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Few studies analyze the role of B-cell subpopulations in rheumatoid arthritis (RA) pathophysiology. Therefore, this study aimed to analyze the differences in B-cell subpopulations and B-cell activation according to disease activity, RA subtype, and absence of disease-modifying antirheumatic drugs (DMARDs) therapy. These subgroups were compared with control subjects (CS). One hundred and thirty-nine subjects were included, of which 114 were RA patients, and 25 were controls. Patients were divided into 99 with seropositive RA, 6 with seronegative RA, and 9 without DMARDs. The patients with seropositive RA were subclassified based on the DAS28 index. A seven-color multicolor flow cytometry panel was used to identify B-cell immunophenotypes and cell activation markers. There were no changes in total B-cell frequencies between RA patients and controls. However, a lower frequency of memory B cells and pre-plasmablasts was observed in seropositive RA compared to controls (P < 0.0001; P = 0.0043, respectively). In contrast, a higher frequency of mature B cells was observed in RA than in controls (P = 0.0002). Among patients with RA, those with moderate activity had a higher percentage of B cells (P = 0.0021). The CD69+ marker was increased (P < 0.0001) in RA compared to controls, while the CD40+ frequency was decreased in patients (P < 0.0001). Transitional, naïve, and double-negative B-cell subpopulations were higher in seronegative RA than in seropositive (P < 0.01). In conclusion, in seropositive and seronegative RA patients, there are alterations in B-cell activation and B-cell subpopulations, independently of clinical activity and DMARDs therapy.
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Antirreumáticos , Artrite Reumatoide , Humanos , Autoanticorpos , Artrite Reumatoide/tratamento farmacológico , Linfócitos B , Antirreumáticos/uso terapêutico , Citometria de FluxoRESUMO
Rheumatoid Arthritis (RA) is characterized by joint destruction, chronic inflammation, and autoantibody production. IL-21/IL-21R plays an essential role in the immunopathology of RA. Elevated IL-21 serum levels have been associated with RA and disease activity. Here, we evaluated the association of IL-21/IL-21R polymorphisms and IL-21 serum levels with RA. The study included 275 RA patients and 280 Control subjects (CSs). Single nucleotide polymorphisms IL-21 (rs2055979 and rs2221903) and IL-21R (rs3093301) were genotyped using PCR-RFLP. Clinical activity was evaluated by DAS28-ESR; IL-21 and anti-CCP serum levels were quantified by ELISA. The IL-21 rs2055979 AA genotype was higher in RA patients than in the CS group (p = 0.0216, OR = 1.761, 95% CI = 1.085-2.859); furthermore, RA patients showed anti-CCP elevated levels compared to the CA genotype (p = 0.0296). The IL21R rs3093301 AA genotype was also higher in RA patients than in the CS group (p = 0.0122, OR = 1.965, 95% CI = 1.153-3.348). The AT haplotypes of IL-21 rs2055979 and rs2221903 were more frequent (49%) in the RA group (p = 0.006). IL-21 serum levels were significantly elevated in the RA group, but without an association with IL-21 polymorphisms. In conclusion, IL-21 rs2255979 and IL-21R rs3093301 are associated with a higher risk of RA, and could be a genetic marker. Moreover, the elevated IL-21 levels in RA suggest that IL-21/IL-21R could be a therapeutic target in RA.
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Anticorpos Antiproteína Citrulinada , Artrite Reumatoide , Humanos , Interleucinas/genética , Polimorfismo de Nucleotídeo Único , Artrite Reumatoide/genéticaRESUMO
Citrullination is catalyzed by the peptidyl arginine deiminase 4 (PAD4) enzyme, encoded by the PADI4 gene. Increased PAD4 activity promotes the onset and progression of rheumatoid arthritis (RA). This study aimed to evaluate the association of PADI4 haplotypes with RA risk, mRNA expression, and the PAD4 activity in patients with RA from Mexico. Methodology: 100 RA patients and 100 control subjects (CS) were included. Genotyping was performed by PCR-RFLP method, PADI4 mRNA expression was quantified by real-time PCR, the contribution of PADI4 alleles (PADI4_89 G>A, PADI4_90 T>C, and PADI4_92 G>C) to mRNA expression by the ASTQ method, and PAD4 activity by HPLC. Also, the anti-CCP and anti-PADI4 antibodies were quantified by ELISA. Results: The three PADI4 polymorphisms were associated with RA susceptibility (OR = 1.72, p = 0.005; OR = 1.62; p = 0.014; OR = 1.69; p = 0.009; respectively). The 89G, 90T, and 92G alleles have a higher relative contribution to PADI4 mRNA expression from RA patients than 89A, 90C, and 92C alleles in RA patients. Moreover, the GTG/GTG haplotype was associated with RA susceptibility (OR = 2.86; p = 0.024). The GTG haplotype was associated with higher PADI4 mRNA expression (p = 0.04) and higher PAD4 enzymatic activity (p = 0.007) in RA patients. Conclusions: The evaluated polymorphisms contribute to PADI4 mRNA expression and the enzymatic activity of PAD4 in leukocytes. Therefore, the GTG haplotype is a genetic risk factor for RA in western Mexico, and is associated with increased PADI4 mRNA expression and higher PAD4 activity in these patients.
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Background: Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease, which affects exocrine glands. T cell activation is a trigger mechanism in the immune response. Hyperreactivity of T cells and antibody production are features in pSS. ICOS can be critical in the pathogenesis of pSS. Methods: A total of 134 pSS patients and 134 control subjects (CS) were included. Genotyping was performed by PCR-RFLP. ICOS mRNA expression was quantified by real-time PCR, and CD4+ ICOS+ T cells were determined by flow cytometry. Results: The ICOS IVS1 + 173 T>C polymorphisms were not associated with susceptibility to pSS (p = 0.393, CI = 0.503−1.311). However, the c.1624 C>T polymorphism was associated with a reduction in the risk of development of pSS (p = 0.015, CI = 0.294−0.884). An increase in ICOS mRNA expression in patients was observed (3.7-fold). Furthermore, pSS patients showed an increase in membranal-ICOS expression (mICOS). High expression of mICOS (MFI) was associated with lymphocytic infiltration. Conclusions: The IVS1 + 173 polymorphism is not a genetic marker for the development of pSS, while c.1624 T allele was associated with a low risk. However, elevated mICOS expression in pSS patients with high lymphocytic infiltration was found. ICOS may have an important role in the immunopathogenesis of pSS and should be analyzed in T cell subsets in pSS patients as a possible disease marker.
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INTRODUCTION: Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial membrane damage and autoantibody production. RA is a heterogeneous disease, where cytokines such as IL-15, IL-21, and IFN-γ have been associated. However, their association with the autoantibodies has not been clearly described. The aim of this study was to evaluate the relationship between the cytokines IL-15, IL-21, and IFN-γ with the autoantibodies (RF, anti-CCP, anti-MCV, and anti-PADI4) in RA and disease activity. METHODOLOGY: This study included 153 RA patients and 80 control subjects (CS). The levels of IL-15, IL-21, IFN-γ, anti-CCP, anti-MCV, and anti-PADI4 were quantified by ELISA, whereas RF was quantified by turbidimetry. The disease activity was evaluated by the indices disease activity score 28-erythrocyte sedimentation rate (DAS28-ESR), clinical disease activity index (CDAI), and simple disease activity index (SDAI). RESULTS: The serum levels of IL-15, IL-21, and IFN-γ, and autoantibodies were increased in RA patients, compared with CS (p < 0.05). A correlation was found between IL-21 and anti-CCP and anti-MCV (p < 0.05). According to RA evolution, RF, anti-CCP, and anti-MCV had higher levels in early RA. In addition, increased levels of IL-21 were observed in RA seropositive patients (RF/anti-CCP/anti-MCV). The higher levels of both cytokines and autoantibodies were observed in moderate activity, evaluated by the three indices. CONCLUSIONS: Our results suggest that the increased soluble levels of IL-15, IL-21, and IFN-γ are involved in the inflammatory network in RA. However, IL-21 serum levels are associated with higher titers of autoantibodies (RF, anti-CCP, and anti-MCV) and IL-15 with moderate activity. Key Points ⢠IL-15, IL-21, and IFN-y are associated with the immunopathology of RA, but not significantly with the evolution of the disease. ⢠RF, anti-CCP, and anti-MCV had higher levels in early than established RA. ⢠IL-21 has an association with RF, anti-CCP, and anti-MCVand, for this reason, could be proposed as a disease biomarker. ⢠Patients with activity moderate of disease showed higher levels of RF, anti-CCP, anti-MCV, and IL-15.
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Artrite Reumatoide/sangue , Autoanticorpos/sangue , Citocinas/sangue , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Adulto JovemRESUMO
Peptidyl arginine deiminase IV (PADI4) enzyme catalyzes the citrullination of proteins, which are recognized by anti-cyclic citrullinated peptide antibodies (anti-CCP) in rheumatoid arthritis (RA) patients. Here, we determined the association between PADI4 gene polymorphisms and haplotypes with RA susceptibility and clinical characteristics in a western Mexican population. The relationship of PADI4 polymorphisms with anti-CCP and PADI4 mRNA expression was also evaluated. PADI4_89, PADI4_90 and PADI4_92 polymorphisms were individually associated with RA susceptibility. The GTG haplotype was significantly associated with: RA susceptibility; disease onset at ≤ 40 years and anti-CCP antibodies. PADI4 expression was three fold higher in RA patients carrying the susceptibility haplotype (GTG) than in non-susceptibility haplotype carriers (ACC). In conclusion, polymorphisms and functional haplotype (GTG) in PADI4 are associated with RA susceptibility as well as anti-CCP antibodies in a Mexican population. This supports the role of PADI4 early in RA pathogenesis by promoting the generation of citrullinated autoantigens.
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Artrite Reumatoide/genética , Predisposição Genética para Doença/genética , Haplótipos , Hidrolases/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Alelos , Artrite Reumatoide/sangue , Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Feminino , Regulação Enzimológica da Expressão Gênica , Frequência do Gene , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , México , Pessoa de Meia-Idade , Peptídeos Cíclicos/imunologia , Proteína-Arginina Desiminase do Tipo 4 , Desiminases de Arginina em Proteínas , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Knee osteoarthritis (OA) is a common chronic degenerative disease characterized by the loss of articular cartilage components due to an imbalance between extracellular matrix destruction and repair. The proinflammatory cytokines involved in OA, TNFα and IL1ß, are considered the major implicated. The aim of this study was to investigate the relationship between TNFα -308 and -238 polymorphisms with messenger RNA (mRNA) and soluble TNFα expression in knee OA patients and healthy subjects (HS). Case-control study involved 50 knee OA patients classified according to 1986 ACR Classification Criteria, as well as 100 HS. The Western Ontario and McMaster Universities Osteoarthritis Index and Lequesne disability index were applied to OA patients. The -308 and -238 polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism technique. The TNFα mRNA expression was quantified by real-time PCR using TaqMan method. The sTNFα levels were measured by enzyme-linked immunosorbent assay. The TNFα mRNA expression in knee OA patients was higher than in HS (1.56-fold). In addition, the TNFα mRNA expression was higher in carriers of G allele in the knee OA group for both polymorphisms. The sTNFα levels were increased in G/G versus G/A genotypes in both studied polymorphisms (p < 0.05). However, the TNFα -308 and -238 genotypes did not show statistical differences between groups. The G allele of TNFα -308 and -238 polymorphisms is associated with high mRNA and soluble expression in knee OA patients. However, it is not a marker of susceptibility in Western Mexico. Further studies are necessary to confirm these findings.
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Predisposição Genética para Doença , Osteoartrite do Joelho/imunologia , Polimorfismo Genético , Regiões Promotoras Genéticas , Elementos Reguladores de Transcrição , Fator de Necrose Tumoral alfa/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Perfilação da Expressão Gênica , Técnicas de Genotipagem , Humanos , Masculino , México , Pessoa de Meia-Idade , Ontário , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , RNA Mensageiro/biossíntese , Reação em Cadeia da Polimerase em Tempo Real , Adulto JovemRESUMO
INTRODUCTION: Rheumatoid arthritis (RA) is a common autoimmune disease with a complex genetic background. The PTPN22 gene encodes lymphoid tyrosine phosphatase LYP, a potent negative regulator of T cell activation. Polymorphic variants of this gene have previously been associated with various autoimmune disorders. The +1858C/T single-nucleotide polymorphism (SNP) (rs2476601), in the exon 14 of the PTPN22 gene has been associated with susceptibility to RA in several population. OBJECTIVE: The aim of this work was to investigate whether the +1858C/T of the PTPN22 gene is associated with susceptibility to RA in Western Mexico population. METHODS: A total of 309 unrelated RA patients, classified according to American College of Rheumatology (ACR) 1987 criteria, as well as 347 controls residents from Western Mexico were recruited for this study. The DNA samples were genotyped for +1858C/T PTPN22 gene SNP using the PCR-RFLP technique. Antibodies to cyclic citrullinated peptides (anti-CCP) were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The frequency of +1858T risk allele was significantly increased in patients with RA compared with controls (p=0.001, OR=2.83, 95%CI=1.50-5.32). To confirm this results we established a comparison between subjects carrying of CT+TT genotypes versus those carrying CC genotype, between both groups (p=0.004, OR=2.65, 95%CI=1.33-5.36). Nevertheless, we not observed association of the +1858C/T PTPN22 gene SNP with clinical activity and functional disability in RA patients. Likewise, the +1858T variant in RA patients seropositive for anti-CCP antibodies, increased the risk for RA (p=0.008, OR=2.5, 95%CI=1.3-5.0) when we compared with controls; however, in the group of seronegative patients, no was found significant difference (p=0.1, OR=2.5, 95%CI=0.9-7.2). CONCLUSIONS: Our results support the association of the +1858T risk allele of the +1858C/T PTPN22 polymorphism with susceptibility to RA and confirm that, in combination with anti-CCP antibodies, this SNP influence the autoimmune processes towards a development of RA in Mexican population.
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Artrite Reumatoide/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Artrite Reumatoide/diagnóstico , Autoanticorpos/sangue , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , México , Pessoa de Meia-Idade , Adulto JovemRESUMO
The objective of this study is to establish whether there is an association between the presence of FCGR3A V(176) polymorphism with SLE or its manifestations. We included 94 patients according to the 1982 ACR criteria as well as 98 controls matched by age and gender. The 11 ACR diagnostic criteria were analyzed on the clinical files. The polymorphism FCGR3A V(176) was determined by direct sequencing. There was not an association between the polymorphism FCGR3A V(176) with SLE or its main manifestations. The allelic frequency for F(176) was: 0.80 and 0.72 in cases and controls, respectively (P = 0.09, IC95%: 0.42-1.07); and the genotypic frequency in the group of cases was: 0.65 for homozygotes F(176)/F(176), 0.30 for heterozygotes and 0.05 for the homozygotes V(176)/V(176), while for the control group it was 0.53, 0.39 and 0.08, respectively. The polymorphism FCGR3A V(176) is not associated with SLE or any of its manifestations in patients with SLE from the West of Mexico.
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Lúpus Eritematoso Sistêmico/genética , Polimorfismo Genético , Receptores de IgG/genética , Adulto , Feminino , Frequência do Gene , Humanos , Lúpus Eritematoso Sistêmico/epidemiologia , Masculino , México/epidemiologiaRESUMO
Plasminogen activator inhibitor type 1 (PAI-1) is an inhibitor of plasmin production. Plasmin can directly or indirectly to degrade cartilage and bone matrix. The PAI-1 HindIII polymorphism has been associated with high PAI-1 plasma levels in myocardial infarction patients and control populations. Furthermore, it has been associated with the angiographic extent of coronary artery disease, but their involvement in other diseases is still uncertain. Here, we assessed the relationship between PAI-1 HindIII polymorphism and PAI-1 plasma levels in rheumatoid arthritis (RA). One hundred and twenty-five RA patients and 132 control subjects (CS) were included. Genotypes were identified by the polymerase chain reaction-restriction fragment length polymorphism technique and PAI-1 plasma levels were quantified using an ELISA kit. Not significant differences in genotype and allele frequencies between both studied groups were observed (P > 0.05). RA patients showed lower PAI-1 plasma levels (18.92 +/- 12.94 ng/ml) than CS (23.68 +/- 23.38 ng/ml), without significant difference (P = 0.299). However, in RA patients the C/G genotype carriers showed higher PAI-1 plasma levels (23.00 +/- 13.81 ng/ml) with respect to C/C (16.77 +/- 11.97 ng/ml) and G/G (10.47 +/- 7.07 ng/ml) genotype carriers (P = 0.036). The PAI-1 HindIII polymorphism was not associated with RA susceptibility. However, the C/G genotype is associated with high PAI-1 plasma levels in RA patients.
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Artrite Reumatoide/patologia , Inibidor 1 de Ativador de Plasminogênio/sangue , Inibidor 1 de Ativador de Plasminogênio/genética , Polimorfismo Genético , Desoxirribonuclease HindIII/metabolismo , Suscetibilidade a Doenças , Ensaio de Imunoadsorção Enzimática/métodos , Frequência do Gene , Humanos , Plasma/química , Reação em Cadeia da Polimerase/métodos , Polimorfismo de Fragmento de RestriçãoRESUMO
The depressive symptoms are associated with chronic pain in this study. A cross-sectional study was performed. A visual analog scale was used to register pain intensity. Depressive symptoms were measured using the Center of Epidemiological Studies (CES-Dr) scale as modified by Eaton and reviewed for use in the Mexican population. The study included 245 patients, with a mean age of 46 years, 86.1% of whom were female. The prevalence of some degree of depression was 55.1%. Patients with fibromyalgia had the highest prevalence of symptoms of depression (78.38%) and major depression (29.73%). Stepwise multiple regressions indicated that the best model (r2 = 0.26) to predict the CES-Dr score included the global pain score (P < 0.0001) and education level (P < 0.004). The Cronbach's alpha of the CES-Dr was high (alpha = 0.888). There was moderate correlation (r = 0.442), P < 0.0001 of the CES-Dr numeric score with the intensity of global pain.
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Transtorno Depressivo/diagnóstico , Transtorno Depressivo/epidemiologia , Hospitais de Ensino , Dor , Reumatologia , Estudos Transversais , Feminino , Humanos , Entrevistas como Assunto , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Pacientes Ambulatoriais/estatística & dados numéricos , Prevalência , Escalas de Graduação Psiquiátrica , População Rural , População UrbanaRESUMO
We investigate the clinical association of tumor necrosis factor receptor 2 (TNFR2) M196R polymorphism with rheumatoid arthritis (RA) and knee osteoarthritis (OA). Acute phase reactants, lipid profile, sTNFR2 levels, disease activity-disability indexes, and TNFR2 M196R polymorphism were analyzed in 50 RA, 50 knee OA patients, and 120 healthy subjects (HS). The M/M genotype frequency was 0.74 (RA), 0.80 (OA), and 0.64 (HS). The M/R genotype frequency was RA (0.26), OA (0.20), and HS (0.29). The R/R genotype was observed only in HS (0.07). The M allele was associated with OA (P = 0.0137, OR = 2.43). Total cholesterol, triglyceride levels, apolipoprotein A-I and B showed significant differences (P < 0.05). The highest sTNFR2 levels were observed in RA and OA (P = 0.001), however M/M and M/R carriers do not correlate with sTNFR2 production. Our findings suggest an association of the M allele with knee OA. In addition, high sTNFR2 levels in RA and OA were found.
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Artrite Reumatoide/sangue , Artrite Reumatoide/genética , Osteoartrite do Joelho/sangue , Osteoartrite do Joelho/genética , Polimorfismo Genético/genética , Receptores Tipo II do Fator de Necrose Tumoral/genética , Índice de Gravidade de Doença , Adulto , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína A-I/sangue , Apolipoproteínas B/sangue , Estudos de Casos e Controles , Colesterol/sangue , Avaliação da Deficiência , Genótipo , Humanos , México , Pessoa de Meia-Idade , Triglicerídeos/sangueRESUMO
El alendronato sódico es un fármaco empleado como inhibidor de la resorción ósea y con ello para el manejo de la osteoporosis. Se presentan los resultados en 42 pacientes diagnosticados con osteoporosis por medio de densitometría ósea (DO) que fueron sometidos a tratamiento con alendronato sódico durante 21 meses en promedio. El tipo de osteoporosis fue principalmente posmenopáusica. Además, todos los pacientes recibieron indicaciones de continuar la ingestión de calcio oral. La DO reveló ganancia ósea a nivel de columna lumbar en 40 (95 por ciento) de los 42 pacientes cuyó valor medio fue 6 por ciento comparando con la densitometría inicial (p<0.01) y a nivel de cuello femoral la ganancia observada aunque ocurrió en algunos casos, en el conjunto del grupo no fue significativa desde el punto de vista estadístico. Con base en estos resultados, se conluye que el alendronato sódico fue eficaz para lograr incremento de la masa ósea medida por DO-principalmente en columna lumbar- en pacientes con osteoporosis
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Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Osteoporose/etiologia , Osteoporose/tratamento farmacológico , Cálcio/uso terapêutico , Densitometria , Densidade ÓsseaRESUMO
La artritis reumatoide juvenile (ARJ) es considerada como la enfermedad del tejido conectivo más frecuente en la infancia. La incidencia de manifestaciones oculares, es variable y ha sido reportado entre 5 y 24 por ciento. La iridociclitis que se desarrolla en los pacientes con ARJ, es la alteración más grave y puede llevar a los niños a la pérdida total de la visión. El objetivo de este estudio fue conocer la frecuencia y tipo de manifestaciones oculares en pacientes con ARJ en nuestro medio. Se realizó un estudio descriptivo y trasversal. Se analizaron 30 pacientes con diagnóstico de ARJ con edad promedio de inicio de 10.2 años (2-5 años), evaluación promedio de la enfermedad de 4.6 años (3 meses-35 años). En este estudio la frecuencia de alteraciones oculares fue de 40 por ciento (12 pacientes). Sin embargo, no todas las alteraciones encontradas se asociarion a la presencia de ARJ. La queratoconjuntivitis sieca se presentó en el 23 por ciento (7 pacientes) y en ningún caso se detectó iridociclitis aguda o crónica. La presencia de daño ocular en estos pacientes pudiera depender de otros factores (genéticos, ambientales, etc.) aunque la evaluación periódica no detecte patología grave; se pueden encontrar alteraciones menos mediante vigilancia y seguimiento oportunos