RESUMEN
The major pathological hallmark of the systemic sclerosis (SSc) is skin and internal organ fibrosis, which results from normal tissue architecture alterations and extracellular matrix (ECM) protein deposition. ECM components are degraded by matrix metalloproteinases (MMP). Promoter region polymorphisms in MMP genes may influence gene expression, resulting in an imbalance between ECM protein production and degradation. Here, we analyzed MMP1 -1607 1G/2G (rs1799750), MMP3 -1171 5A/6A (rs3025058), and MMP9 -1562 C/T (rs3918242) polymorphisms in relation to susceptibility to SSc and its clinical features. The patient group included 98 individuals with longstanding or recently diagnosed disease, meeting the American College of Rheumatology or LeRoy and Medsger criteria for SSc; the control group included 100 healthy blood donors. All participants were of European descent. Genotyping was performed by polymerase chain reaction followed by restriction digestion. Genotype and allele frequencies of MMP polymorphisms were similar between the two groups. In secondary analyses, significantly higher frequency of 1G/2G genotype from MMP1 polymorphism was observed for patients testing positive for antinuclear autoantibodies (P = 0.007), while 1G/1G genotype was associated with interstitial lung disease development (P = 0.018). The 6A/6A genotype from MMP3 polymorphism was absent in patients with calcinosis (P = 0.011), while the MMP3 5A/5A genotype correlated with the presence of anti-topoisomerase I antibodies (P = 0.009) and reduced diffusing capacity for carbon monoxide (P = 0.024). These results suggest that MMP polymorphisms are not associated with SSc susceptibility, although MMP1 and MMP3 variants are associated with specific SSc clinical and laboratory features.
Asunto(s)
Metaloproteinasa 1 de la Matriz/genética , Metaloproteinasa 3 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/genética , Polimorfismo de Nucleótido Simple , Esclerodermia Sistémica/genética , Adulto , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Regiones Promotoras Genéticas , Esclerodermia Sistémica/patologíaRESUMEN
OBJECTIVE: The ovarian reserve of patients with systemic lupus erythematosus (SLE) may be affected by disease activity and medication use. Studies have found that patients with SLE have similar fertility rates as healthy women of the same age. The goal of the present study was to investigate the ovarian reserve of patients with SLE by measuring anti-Müllerian hormone (AMH) levels, and compare it to that of healthy controls. METHOD: This was a case-control study performed on 80 premenopausal women, of whom 40 fulfilled the 1997 American College of Rheumatology (ACR) criteria for SLE and 40 healthy controls paired by oral contraceptive use. Serum concentrations of AMH in peripheral venous blood were measured using a human AMH ELISA kit (CUSABIO, Wuhan, China). RESULTS: AMH serum levels did not differ between patients with SLE and controls (22.79 ± 17.32 ng/ml versus 21.41 ± 16.22 ng/ml, respectively, p = 0.7), even after adjusting for age (21.03 ± 2.074 ng/ml versus 23.97 ± 2.71 ng/ml; p = 0.5). AHM levels were not significantly correlated with disease duration (r = 0.2; p = 0.3), body mass index (r = 0.2; p = 0.2) and disease activity (SLEDAI (r = 0.1; p = 0.7)) and damage indices (SLICC (r = 0.1; p = 0.7)). No associations were found between AMH and ethnicity, current smoking, as well as current or prior use of cyclophosphamide and other immunosuppressants. CONCLUSION: In this cross-sectional study, women with SLE demonstrated similar AMH levels as healthy controls, suggesting preserved ovarian reserve in this population.
Asunto(s)
Hormona Antimülleriana/sangre , Lupus Eritematoso Sistémico/sangre , Reserva Ovárica , Premenopausia/sangre , Adulto , Biomarcadores/sangre , Estudios de Casos y Controles , Estudios Transversales , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/fisiopatologíaRESUMEN
In this study, we sought to investigate the genetic influence of two HLA-G 3'-untranslated region (3'-UTR) polymorphisms - 14 bp (rs66554220) and +3142C>G (rs1063320) and their compounding haplotypes in susceptibility to rheumatoid arthritis (RA) in a two-region Brazilian study comprising of 539 patients and 489 controls. All subjects were polymerase chain reaction (PCR) genotyped for the referred polymorphisms and logistic regression models controlling for sex, city and age were performed. Homozygozity for the +3142G allele was associated with an increased risk of RA [odds ratio (OR) = 1.45, 95% confidence interval (CI) = 1.075-1.959, P(Bonf) = 0.030], whereas no association was observed for the 14 bp polymorphism. Haplotype comparisons between patients and controls showed a decreased frequency of the delC haplotype in patients (OR = 0.70, 95% CI = 0.521-0.946, P(Bonf) = 0.040), which remained significant in the rheumatoid factor (RF)-positive group (OR = 0.66, 95% CI = 0.482-0.900, P(Bonf) = 0.018), but not in the RF-negative group. These results corroborate the hypothesis of an involvement of HLA-G in the susceptibility of RA. The +3142G allele is associated with haplotype lineages that share high identity and are regarded as low producers. The presence of the G allele in homozygosis could be responsible for a low HLA-G expression profile that could favor the triggering of RA.
Asunto(s)
Regiones no Traducidas 3' , Alelos , Artritis Reumatoide/genética , Frecuencia de los Genes , Antígenos HLA-G/genética , Polimorfismo Genético , Adulto , Anciano , Brasil , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la PolimerasaRESUMEN
The aim of this study was to analyze the allelic and genotypic frequencies of the CCR5delta32 polymorphism in systemic lupus erythematosus (SLE) patients and to investigate a possible association of this allele with SLE susceptibility and clinical outcome. A total of 367 SLE patients and 435 healthy controls were genotyped for the CCR5delta32 polymorphism. We observed that, in European-derived individuals, the frequency of the CCR5delta32 allele was smaller in patients than in controls (2.7% vs. 7.5%, OR 0.34, 95% CI 0.17-0.65, p Bonf=0.002), suggesting that this allele could be considered a protective factor for the disease. Regarding clinical manifestations, we observed that CCR5delta32 female African-derived carrier patients presented a higher predisposition to class IV nephritis when compared with absent nephritis/other class group (13.8% vs. 3.8%, OR 37.1, 95% CI 2.8-1854.7, p Bonf=0.030). A multivariate analysis including all female patients and controlling for the presence or absence of anti-dsDNA antibodies, ethnicity and age at diagnosis showed an increased relative risk of 3.9 times for patients carrying the CCR5delta32 allele to develop class IV nephritis as compared with noncarriers. Our data suggest that the CCR5delta32 allele is a protective factor for the disease in European-derived patients and a susceptibility factor to class IV nephritis in African-derived female patients.
Asunto(s)
Predisposición Genética a la Enfermedad , Lupus Eritematoso Sistémico/genética , Nefritis Lúpica/genética , Receptores CCR5/genética , Adulto , Alelos , Población Negra , Brasil , Estudios de Casos y Controles , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Polimorfismo Genético , Factores Sexuales , Población BlancaRESUMEN
SUMMARY: We investigated vitamin D status in Brazilian cities located at different latitudes. Insufficiency (<50 nmol/L) was common (17 %), even in those living in a tropical climate. Vitamin D insufficiency increased as a function of latitude. Mean 25-hydroxyvitamin D (25(OH)D) levels in each site and latitude correlation were very high (r = -0.88; p=0.02). [corrected]. INTRODUCTION: Inadequate vitamin D, determined by low levels of 25(OH)D, has become very common despite the availability of sunlight at some latitudes. National data from a country that spans a wide range of latitudes would help to determine to what extent latitude or other factors are responsible for vitamin D deficiency. We investigated vitamin D status in cities located at different latitudes in Brazil, a large continental country. METHODS: The source is the Brazilian database from the Generations Trial (1,933 osteopenic or osteoporotic postmenopausal women (60 to 85 years old) with 25(OH)D measurements). 25(OH)D below 25 nmol/L (10 ng/mL) was an exclusion criterion. Baseline values were between fall and winter. The sites included Recife, Salvador, Rio de Janeiro, São Paulo, Curitiba, and Porto Alegre. Mean and standard deviation of 25(OH)D, age, spine and femoral neck T-score, calcium, creatinine, and alkaline phosphatase were calculated for each city. Pearson correlation was used for 25(OH)D and latitude. RESULTS: Insufficiency (<50 or <20 ng/mL) was common (329 subjects, 17 %). Vitamin D insufficiency increased as a function of latitude, reaching 24.5 % in the southernmost city, Porto Alegre. The correlation between mean 25(OH)D levels in each site and latitude was very high (r = -0.88, p < 0.0001). CONCLUSION: There is a high percentage of individuals with vitamin D insufficiency in Brazil, even in cities near the equator, and this percentage progressively increases with more southern latitudes.
Asunto(s)
Posmenopausia/sangre , Deficiencia de Vitamina D/epidemiología , Vitamina D/análogos & derivados , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , Brasil/epidemiología , Bases de Datos Factuales , Femenino , Humanos , Persona de Mediana Edad , Osteoporosis Posmenopáusica/sangre , Prevalencia , Pigmentación de la Piel , Luz Solar , Salud Urbana/estadística & datos numéricos , Vitamina D/sangre , Deficiencia de Vitamina D/sangreRESUMEN
Systemic sclerosis (SSc) is a connective tissue disease characterized by fibrotic, immunological and vascular abnormalities. Nuclear factor-kB (NFKB), as a key transcription factor involved in the regulation of immune responses, appears to be a good candidate for studies on the pathogenesis of autoimmune diseases, as well as the interleukin-10 (IL-10) polymorphism, which other studies have suggested an association with SSc. Our objective was to study the association of NFKB and IL-10 gene polymorphisms with SSc. One hundred and fifty-one SSc patients and 147 healthy bone marrow donors were enrolled in a case-control study. Blood was collected for DNA extraction; typing of IL-10 genes was made by polymerase chain reaction with sequence-specific primers (PCR-SSP), and NFKB gene typing was made by restriction fragment length polymorphism (RFLP). Patients underwent clinical evaluation, serology, Doppler echocardiography and chest high-resolution computed tomography. The frequency of IL-10 (-1082) GG genotype was found to be significantly higher in SSc patients (36.4%) as compared to healthy controls (22.4%) (P = 0.012). The frequency of heterozygous genotype GA was significantly lower (P = 0.004) in patients (38.4%) in comparison with control subjects (55.8%). A predominance of the high-producing IL-10 phenotype (GCC(+) /GCC(+) ) was observed in SSc patients compared with healthy controls (37.7% versus 24.5%, respectively; OR: 1.87, 95% CI: 1.10-3.19, P = 0.019). No significant difference was found in the allelic and genotype distribution of the NFKB promoter polymorphism between patients and controls. No statistically significant associations were found between IL-10 or NFKB polymorphisms clinical and laboratory features of SSc. Our results confirmed the association of the high-producing phenotype (GCC(+) /GCC(+) ) with increased risk for SSc, but found no correlation with NFKB polymorphisms.
Asunto(s)
Interleucina-10/genética , Subunidad p50 de NF-kappa B/genética , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Esclerodermia Sistémica/genética , Alelos , Estudios de Casos y Controles , Epistasis Genética , Frecuencia de los Genes , Genotipo , Haplotipos , Humanos , Fenotipo , Esclerodermia Sistémica/diagnósticoRESUMEN
OBJECTIVES: To evaluate the prevalence of metabolic syndrome (MetS) in patients with rheumatoid arthritis (RA) vs. controls, and to verify possible associations of MetS with specific disease-related factors. METHODS: The subjects were 283 RA patients and 226 healthy controls, frequency matched by age and sex. MetS was defined according to National Cholesterol Education Program (NCEP) criteria. Disease activity was evaluated with the Disease Activity Score using 28 joints (DAS28). A standardized clinical evaluation was performed and cardiovascular risk factors were assessed. RESULTS: The criteria for MetS were met by 39.2% RA patients vs. 19.5% in the control group (p < 0.001). Increased waist circumference, elevated blood pressure (BP), and fasting glucose were more frequent in RA patients than controls (p < 0.001 for all associations). By multiple logistic regression analysis (adjusted for age, sex, and years at school), the risk of having MetS was significantly higher for RA patients than for controls [odds ratio (OR) 1.87, 95% confidence interval (CI) 1.17-3.00, p = 0.009]. The DAS28 was significantly higher in RA patients with MetS than in those without MetS (3.59 ± 1.27 vs. 3.14 ± 1.53; p = 0.01). Disease duration, the presence of rheumatoid factor, and extra-articular manifestations were similar for patients with and without MetS. CONCLUSIONS: MetS frequency was higher in RA patients than in controls. Among RA patients, MetS was associated with disease activity. The higher prevalence of cardiovascular risk factors in RA suggests that inflammatory processes play a notable role in the development of cardiovascular disease (CVD), and indicates that tight control of systemic inflammatory activity and CVD modifiable risk factors should be recommended.
Asunto(s)
Artritis Reumatoide/epidemiología , Síndrome Metabólico/epidemiología , Índice de Severidad de la Enfermedad , Adulto , Anciano , Artritis Reumatoide/fisiopatología , Glucemia/análisis , Presión Sanguínea/fisiología , Brasil/epidemiología , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Síndrome Metabólico/fisiopatología , Persona de Mediana Edad , Prevalencia , Factores de Riesgo , Circunferencia de la CinturaRESUMEN
Vitamin D deficiency has been described in systemic lupus erythematosus (SLE). BsmI VDR (vitamin D receptor) gene polymorphism was associated with SLE in Asian patients. Studies in Brazilian populations have not been realized. A case-control study with 195 SLE patients and 201 healthy controls was conducted to investigate the influence of BsmI and FokI VDR gene polymorphisms on susceptibility to SLE. In addition, 25-hydroxyvitamin D [25(OH)D] was measured in SLE patients to evaluate possible associations with VDR polymorphic variants and clinical and laboratory expressions of disease. Genotyping was performed by RFLP-PCR. The measurement of 25(OH)D was performed by chemiluminescence. There was no statistically significant difference in genotype and allelic frequencies of BsmI and FokI polymorphisms between European-derived cases and controls. The mean serum levels of 25(OH)D were 25.51 ± 11.43 ng/ml in SLE patients. According to genotype distribution, 25(OH)D concentrations were significantly higher in patients carrying the FokI f/f genotype compared with patients carrying the F/F genotype (31.6 ± 14.1 ng/ml versus 23.0 ± 9.2 ng/ml, p = 0.004), reinforcing its role in the functional activity of VDR. This feature may be considered in future clinical and experimental studies involving vitamin D measurements. Therefore, genetic-specific definitions of ideal levels of vitamin D in SLE need to be established in future studies.
Asunto(s)
Desoxirribonucleasas de Localización Especificada Tipo II/metabolismo , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/genética , Polimorfismo Genético , Receptores de Calcitriol/genética , Vitamina D/análogos & derivados , Adulto , Brasil , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Vitamina D/sangre , Población BlancaRESUMEN
Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease and can affect several organs and systems. It is characterized by high production of autoantibodies against nuclear compounds. TLR7/8/9 are responsible for nucleic acid recognition and they trigger proinflammatory responses through activation of NK-kappaB and Type I IFN production, making a bridge between the innate and the adaptative immune systems. We analyzed the frequency of TLR7 rs179008, TLR8 rs3764880, TLR9 rs5743836 and rs352140 in 370 patients with SLE and 415 healthy controls from southern Brazil. All analyses were conducted with regard to gender and ethnicity. Genotypic and allelic frequencies were different for TLR7 rs179008 (0.253 vs. 0.163, p = 0.020 and p = 0.003, OR for T allele: 1.74 CI 95% 1.12-2.70) and TLR9 rs5743836 (0.174 vs. 0.112, p = 0.045 and p = 0.017, OR for C allele: 1.59, CI 95% 0.99-2.57) between European-derived female groups. A higher frequency was observed for the presence of Anti-SSa/Ro for TRL9 rs5743836 C allele carriers (0.228 vs 0.126, Bonferroni corrected p = 0.06). No statistical differences were found for TLR9 haplotypic analyses. We suggest that TLR7 rs179008 and TLR9 rs5743836 can be considered SLE susceptibility factors for women of European descent in our population.
Asunto(s)
Lupus Eritematoso Sistémico/genética , Receptor Toll-Like 7/genética , Receptor Toll-Like 8/genética , Receptor Toll-Like 9/genética , Alelos , Población Negra/genética , Brasil , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Humanos , Lupus Eritematoso Sistémico/inmunología , Masculino , Polimorfismo Genético , Factores Sexuales , Población Blanca/genéticaRESUMEN
OBJECTIVE: To evaluate the antiinflammatory effects of RC-3095 in 2 experimental models of arthritis, collagen-induced arthritis (CIA) and antigen-induced arthritis (AIA), and to determine the mechanisms of action involved. METHODS: RC-3095 was administered daily to mice with CIA and mice with AIA, after induction of disease with methylated bovine serum albumin. Disease incidence and severity were assessed using a clinical index and evaluation of histologic features, respectively. In mice with CIA, gastrin-releasing peptide receptor (GRPR) was detected by immunohistochemical analysis, while in mice with AIA, migration of neutrophils, presence of glycosaminoglycans, and lymphocyte proliferation, determined using the MTT assay, were assessed. Expression of cytokines interleukin-17 (IL-17), IL-1ß, and tumor necrosis factor α (TNFα) was evaluated in all mouse knees using enzyme-linked immunosorbent assay. Treg cell production was assessed by flow cytometry in the joints of mice with AIA. RESULTS: In mice with AIA, administration of RC-3095 reduced neutrophil migration, mechanical hypernociception, and proteoglycan loss. These findings were associated with inhibition of the levels of all 3 proinflammatory cytokines, decreased lymphocyte proliferation, and increased Treg cell numbers. In the CIA model, treatment with RC-3095 led to a significant reduction in arthritis clinical scores and the severity of disease determined histologically. Synovial inflammation, synovial hyperplasia, pannus formation, and extensive erosive changes were all dramatically reduced in the arthritic mice treated with RC-3095. Furthermore, arthritic mice treated with RC-3095 showed a significant reduction in the concentrations of IL-17, IL-1ß, and TNFα, and showed a diminished expression of GRPR. CONCLUSION: These findings suggest that the GRP pathway has a significant role in chronic arthritis, and its inhibition can be explored as a possible therapeutic strategy in rheumatoid arthritis.
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Bombesina/análogos & derivados , Fragmentos de Péptidos/uso terapéutico , Receptores de Bombesina/antagonistas & inhibidores , Animales , Bombesina/uso terapéutico , Cartílago Articular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Articulaciones/efectos de los fármacos , Masculino , Ratones , Neutrófilos/efectos de los fármacos , Membrana Sinovial/efectos de los fármacos , Resultado del TratamientoRESUMEN
Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease that affects several organs and systems. Its etiology remains unknown, although it is probably multifactorial. The human leukocyte antigen G (HLA-G) is a nonclassic major histocompatibility complex I molecule characterized by restricted expression and low DNA polymorphism. HLA-G plays a role in immunosuppression through different mechanisms. In inflammatory diseases, it has been postulated that HLA-G expression may be a possible mechanism of tissue protection against exacerbated inflammatory response. On the 3' untranslated region (3' UTR) of the HLA-G gene, there is an insertion/deletion polymorphism of 14 bp (rs1704) that was shown to influence the mRNA stability. The influence of this polymorphism in disease susceptibility is controversial. Also in the 3' UTR there is a single nucleotide polymorphism C/G (rs1063320) on the position +3142, at a possible binding site for microRNAs (miRNAs) and having an influence on miRNA affinity. In this study, we analyzed the +3142C>G and the 14 bp polymorphisms in 195 SLE European-derived female patients. Our findings show a significant increase of the +3142G allele frequency among patients as compared with controls (0.58 vs 0.47, P = 0.011). Also, patients presented a higher frequency of the GG genotype (OR = 1.90, 95% CI: 1.08-3.42). Double heterozygotes for the two polymorphisms presented a milder mean systemic lupus erythematosus disease activity index (SLEDAI) than heterozygotes for only one of the variants or non-heterozygous individuals (1.56 vs 3.15 and 3.26, respectively, corrected P = 0.044). These results suggest the involvement of the HLA-G molecule on SLE susceptibility and outcome.
Asunto(s)
Antígenos HLA/genética , Antígenos de Histocompatibilidad Clase I/genética , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Polimorfismo Genético , Regiones no Traducidas 3' , Adulto , Alelos , Sitios de Unión , Estudios de Casos y Controles , Exones , Femenino , Frecuencia de los Genes , Genotipo , Antígenos HLA-G , Heterocigoto , Humanos , Terapia de Inmunosupresión , Masculino , MicroARNs/metabolismo , Persona de Mediana EdadRESUMEN
The mannose-binding lectin gene (MBL-2) has emerged as a candidate for systemic lupus erythematosus susceptibility, but studies in Brazilian population have not been conducted. To examine potential associations of mannose-binding lectin alleles G57E, G54D, IVSnt5, R52C and R52H with susceptibility to and clinical expression of systemic lupus erythematosus in southern Brazilian patients, we conducted a case-control study with 327 consecutive patients with diagnosis of systemic lupus erythematosus and 345 healthy controls. Genotyping was performed by restriction fragment length polymorphism-polymerase chain reaction assay. A statistically significant difference in the frequencies of allele R52C was observed in European-derived systemic lupus erythematosus patients when compared with controls (9.6% vs. 3.3%, p < 0.001, odds ratio: 3.15, 95% confidence interval: 1.76-5.62, p < 0.05). The frequencies of alleles G54D and G57E were not different between European-derived systemic lupus erythematosus patients and controls. There were no differences between clinical and laboratory features in systemic lupus erythematosus patients according to the presence or absence of mannose-binding lectin allelic variants. These results support an increased risk of systemic lupus erythematosus in European-derived individuals carrying allele R52C. Patients carrying this allele have an approximately three-fold higher odds ratio of developing systemic lupus erythematosus when compared with controls. Our data do not support associations between the mannose-binding lectin allelic variants studied and clinical expression of systemic lupus erythematosus.
Asunto(s)
Predisposición Genética a la Enfermedad , Lupus Eritematoso Sistémico/genética , Lectina de Unión a Manosa/genética , Adulto , Alelos , Brasil , Estudios de Casos y Controles , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
Human leukocyte antigen-G (HLA-G) is a nonclassical class I major histocompatibility complex molecule which is induced at the course of inflammatory pathologies, and its expression has been suggested as a possible mechanism of tissue protection against autoimmune inflammatory responses, therefore acting as a mechanism of immune surveillance. We investigated the influence of the 14 bp polymorphism of the HLA-G gene on systemic lupus erythematosus (SLE) by analyzing 293 patients with SLE and 460 healthy controls. The patient's group was not in Hardy-Weinberg equilibrium, presenting an excess of heterozygotes (P = 0.014). The heterozygote group exhibited lower systemic lupus erythematosus disease activity indexes than the homozygous deletion group and the homozygous insertion group (mean value = 2.29 against 2.97 and 3.4, respectively, P = 0.035). Photosensitive patients showed a higher frequency of heterozygotes and an equivalent lower frequency of homozygotes for deletion; on the other hand, patients without arthritis presented a higher frequency of heterozygotes than the arthritis group and also a lower frequency of the del/del genotype. Overall, our results support the idea of a role of the HLA-G insertion/deletion polymorphism and therefore a role for the HLA-G molecule, on the pathology of SLE.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Antígenos HLA/genética , Antígenos de Histocompatibilidad Clase I/genética , Lupus Eritematoso Sistémico/genética , Polimorfismo de Nucleótido Simple/genética , Adolescente , Adulto , Población Negra/genética , Estudios de Casos y Controles , Femenino , Eliminación de Gen , Frecuencia de los Genes/genética , Antígenos HLA-G , Heterocigoto , Humanos , Masculino , Trastornos por Fotosensibilidad/genética , Población Blanca/genética , Adulto JovenRESUMEN
P-glycoprotein (Pgp), the ABCB1 gene product, acts as an efflux pump that transports a large variety of substrates and is a mechanism of cell protection against xenobiotics. An increasing number of studies have shown that some ABCB1 polymorphisms may affect Pgp expression and activity, as well as affecting the development and susceptibility to diseases and pharmacological response. High activity of Pgp has been detected in systemic lupus erythematosus (SLE) patients. The C1236T, G2677T/A, and C3435T are the most commonly studied single nucleotide polymorphisms in the ABCB1 gene. Therefore, their frequencies were determined in Brazilian individuals with European ancestry (N = 143) and in SLE patients (N = 137). Genotyping was performed by PCR-RFLP analysis using specific primers followed by incubation with the appropriate restriction enzymes. The resulting DNA fragments were visualized on agarose or polyacrylamide gels. No statistically significant differences were observed in allelic and genotypic frequencies between SLE and healthy subjects (Fisher exact test). Nevertheless, the 2677A allelic frequency was lower in SLE patients with malar rash (0.007) compared with patients without this feature (0.04; P = 0.0054), while the frequency of this variant was higher in SLE patients with pleuritis (0.07) compared with patients without this feature (0.01; P = 0.0156). We suggest that although the ABCB1 polymorphisms do not directly interfere in SLE susceptibility, their evaluation, especially the 2677A allele, in other immunological processes may be interesting since they can interfere in clinical features of this disease.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Lupus Eritematoso Sistémico/genética , Polimorfismo de Nucleótido Simple/genética , Subfamilia B de Transportador de Casetes de Unión a ATP , Adolescente , Adulto , Población Negra , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Lactante , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Población Blanca , Adulto JovenRESUMEN
P-glycoprotein (Pgp), the ABCB1 gene product, acts as an efflux pump that transports a large variety of substrates and is a mechanism of cell protection against xenobiotics. An increasing number of studies have shown that some ABCB1 polymorphisms may affect Pgp expression and activity, as well as affecting the development and susceptibility to diseases and pharmacological response. High activity of Pgp has been detected in systemic lupus erythematosus (SLE) patients. The C1236T, G2677T/A, and C3435T are the most commonly studied single nucleotide polymorphisms in the ABCB1 gene. Therefore, their frequencies were determined in Brazilian individuals with European ancestry (N = 143) and in SLE patients (N = 137). Genotyping was performed by PCR-RFLP analysis using specific primers followed by incubation with the appropriate restriction enzymes. The resulting DNA fragments were visualized on agarose or polyacrylamide gels. No statistically significant differences were observed in allelic and genotypic frequencies between SLE and healthy subjects (Fisher exact test). Nevertheless, the 2677A allelic frequency was lower in SLE patients with malar rash (0.007) compared with patients without this feature (0.04; P = 0.0054), while the frequency of this variant was higher in SLE patients with pleuritis (0.07) compared with patients without this feature (0.01; P = 0.0156). We suggest that although the ABCB1 polymorphisms do not directly interfere in SLE susceptibility, their evaluation, especially the 2677A allele, in other immunological processes may be interesting since they can interfere in clinical features of this disease.
Asunto(s)
Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Adulto Joven , Lupus Eritematoso Sistémico/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Polimorfismo de Nucleótido Simple/genética , Población Negra , Estudios de Casos y Controles , Población Blanca , Frecuencia de los Genes , Genotipo , Reacción en Cadena de la Polimerasa , Adulto JovenRESUMEN
OBJECTIVE: To determine the effects of RC-3095 in clinical and histopathologic parameters and inflammatory mediators on complete Freund's adjuvant-induced arthritis (CFA). METHODS: The arthritis was induced by injection of CFA into the left hind footpad. The animals were divided into control, vehicle injected control, placebo group (saline subcutaneously 50ml/kg, once daily for 8 days after modeling), treatment group (0.3mg/kg of RC-3095 subcutaneously, once daily for 8 days after induction). Clinical evaluation was accomplished daily, through scoring of the paw edema. The animals were sacrificed 15 days after induction for collection of hind foot joints for histology. We used a histological scoring system which was previously described, and interferon (INF)-gamma, interleukin (IL)-1beta, tumor necrosis factor (TNF), interleukin (IL)-6 and interleukin (IL)-10 were measured by ELISA. RESULTS: There was a significant inhibition of joint histological findings in the RC-3095 treated group, including synovial inflammatory infiltration and hyperplasia, cartilage and bone erosion. IFN-gamma, IL-1beta, TNF, IL-6 and IL-10 serum levels were significantly lower in the treated group. Paw swelling and subcutaneous inflammation, evaluated clinically, were not different between CFA-induced groups. CONCLUSIONS: RC-3095 was able to improve experimental arthritis, attenuate joint damage and decrease serum levels of IFN-gamma, IL-1beta, TNF, IL-6 and IL-10. These data indicate that interference with GRP pathway is a potential new strategy for the treatment of RA that needs further investigational studies.
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Artritis Experimental/tratamiento farmacológico , Bombesina/análogos & derivados , Fragmentos de Péptidos/uso terapéutico , Receptores de Bombesina/antagonistas & inhibidores , Animales , Artritis Experimental/inmunología , Artritis Experimental/patología , Bombesina/uso terapéutico , Adyuvante de Freund/inmunología , Interferón gamma/sangre , Interleucina-10/sangre , Interleucina-1beta/sangre , Interleucina-6/sangre , Masculino , Placebos , Distribución Aleatoria , Ratas , Ratas Wistar , Tarso Animal/inmunología , Tarso Animal/patología , Factor de Necrosis Tumoral alfa/sangreRESUMEN
OBJECTIVE: In this study we have analyzed GSTM1, GSTT1 and GSTP1 polymorphisms in patients with juvenile idiopathic arthritis (JIA), to investigate a possible role of these genes as genetic components of the disease. METHODS: A total of 103 individuals (49 oligoarticular, 41 polyarticular and 13 systemic) were analyzed for the three polymorphisms, using a PCR/RFLP methodology. RESULTS: We have observed significantly increased frequencies of individuals with GSTT1 null genotype in JIA patients comparing to controls (37% x 21%; p=0.0183). There was a 2-fold increased risk (OR 2.2, 95% CI 1.2-4.1) associating the disease with the GSTT1 null genotype. Considering the subgroups (oligoarticular, polyarticular and systemic), the results indicated an association between polyarticular and systemic patients and the GSTT1 null genotype. There was a 2-fold increased risk for polyarticular patients (OR 2.4, 95%, CI 1.1-5.4), and a 4-fold increased risk for systemic patients (OR 4.4, 95%, 1.3-14.5). CONCLUSION: The GSTT1 null genotype seems to be involved in polyarticular and systemic JIA.
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Artritis Juvenil/genética , Susceptibilidad a Enfermedades , Gutatión-S-Transferasa pi/genética , Glutatión Transferasa/genética , Niño , Preescolar , Femenino , Humanos , Lactante , MasculinoRESUMEN
OBJECTIVES: To identify the genetic polymorphism of the chemokine receptor CCR5 (the Delta32 allelic variant) in patients with rheumatoid arthritis (RA) and compare the findings with healthy controls. To compare the CCR5 phenotypic expression in T cells and monocytes isolated from the peripheral blood and synovial fluid in a subgroup of RA patients. METHODS: CCR5 genes of 92 RA patients and 160 healthy controls were genotyped using specific primers flanking the region of deletion. The ethnic distribution was similar between the groups. Flow cytometric analysis was used for immunophenotyping the T cells and monocytes isolated from the peripheral blood and synovial fluid of eight RA patients. The isolated cells were triple stained with CD4 or CD8, CD25 and CCR5 monoclonal antibodies. RESULTS: There was no difference in the CCR5Delta32 genotypic frequency between the RA patients and the control group (0.055 and 0.063, respectively, p = 0.989). No homozygote for the CCR5Delta32 allele was seen in either group. Five heterozygotes were identified in the RA patient group, whose disease was shown to be aggressive. A significant enrichment of activated CCR5+ monocytes was seen in the synovial fluid of the RA patients subjected to arthrocentesis, who were all homozygotes for the CCR5 wild-type genotype. CONCLUSION: A protective role for the CCR5 allelic variant in RA development was not observed. Disease severity in the heterozygotes suggests that other proinflammatory mechanisms might overcome this mutation in vivo. The activated CCR5+ monocyte enrichment in the rheumatoid synovial fluid might indicate that this cell population has an important role in the pathogenesis of the disease.
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Artritis Reumatoide/genética , Polimorfismo Genético , Receptores CCR5/genética , Adolescente , Adulto , Antígenos CD/genética , ADN/sangre , ADN/genética , ADN/aislamiento & purificación , Etnicidad , Variación Genética , Genotipo , Humanos , Linfocitos T/inmunologíaRESUMEN
Complete Freund's adjuvant (CFA)-induced arthritis in rats, which presents similar features to rheumatoid arthritis, is a model widely used in aetiopathogenetic and investigational drug studies. In this model, arthritis is induced by intradermal injection of Mycobacterium tuberculosis suspended in mineral oil in the hind footpad. Although the histopathology findings in the joint are well described, the marked subcutaneous features of panniculitis that concomitantly occur in this model have received no attention. The objective of this paper is to describe the subcutaneous histopathological features in 8 Wistar rats after intraplantar injection of CFA. We studied the subcutaneous histopathological features in 8 Wistar rats after intraplantar injection of CFA in the left hind paw. The levels of subcutaneous inflammation of the animals in this study were evaluated for the histological characteristics present in the tissue and scored with 4 parameters (acute inflammation, chronic inflammation with fibrosis, subcutaneous and profound soft tissue necrosis, and the presence of giant cells, neutrophils, macrophages and lymphocytes) on days 4, 7, 11 and 15 after induction. All animals developed intense subcutaneous inflammation characteristic of panniculitis, with predominance of acute changes in the initial period, with progression to a self-perpetuating chronic fibrotic process on day 15. These observations precede the joint changes. Besides being an interesting model for better studying diseases with panniculitis, our observations bring up issues concerning the possible relations between subcutaneous and joint inflammatory changes.
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Articulación del Tobillo/patología , Paniculitis/patología , Animales , Modelos Animales de Enfermedad , Adyuvante de Freund , Masculino , Ratas , Ratas WistarRESUMEN
The aim of this study was to compare oesophageal abnormalities observed in high-resolution CT with radionuclide transit in patients with systemic sclerosis. 76 patients with systemic sclerosis were evaluated by high-resolution CT and oesophageal transit scintigraphy. Residual activity > or =20% (in relation to peak activity) at 15 s after the beginning of the swallow of the labelled liquid (in supine position) was considered indicative of oesophageal dysfunction. Supra-aortic and infra-aortic oesophageal coronal diameters were measured in high-resolution CT. Oesophageal dilatation was deemed present when the diameters exceeded 10 mm. 19 patients (25%) had supra-aortic oesophageal dilatation and 48 patients (63.1%) had infra-aortic dilatation. The prevalence of radionuclide transit delay was 77.6%. All patients (19/19) with supra-aortic dilatation had oesophageal dysfunction, compared with 70.2% (40/57) of the patients with no supra-aortic dilatation (p = 0.004). Oesophageal dysfunction was present in 97.9% (47/48) of patients with infra-aortic dilatation, compared with 42.9% (12/28) in patients without it (p < 0.001). Receiver operating characteristic (ROC) curves have demonstrated that the supra-aortic and infra-aortic diameters had good discriminatory capacity for oesophageal dysfunction in systemic sclerosis (area under the curve, 95% confidence interval: 0.80, 0.70-0.89 and 0.92, 0.86-0.98, respectively). There is a clinically significant association between oesophageal dysmotility and high-resolution CT findings of oesophageal coronal dilatation. The evaluation of infra-aortic oesophageal coronal diameter can provide additional useful information about the functional and anatomic conditions of the oesophagus in systemic sclerosis.