibodies by ELISA recognised the same band corresponding to PDGFR-alpha by immunoblot.
Although anti-PDGFR-alpha antibodies seem to be disease-specific when determined by bioactivity assays, these antibodies are also detected in normal subjects when immunological methods are used. Thus, anti-PDGFR-alpha antibodies may arise from natural autoantibodies. Possibly, SSc autoantibodies recognise a different epitope on the PDGFR-alpha molecule which triggers its stimulatory effect when analysed by functional assays. Alternatively, naturally occurring autoantibodies may even become pathogenic after affinity maturation and class switching in genetically susceptible subjects.
Annals of the rheumatic diseases 08/2008; 67(7):1027-9. · 8.11 Impact Factor
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I Ferreiro-Neira,
M Calaza,
E Alonso-Perez,
M Marchini,
R Scorza,
G D Sebastiani,
F J Blanco,
I Rego,
R Pullmann,
C G Kallenberg, [......],
T Witte,
C Papasteriades,
I Kappou-Rigatou,
E Endreffy,
A Kovacs,
J Ordi-Ros, E Balada,
P Carreira,
J J Gomez-Reino,
A Gonzalez
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ABSTRACT: Genetic variation in the interferon regulatory factor 5 (IRF5) gene affects systemic lupus erythematosus (SLE) susceptibility. However, association is complex and incompletely defined. We obtained fourteen European sample collections with a total of 1383 SLE patients and 1614 controls to better define the role of the different IRF5 variants. Eleven polymorphisms were studied, including nine tag single nucleotide polymorphisms (SNPs) and two extra functional polymorphisms. Two tag SNPs showed independent and opposed associations: susceptibility (rs10488631, P<10(-17)) and protection (rs729302, P<10(-6)). Haplotype analyses showed that the susceptibility haplotype, identified by the minor allele of rs10488631, can be due to epistasis between three IRF5 functional polymorphisms. These polymorphisms determine increased mRNA expression, a splice variant with a different exon 1 and a longer proline-rich region in exon 6. This result is striking as none of the three polymorphisms had an independent effect on their own. Protection was independent of these polymorphisms and seemed to reside in the 5' side of the gene. In conclusion, our results help to understand the role of the IRF5 locus in SLE susceptibility by clearly separating protection from susceptibility as caused by independent polymorphisms. In addition, we have found evidence for epistasis between known functional polymorphisms for the susceptibility effect.
Genes and Immunity 07/2007; 8(5):429-38. · 3.87 Impact Factor
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ABSTRACT: Difuse proliferative lupus nephritis (DPLN) is the most common and severe form of lupus nephritis. A predominance of IFN-gamma-producing T cells in both peripheral and renal tissues of patients with DPLN has been identified which suggests an important role for cell-mediated immunity in the pathogenesis of this complication in SLE. The biological effects of IFN-gamma rely mainly on the activity of the transcription factor called signal transducer and activator of transcription (STAT)-1. To assess the IFN-gamma/STAT-1 pathway in DPLN, we examined the expression of STAT-1 in renal biopsies from 15 DPLN patients by immunohistochemical staining with an anti-STAT-1 antibody. The expression of STAT-1 in renal tissues was correlated with several clinical and laboratory findings in these DNPN patients.STAT-1 was activated in the tubular cells in all DPLN patients. Seven of 15 DPLN biopsies (46.7%) showed positive cells in glomeruli. Five of these seven DPLN biopsies (71.4%) with positive glomerular cells showed a serum creatinine >1.5 mg/mL at the time the biopsy was carried out whereas only one of eight DPLN biopsy specimens (12.5%) without positive glomerular cells, showed a serum creatinine >1.5 mg/mL (P = 0.041). Moreover, the percentage of DPLN patients with a worse renal outcome in those who showed expression of STAT-1 in glomerulari were higher in comparison to those without STAT-1 expression (P = 0.041). Our results show that STAT-1 is activated in DPLN suggesting that biological effects of IFN-gamma in renal tissues depend, at least in part, on the activation of STAT-1.
Lupus 01/2007; 16(7):483-8. · 2.34 Impact Factor
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ABSTRACT: 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.
Tissue Antigens 12/2006; 68(5):432-8. · 2.59 Impact Factor
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ABSTRACT: Purpose. Global DNA hypomethylation in CD4+ T has been detected in systemic lupus erythematosus (SLE) patients and it has been suggested that such a phenomenon could directly be linked to the pathogenesis of the disease. The present study was aimed to investigate the relationship between overall DNA methylation and the expression of five genes involved in the DNA methylation process.
Methods. DNA deoxymethylcytosine (dmC) content of purified CD4+ T cells from 29 SLE patients and 30 healthy controls was measured by means of an enzyme-linked immunosorbent assay (ELISA). Transcript levels of three DNA (cytosine-5) methyltransferases (DNMT1, DNMT3A, and DNMT3B) and two methyl-CpG-binding proteins (MBD2 and MBD4) were quantified by real-time reverse-transcription polymerase chain reaction (RT-PCR). Association studies were also carried out with several laboratory parameters, as well as with the patients’ clinical manifestations.
Results. SLE patients had significantly less CD4+ T cell DNA dmC content than controls (0.802±0.134 vs. 0.901±0.133) (p=0.007). No differences in transcript levels were observed for DNMT1, DNMT3A, and DNMT3B between SLE patients and controls. On the contrary, MBD2 and MBD4 mRNA levels were considerably higher in the patients group: 0.975±0683 vs. 0.604±0.614 (p=0.004), and 0.359±0.330 vs. 0.092±0.169, respectively (p<0.0005). Interestingly, SLE patients showed a negative correlation between methylation indexes and MBD2 (r=-0.609, p<0.0005) and MBD4 (r=-0.395, p=0.034) transcripts levels. Simultaneous association of low complement counts with either lymphopenia, high titers of anti-dsDNA antibodies, or a SLEDAI higher than 5, resulted in the increase of at least one of the three DNA methyltransferases.
Conclusions. Patients were indirectly reacting to an underlying DNA hypomethylation status by increasing mRNA levels of DNA methyltransferases when the disease was being (either serologically or clinically) really active. MBD2 and MBD4 transcript overexpression and inverse correlations with DNA methylation indexes indicate that both enzymes may really have a direct and active role on the genome wide hypomethylation observed in CD4+T cells from SLE patients.
70th Annual Scientific Meeting of the American-College-of-Rheumatology/41st Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals, Washington, DC; 11/2006
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ABSTRACT: To investigate the association of a non-synonymous single-nucleotide polymorphism (SNP) in DNASEI with susceptibility to systemic lupus erythematosus (SLE) and the production of autoantibodies to nuclear antigens.
The Gln244Arg (rs1053874) SNP was studied in 276 SLE patients and in 368 healthy controls of Spanish ancestry. Its relationship with SLE susceptibility, serum DNase I activity, anti-ribonucleoprotein (RNP), anti-double-stranded DNA (dsDNA), anti-nucleosome and anti-single-stranded DNA (ssDNA) antibodies was determined.
An association of the Gln244Arg SNP with SLE susceptibility that followed a recessive genetic model (P=0.002) was found. The GG genotype was more common in SLE patients (59.8%) than in controls (47.3%). However, the Gln244Arg genotype did not correlate with DNase I activity in sera from SLE patients or from controls. In addition, the Gln244Arg SNP did not influence autoantibody titres significantly.
The association of the Gln244Arg SNP with SLE susceptibility indicates that common polymorphisms in DNASEI play a role in the genetics of SLE. However, the lack of effect of the Gln244Arg SNP on serum DNase I activity calls into question the direct involvement of this specific SNP.
Rheumatology 08/2006; 45(7):819-23. · 4.06 Impact Factor
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ABSTRACT: We present the case of a 57-year old female patient diagnosed with systemic lupus erythematosus (SLE) along with glomerulonephritis and chronic intestinal pseudo-obstruction (CIPO). Dilatation of bile and pancreatic ducts not associated with malignant or litiasic obstruction is reported. The combination of bile duct associated with CIPO in a patient with lupus has not been previously reported in the literature and it probably suggests a smooth muscle dysmotility.
Lupus 02/2005; 14(4):328-30. · 2.34 Impact Factor
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ABSTRACT: 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.
Lupus 01/2003; 12(4):287-96. · 2.34 Impact Factor
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ABSTRACT: Mannose binding lectin (MBL) and FcgammaRII (CD32) polymorphisms have both been implicated as candidate susceptibility genes in systemic lupus erythematosus (SLE). The aim of this study was to evaluate the relationship of these polymorphisms with SLE.
We studied a cohort of 125 SLE patients from Barcelona, Spain and 138 geographically matched controls. Sequence-specific primer-polymerase chain reaction (SSP-PCR) amplification was used to determine CD32 and MBL structural polymorphisms. MBL haplotypes were established using sequence-specific oligonucleotide probing techniques.
Patients carried the MBL codon 54 mutant allele more frequently than controls [odds ratio (OR) 2.2; 95% confidence interval (CI) 1.2-4.0; P=0.007] and the haplotype HY W52 W54 W57 was found to be significantly lower in cases compared with controls (OR 0.6; 95% CI 0.4-0.9; P=0.016).
The MBL gene codon 54 mutant allele appears to be a risk factor for SLE, whilst haplotypes encoding for high levels of MBL are protective against the disease. Differences between controls and patients were not significant when considering the FcgammaRIIa polymorphisms; similar results were observed for renal affectation.
Rheumatology 10/2001; 40(9):1009-12. · 4.06 Impact Factor
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ABSTRACT: To evaluate the correlation between antiphosphatidylethanolamine antibodies (aPE) and some antiphospholipid antibodies (aPL)-related clinical manifestations in patients with systemic lupus erythematosus (SLE).
Patients with SLE (n=217) were tested for the presence of aPE, anticardiolipin antibodies (aCL), and lupus anticoagulant (LA). The prospective aPL-related clinical manifestations studied were: thrombosis, thrombocytopenia, recurrent fetal losses, heart valvulopathies, hemolytic anemia, livedo reticularis, and pulmonary hypertension.
A total of 109 SLE patients (50.23%) were IgG aPE-positive; 17.51% presented aPE as the sole autoantibody and had some clinical features of aPL-related clinical manifestations. IgG aPE were associated to the presence of heart valvulopathies (p=0.002). A statistical difference was also found when considering high levels of IgG aPE (O.D.>0.600) in patients with livedo reticularis (p=0.008).
The evaluation of IgG aPE may allow us to detect some more patients with aPL-related clinical manifestations in the SLE population, aPE correlated particularly with valvulopathies and livedo reticularis.
Scandinavian Journal of Rheumatology 01/2001; 30(4):235-41. · 2.47 Impact Factor
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ABSTRACT: A technique for determining the susceptibility to ganciclovir of cytomegalovirus (CMV) strains isolated in clinical samples is described. The inoculum was composed of a partially infected suspension of cells from a young positive culture (< 10 days), usually the first passage of the primary culture. The appropriate dilution of the cell suspension to provide a suitable inoculum was based on a previous study of five strains grown in different dilutions which provided a countable number of plaques and avoided titration of each of the isolated strains. Fifty-three strains were studied at three different dilutions. Five from patients on maintenance ganciclovir therapy with poor clinical response had a 50% inhibitory dose (ID50) between 21.46 and 13.35 microM and the remainder an ID50 between 2.31 and 10.5 microM, comparable to results obtained by other authors using susceptibility techniques with a sonicated inoculum. Three of these strains were studied by both methods using sonicated inoculum and cell suspension inoculum. The mean time which elapsed between seeding the specimen and obtaining sensitivity was 39.00 and 27.66 days, respectively. The technique reduces significantly the time involved since relatively young cultures can be studied and previous titration is not required.
Journal of Virological Methods 07/1996; 60(1):59-64. · 2.01 Impact Factor
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ABSTRACT: It has recently been reported that some autoimmune diseases seem to be associated with a functional polymorphism in PTPN22, a gene which encodes a phosphatase known to be important in T-cell signaling. The aim of our study was to check for the prevalence of the PTPN22 R620W polymorphism in patients with systemic sclerosis.
DNA samples from 54 systemic sclerosis patients and 55 healthy controls were obtained from peripheral blood and genotyping was performed by means of a restriction fragment length polymorphism analysis of PCR products (RFLP-PCR).
Allele frequency for the T allele was slightly higher in the patients group (0.074 versus 0.055). Eight out of the 54 systemic sclerosis patients (14.8 %) were heterozygous for this single nucleotide polymorphism whereas the CT genotype was found in 6 out of the 55 controls (10.9%). Nevertheless, the difference did not reach statistical significance (p = 0.542). Neither certain antibodies linked to systemic sclerosis (anti-centromere and anti-topoisomerase I antibodies) nor any particular clinical involvement were associated with the polymorphism.
This particular single nucleotide polymorphism of PTPN22 does not seem to be associated with systemic sclerosis.
Clinical and experimental rheumatology 24(3):321-4. · 2.15 Impact Factor
