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This study aimed to investigate the role of TSPAN32, a member of the tetraspanin family, in rheumatoid arthritis (RA). The objective was to assess the expression levels of TSPAN32 in experimental RA models and in RA patient immune cells, exploring its potential as a regulatory factor in RA pathogenesis. The study employed adjuvant-induced arthritis in rats and collagen-induced arthritis (CIA) in mice as experimental models. Ex vivo analyses included evaluating TSPAN32 expression in immune cells at different stages of the disease. In silico data analysis involved examining transcriptomic datasets from drug-naïve and treated RA patients to correlate TSPAN32 expression with clinical parameters. TSPAN32 overexpression experiments in splenocytes from CIA mice aimed to demonstrate its functional impact on antigen-specific immune responses. The animal models revealed a significant downregulation of TSPAN32, particularly in synovial-infiltrating T cells. Also, TSPAN32 overexpression inhibited pro-inflammatory cytokine production in splenocytes. In RA patients, TSPAN32 was consistently downregulated in circulating and synovial-infiltrating T cells, as well as in CD8+ T cells, B cells and NK cells. Drug treatment did not significantly alter TSPAN32 levels. Negative correlations were observed between TSPAN32 expression and inflammatory markers (CRP, ESR) and clinical scores (SDAI) in RA patients. This study suggests that reduced TSPAN32 expression characterizes pathogenic T-cell populations in RA, highlighting its potential as biomarker for inflammation and disease activity. TSPAN32 may play a crucial role in shaping adaptive immune responses in RA, opening avenues for novel therapeutic strategies targeting this tetraspanin family member., (© 2024 The Author(s). Scandinavian Journal of Immunology published by John Wiley & Sons Ltd on behalf of The Scandinavian Foundation for Immunology.)

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and diverse tissue and organ inflammatory affections. Interleukin 21 (IL-21) is implicated in B cell survival, proliferation, differentiation, class switching, and immunoglobulin production; therefore, it is considered a key cytokine in the pathogenesis of SLE. However, its association with disease activity and clinical phenotypes remains unclear. We aimed to evaluate the association of IL-21 levels with the disease activity and clinical phenotypes in patients with SLE. Also, we analyzed the IL21 polymorphisms associated with increased IL-21 levels. Methods : The IL-21 serum levels were determined using the enzyme-linked immunosorbent assay (ELISA) method. The rs2221903 and rs2055979 polymorphisms were assessed in 300 healthy controls (HCs) and 300 patients with SLE by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The levels of IL-21 were monitored during follow-up visits in 59 patients with SLE. Results : The patients with SLE showed higher IL-21 levels compared to the HCs. The IL-21 levels did not correlate with Mex-SLEDAI and were not different in patients with inactive, mild-moderate, and severe disease. The IL-21 levels were increased in patients with hematological affection. The ROC curve analysis revealed that the IL-21 levels had good predictive power in discriminating among patients with SLE and HCs. In a follow-up analysis, the levels of IL-21 remained higher in the patients with SLE even when the patients were in remission. Also, the rs2221903 polymorphism was associated with increased IL-21 levels. Conclusions : This study highlights the importance of IL-21 as a key cytokine in SLE. IL-21 levels are higher in patients with SLE and remain increased regardless of disease activity. According to the ROC analysis, IL-21 is a potential biomarker of SLE. Further longitudinal studies are needed to explore the relationship between IL-21 and the clinical phenotypes of SLE.

Despite advances in understanding systemic lupus erythematosus (SLE), many challenges remain in unraveling the precise mechanisms behind the disease's development and progression. Recent evidence has questioned the role of programmed cell death protein 1 (PD-1) in suppressing autoreactive CD4 + T cells during autoimmune responses. Research has investigated the potential impacts of PD-1 on various CD4 + T-cell subpopulations, including T follicular helper (Tfh) cells, circulating Tfh (cTfh) cells, and T peripheral helper (Tph) cells, all of which exhibit substantial PD-1 expression and are closely related to several autoimmune disorders, including SLE. This review highlights the complex role of PD-1 in autoimmunity and emphasizes the imperative for further research to elucidate its functions during autoreactive T-cell responses. Additionally, we address the potential of PD-1 and its ligands as possible therapeutic targets in SLE.

Introduction: Cytokine levels are related to the aethiopathogenia of acute apical abscesses (AAA); however, the specific cytokine profiles in these cases are unclear. This study aimed to investigate the changes in systemic cytokine levels in patients with AAA and trismus onset, postantibiotic treatment, and postroot canal disinfection., Methods: In total, 46 AAA patients with trismus and 32 control subjects were included. After seven days of antibiotic therapy, root canal disinfection was performed in the AAA patients. The serum levels of cytokines were evaluated at basal, seven, and 14 days after endodontic treatment. Quantification of cytokines from T helper (Th) 1, Th2, Th17, and regulatory T cells profiles was determined using the BioPlex MagPix system, and the obtained data were analyzed using SPSS statistical software (P < .05)., Results: AAA patients showed higher tumor necrosis factor-alpha (TNF-α), interleukin (IL) -6, and IL-10 levels than control subjects, at basal measurement (P < .05); there were similar levels of interferon gamma, IL-1β, IL-4, and IL-17 between groups (P > .05). IL-6 and IL-10 levels decreased after antibiotic treatment (P < .05), which was also associated with clinical improvement in patients with AAA and trismus. Patients with AAA had a positive correlation with higher serum levels of IL-6 and IL-10. In addition, TNF-α levels decreased only after antibiotic and endodontic treatment., Conclusions: In conclusion, patients with AAA had increased systemic serum levels of TNF-α, IL-6, and IL-10. Moreover, increased levels of IL-6 and IL-10 are associated with acute inflammatory symptoms. However, IL-6 and IL-10 levels decreased after antibiotic treatment, while TNF-α levels decreased after antibiotic and endodontic treatment., (Copyright © 2023 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Introduction: B cell activating factor (BAFF) has an important role in normal B cell development. The aberrant expression of BAFF is related with the autoimmune diseases development like Systemic Lupus Erythematosus (SLE) for promoting self-reactive B cells survival. BAFF functions are exerted through its receptors BAFF-R (BR3), transmembrane activator calcium modulator and cyclophilin ligand interactor (TACI) and B cell maturation antigen (BCMA) that are reported to have differential expression on B cells in SLE. Recently, atypical B cells that express CD11c have been associated with SLE because they are prone to develop into antibody-secreting cells, however the relationship with BAFF remains unclear. This study aims to analyze the BAFF system expression on CXCR5 - CD11c + atypical B cell subsets double negative 2 (DN2), activated naïve (aNAV), switched memory (SWM) and unswitched memory (USM) B cells., Methods: Forty-five SLE patients and 15 healthy subjects (HS) were included. Flow cytometry was used to evaluate the expression of the receptors in the B cell subpopulations. Enzyme-linked immunosorbent assay (ELISA) was performed to quantify the soluble levels of BAFF (sBAFF) and IL-21., Results: We found increased frequency of CXCR5 - CD11c + atypical B cell subpopulations DN2, aNAV, SWM and USM B cells in SLE patients compared to HS. SLE patients had increased expression of membrane BAFF (mBAFF) and BCMA receptor in classic B cell subsets (DN, NAV, SWM and USM). Also, the CXCR5 + CD11c - DN1, resting naïve (rNAV), SWM and USM B cell subsets showed higher mBAFF expression in SLE. CXCR5 - CD11c + atypical B cell subpopulations DN2, SWM and USM B cells showed strong correlations with the expression of BAFF receptors. The atypical B cells DN2 in SLE showed significant decreased expression of TACI, which correlated with higher IL-21 levels. Also, lower expression of TACI in atypical B cell DN2 was associated with high disease activity., Discussion: These results suggest a participation of the BAFF system in CXCR5 - CD11c + atypical B cell subsets in SLE patients. Decreased TACI expression on atypical B cells DN2 correlated with high disease activity in SLE patients supporting the immunoregulatory role of TACI in autoimmunity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Álvarez Gómez, Salazar-Camarena, Román-Fernández, Ortiz-Lazareno, Cruz, Muñoz-Valle, Marín-Rosales, Espinoza-García, Sagrero-Fabela and Palafox-Sánchez.)

Background: Circulating T follicular helper (cTfh) and T peripheral helper (Tph) subpopulations are shown to be higher in systemic lupus erythematosus (SLE) patients and have been involved in promoting extrafollicular B cell responses. However, a possible association with the B cell activating factor (BAFF), a cytokine mainly related to B cell responses and disease activity in SLE, has not been investigated. Therefore, this study aimed to evaluate the association of cTfh and Tph subpopulations with the BAFF system expression and clinical activity in SLE patients., Methods: This study included 43 SLE patients and 12 healthy subjects (HS). The identification of cTfh (CD4 + CXCR5 + PD-1 + ), Tph (CD4 + CXCR5 - PD-1 + ) cells, expression of membrane-bound BAFF (mBAFF), BAFFR, TACI, BCMA, and intracellular IL-21 was performed by flow cytometry. Serum levels of IL-21, CXCL13, and BAFF were analyzed using ELISA. The SLEDAI-2K score was used to evaluate disease activity in SLE patients., Results: Compared with HS, SLE patients showed a significantly increased percentage of cTfh and Tph cells, higher in patients with clearly active disease. SLE patients had markedly higher IL-21-producing cTfh and Tph cells than HS. Both subpopulations were positively correlated with the disease activity in SLE patients. Tph cells were negatively correlated with CD19 + CXCR5 + B cells and positively correlated with CD19 + CXCR5 - B cells. A low expression of mBAFF and their receptors TACI and BCMA was found on cTfh and Tph cells in SLE patients and HS. However, SLE patients with clearly active disease showed decreased expression of BAFFR on cTfh and Tph subpopulations than patients with mildly active/nonactive disease. Serum IL-21, CXCL13, and BAFF levels were higher in SLE patients than in HS. Levels of CXCL13 were correlated with disease activity. Non-significant correlations were observed among T cell subpopulations and IL-21, CXCL13, and BAFF levels., Conclusions: This study emphasizes the importance of cTfh and Tph cells in SLE pathogenesis. Besides the importance of IL-21, our results suggest that BAFFR could play a role in cTfh and Tph subpopulations in the autoimmunity context.

Aim: The aim of this case-control study was to evaluate the association between the TNFSF13B rs9514828 (-871 C > T) polymorphism and soluble BAFF (sBAFF) in apical periodontitis (AP) patients., Methodology: Two hundred and sixty one healthy subjects (HS) and 158 patients with AP classified as: 46 acute apical abscess (AAA), 81 primary AP (pAP) and 31 secondary AP (sAP) patients were included. Genomic DNA (gDNA) was extracted from peripheral blood cells according to the salting out method. The TNFSF13B rs9514828 (NC&#95;000013.11:g.108269025C > T) were identified using polymerase chain reaction (PCR) followed by restriction fragment length polymorphisms (RFLP). Serum sBAFF levels were measured by ELISA test. The chi-squared or Fisher's exact test was performed. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated to evaluate the risk of AP associated with the rs9514828. The Mann-Whitney U test and Kruskal-Wallis analysis were used for non-normally distributed data. Differences were considered significant with a p-value <.05., Results: No differences in the genotype/allele frequencies were shown between HS and patients with AAA. However, the TT genotype (OR = 2.68, 95% CI: 1.10-6.53; p = .025) and T allele (OR = 1.46, 95% CI: 1.00-2.12; p = .045) were associated with increased risk of pAP. In contrast, the minor allele T significantly decreased the risk of sAP (OR = 0.49, 95% CI: 0.024-0.99; p = .043). sBAFF serum levels were increased in AAA and pAP compared with HS (p < .01 and p = .021, respectively). The AAA patients had higher sBAFF serum levels than pAP (p = .034) and sAP (p < .01)., Conclusions: These results suggest that the TNFSF13B rs9514828 (-871 C > T) polymorphism is associated with pAP susceptibility and that BAFF is a cytokine that might be involved in acute and chronic AP. The future exploration of the rs9514828 polymorphism in other AP cohorts is recommended., (© 2022 International Endodontic Journal. Published by John Wiley & Sons Ltd.)

Background: Primary Sjögren's syndrome (pSS) is an autoimmune exocrinopathy characterized by lymphocytic infiltration, glandular dysfunction and systemic manifestations. Lyp protein is a negative regulator of the T cell receptor encoded by the tyrosine phosphatase nonreceptor-type 22 ( PTPN22 ) gene. Multiple single-nucleotide polymorphisms (SNPs) in the PTPN22 gene have been associated with susceptibility to autoimmune diseases. This study aimed to investigate the association of PTPN22 SNPs rs2488457 (-1123 G>C), rs33996649 (+788 G>A), rs2476601 (+1858 C>T) with pSS susceptibility in Mexican mestizo subjects., Methods: One hundred fifty pSS patients and 180 healthy controls (HCs) were included. Genotypes of PTPN22 SNPs were identified by PCR-RFLP. PTPN22 expression was evaluated through RT-PCR analysis. Serum anti-SSA/Ro and anti-SSB/La levels were measured using an ELISA kit., Results: Allele and genotype frequencies for all SNPs studied were similar in both groups ( p > 0.05). pSS patients showed 17-fold higher expression of PTNP22 than HCs, and mRNA levels correlated with SSDAI score ( r 2 = 0.499, p = 0.008) and levels of anti-SSA/Ro and anti-SSB/La autoantibodies ( r 2 = 0.200, p = 0.03 and r 2 = 0.175, p = 0.04, respectively). Positive anti-SSA/Ro pSS patients expressed higher PTPN22 mRNA levels ( p = 0.008), with high focus scores by histopathology ( p = 0.02). Moreover, PTPN22 expression had high diagnostic accuracy in pSS patients, with an AUC = 0.985., Conclusions: Our findings demonstrate that the PTPN22 SNPs rs2488457 (-1123 G>C), rs33996649 (+788 G>A) and rs2476601 (+1858 C>T) are not associated with the disease susceptibility in the western Mexican population. Additionally, PTPN22 expression may be helpful as a diagnostic biomarker in pSS.

Background: The B-cell activating factor (BAFF) controls the maturation and survival of B cells. An imbalance in this cytokine has been associated with systemic autoimmunity in SLE and lupus nephritis (LN). However, few investigations have evaluated the tissular expression of BAFF in LN. This study aimed to associate BAFF system expression at the tissular level with the proliferative LN classes. Methods: The analysis included eighteen kidney tissues, with sixteen LN (class III = 5, class IV = 6, class III/IV+V = 4, and class V = 1), and two controls. The tissular expression was evaluated with an immunochemistry assay. A Cytation5 imaging reader and ImageJ software were used to analyze the quantitative expression. A p-value < 0.05 was considered significant. Results: The expressions of BAFF, A proliferation-inducing ligand (APRIL), and their receptors were observed in glomerular, tubular, and interstitial zones, with BAFF being the most strongly expressed in the overall analysis. BAFF-Receptor (BR3), transmembrane activator and CALM interactor (TACI), and B-Cell maturation antigen (BCMA) displayed higher expressions in LN class IV in all zones analyzed (p < 0.05). Additionally, a positive correlation was found between APRIL, TACI, and BCMA at the glomerular level; BCMA and APRIL in the interstitial zone; and BR3, TACI, and BCMA in the tubule (p < 0.05). Conclusions: The expression of BAFF and BAFF receptors is mainly associated with LN class IV, emphasizing the participation of these receptors as an essential pathogenic factor in kidney involvement in SLE patients.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with very heterogeneous clinical behavior between affected individuals. Therefore, the search for biomarkers clinically useful for the diagnosis, prognosis, and monitoring of the disease is necessary. Here, we determined the association between PTPN22 , IL10 , OAS2 , and CD70 mRNA expression with the clinical characteristics and with the serum levels of IL-10, IFN-γ, and IL-17 in SLE patients. Forty patients with SLE and 34 control subjects (CS) were included, mRNA expression was determined by real-time qPCR and cytokine levels were quantified by a multiplex bead-based immunoassay. Compared to CS, SLE patients showed increased IL10 mRNA and high IL-10 and IL-17 serum levels; in contrast, PTPN22 mRNA and IFN-γ were decreased. PTPN22 and IL10 gene expression was negatively correlated with Mex-SLEDAI score and were notably downregulated in SLE patients with lupus nephritis. Interestingly, SLE patients with renal damage were the ones with the lowest levels of PTPN22 and IL10 mRNA and the highest SLEDAI scores. No associations were observed for OAS2 and CD70 mRNA and IL-10, IL-17, and IFN-γ. In conclusion, we suggest that the assessment of IL10 and PTPN22 mRNA could be useful for monitoring disease activity in SLE patients showing renal involvement.

Background: The increased expression of B cell-activating factor (BAFF) has been linked to autoantibody production in autoimmune diseases (ADs). The aim of this study was to investigate the association among TNFSF13B gene (OMIM: 603969) single nucleotide polymorphisms (SNPs), TNFSF13B mRNA, and soluble BAFF (sBAFF) expression in patients with rheumatoid arthritis (RA) and primary Sjögren's syndrome (pSS). The diagnostic value of sBAFF also was evaluated by the area under the curve (AUC) of receiver operating characteristic or receptor (ROC) curves., Methods: Genotypes of the TNFSF13B rs9514827 (-2841 T > C), rs1041569 (-2701 A > T) and rs9514828 (-871 C > T) SNPs were determined by PCR-RFLP assay. TNFSF13B mRNA and sBAFF expression were performed by RT-qPCR and ELISA, respectively. The study included 320 RA patients, 101 pSS patients, and 309 healthy subjects (HS)., Results: The rs9514828 T allele and the TAT haplotype were associated with an increased risk to develop RA. In both ADs, the TNFSF13B mRNA levels were increased in comparison with HS. The rs9514828 (-871 C > T) polymorphism was associated with increased gene expression in RA patients. Also, sBAFF levels were higher in both ADs, however pSS patients showed the highest sBAFF levels. sBAFF showed higher diagnostic performance for pSS with an AUC of 0.968, with a similar accuracy of anti-SSA/Ro antibody diagnosis (AUC = 0.974)., Conclusions: Our findings demonstrate that the TNFSF13B rs9514828 (-871 C > T) polymorphism is a risk factor for RA in the western Mexican population. sBAFF levels may be a potential diagnosis biomarker in pSS., (© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

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.

Background: Primary Sjögren's syndrome (pSS) is an autoimmune disease characterized by a lymphocytic infiltrate in salivary glands driving to epithelial damage. The pSS patients present heterogenic clinical and serological characteristics. This heterogenicity could be due to the cytokine microenvironment. Cytokine levels have been analyzed and reported individually, showing controversial results; for that reason, we considered essential to evaluate a cluster of cytokines and relate them with antibody levels and clinical characteristics to find pSS subgroups., Methods: Ninety-nine pSS patients, diagnosed by the 2016 ACR/EULAR classification criteria, and 76 control subjects (CS) were included. Cytokine quantification was performed by Multiplex assay. Principal component analysis (PCA) was realized, and the K-mean test was used to identify clusters/groups. Groups were analyzed by the Kruskal-Wallis test and the Bonferroni test., Results: Higher IFN-γ, IL-17F, IL-21, IL-23, IL-4, and IL-31 levels were observed in pSS patients in comparison with control subjects. PCA analysis showed three groups. The severe group was characterized by higher cytokine concentrations as well as an increase in clinical parameters such as antibody levels, damage index score, and others. The moderate group presented intermediate severity; meanwhile, the mild group presented the lowest severity., Conclusion: Cluster analysis revealed three groups that were different in cytokine levels and clinical parameters in which the mild group was defined by lower severity, the moderate group with intermediate severity, and the severe group with higher severity. This analysis could help subclassify the primary Sjögren syndrome patients for a better understanding of the clinical phenotype that impacts the treatment approach., (© 2020 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

B cell-activating factor (BAFF) is an essential cytokine in primary Sjögren's syndrome (pSS) physiopathology. It has been reported that pSS patients develop germinal center-like (GC-like) structures in their minor salivary glands (MSGs). BAFF, BAFF-R, TACI, and BCMA expression was analyzed in MSGs from 29 subjects (nonspecific chronic sialadenitis and focal lymphocytic sialadenitis with the presence [pSS-GC(+)] or absence [pSS-GC(-)] of GC-like structures). Twenty-four percent of patients showed ectopic GC-like structures and a high focus score [p < 0.001 vs pSS-GC(-)]. BAFF serum levels (sBAFF) were high in pSS patients (p = 0.025 vs healthy subjects). However, the pSS-GC(-) group showed higher sBAFF levels than pSS-GC(+) patients. BAFF and BAFF-R glandular expression levels were higher in pSS-GC(+) patients, without significant differences compared to pSS-GC(-) patients. Soluble levels of BAFF correlated with anti-La/SSB antibodies and disease duration. Our results showed that BAFF could contribute to focal lymphocytic infiltration. The role of BAFF-binding receptors in MSGs is proposed as a mechanism for the possible establishment of ectopic GC-like structures and disease progression in some patients. In conclusion, this study supports previous evidence that considers the active BAFF system role in the pathogenesis of pSS and the need for strong biomarkers in this disease.

B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) play central roles in B cell development and maturation. Soluble forms of their receptors can be generated by proteolytic cleavage; however, their physiological and clinical roles are unknown. This study aimed to assess the relationships between the receptor soluble B cell maturation antigen (sBCMA) and clinical variables in systemic lupus erythematosus (SLE) patients. Serum cytokine concentrations were measured by ELISA for 129 SLE patients and 34 healthy controls (HCs), and the expression of the receptor BCMA was evaluated on B and plasma cells from 40 subjects. SLE patients showed aberrant expression of the receptor BCMA on B and plasma cells. Soluble levels of the receptor sBCMA and its ligands sAPRIL and sBAFF were increased in SLE patients compared with HCs. Additionally, sBCMA (r s  = 0.6177) and sAPRIL (r s  = 0.4952) correlated strongly with disease activity. Active SLE patients who achieved low disease activity showed decreased sBCMA (53.30 vs 35.30 ng/mL; p < 0.05) and sBAFF (4.48 vs 2.27 ng/mL; p < 0.05) serum levels after treatment, while sAPRIL expression remained unchanged. At a cutoff value of 22.40 ng/mL, sAPRIL showed high sensitivity (96.12%) and specificity (94.12%) for discrimination between HCs and SLE patients, while sBAFF showed lower sensitivity (82.2%) but higher specificity (94.1%) at a cutoff of 1.195 ng/mL. Relatively high levels of sAPRIL and sBCMA clustered active SLE patients. The receptor sBCMA could be a potential biomarker of disease activity in SLE.

Systemic lupus erythematosus (SLE) involves a broad range of factors that contribute to the development of the disease and its comorbidities. Genetic predisposition influences the development of SLE, and the -675 4G/5G PAI-1 polymorphism has been associated with several pathologies with a chronic inflammatory component. Our objective was to investigate the genetic association between the -675 4G/5G PAI-1 polymorphism with SLE, its clinical manifestations, and comorbidities in a Mexican-Mestizo population. The -675 PAI-1 polymorphism was determined by PCR-RFLP in 716 subjects: 293 SLE patients and 423 control subjects. Significant associations for SLE genetic susceptibility were found in carriers of 4G/5G (OR = 2.63; CI 1.81-3.87; p  < .001) and 4G/4G (OR = 2.70; CI 1.62-4.51; p  < .001) genotype in comparison with the 5G/5G genotype; 4G allele carriers also presented genetic risk for SLE (OR = 1.63; CI 1.31-2.03; p  < .001) compared to the 5G allele. Following a dominant genetic model, a similar association was found with the 4G allele to SLE (OR = 2.66; CI1.84-3.84; p  < .001). The 4G/5G genotype was associated with shorter disease duration ( p  = .039), as well as lower levels of haemoglobin ( p  = .001) and haematocrit ( p  = .009); the need for prednisone treatment ( p  = .001), higher BMI ( p  = .03), presence of type 2 DM ( p  = .015), clinical activity (Mex-SLEDAI = 57%; p  = .047), Chronicity (SLICC-ACR = 0; p  = .015) and CRP levels ( p  = .015) were associated with 5G/5G genotypes. In conclusion, the -675 4G/5G and 4G/4G PAI-1 genotypes were found as genetic risk markers of susceptibility for SLE in the Mexican-Mestizo population, and each genotype could influence the clinical manifestations and comorbidities differently in SLE.

Background: CD40 is a transmembrane protein mainly expressed on the antigen-presenting cells surface. CD40 plays a crucial role in immunoglobulin class switching and antibodies production. Genetic polymorphisms in the CD40 gene have been associated with increased risk of systemic lupus erythematosus (SLE) in several populations. This study aimed to evaluate the association of CD40 polymorphisms (-1 C > T, rs1883832 and 6,048 G > T, rs4810485) with SLE susceptibility, as well as with mRNA expression and soluble CD40 (sCD40) levels., Methods: The study included 293 patients with SLE and 294 control subjects (CS). Genotyping was performed by PCR-RFLP method. CD40 mRNA expression was determined by quantitative real-time PCR, and ELISA quantified sCD40 levels., Results: The CD40 polymorphisms -1 C > T and 6,048 G > T were associated with SLE susceptibility. There was no difference between CD40 mRNA expression and CD40 polymorphisms. The sCD40 levels were lower in SLE patients with TT haplotype, whereas higher sCD40 levels were associated with damage and impaired renal function according to SLICC and KDIGO. The sCD40 levels were negatively correlated with eGFR., Conclusion: The CD40 gene polymorphisms increase the risk of SLE in the western Mexican population. The sCD40 levels are associated with -1 C > T polymorphism and chronic kidney disease., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

The predominance of the effector mechanisms by CD4 + T cells is a characteristic of inflammatory autoimmune diseases such as rheumatoid arthritis (RA). The CD40/CD40L costimulatory pathway contributes to these pathogenic mechanisms by promoting autoantibody production and inflammation. Aberrant expression of CD40 and CD40L in RA patients has been shown, the latter prevailing in females. However, contrasting results have emerged regarding the clinical associations of these findings. We determined the association of CD40 and CD40L expression with the clinical activity evaluated through DAS28 in RA patients. A total of 38 female RA patients and 10 age- and sex-matched control subjects were included. CD40 and CD40L mRNA expression was quantified by real-time qPCR, cell surface proteins were determined by flow cytometry, and protein soluble forms were determined by ELISA. The expansion of a CD4 + T cell subpopulation expressing CD40 was identified in the RA group. In addition, high frequencies of CD4 + CD40L + T cells expressing high levels of CD40L, increased levels of sCD40L and overexpression of CD40L mRNA were observed in these patients. Moreover, there was a gradual increase in CD40L when data were stratified according to DAS28, except for very active patients. No correlation was observed between the levels of mRNA, cell surface protein and soluble protein of CD40 and CD40L with the clinical features of RA patients. There is an altered expression of CD40L in female RA patients in association with clinical activity assessed by DAS28, these findings support the evidence that suggests CD40L as a marker of clinical activity.

Electronic apex locators (EAL) have been used to establish the working length (WL) in root canal treatment. In teeth diagnosed with apical periodontitis, resorption of tooth apical structures can lead to difficulties to obtain an appropriate WL. The aim was to compare the capacity of three EAL's (Root ZX II, Raypex 6 and Endo-Eze Quill) to locate the tip of the K-file between 0 to -0.5 mm from the apical foramen (AF) on teeth diagnosed with asymptomatic apical periodontitis (AAP). Electronic working length was performed on 60 roots with AAP. A K-file #15 was inserted in the root canal until the apical foramen (AF) was located, and followed was re-adjusted to -0.5 mm through observation in EAL display. The K-file was fixed to the tooth with composite and teeth were extracted. The 4 apical millimeters were worn out until the K-file could be seen and were prepared and measured its distance to AF in a scanning electron microscope. Appropriate WL was when the tip of the K-file was located between 0 to -0.5 mm from AF. Results: Root ZX II showed significant difference (p<0.01) with the other two EALs. Root ZX II presented the better performance than Raypex 6 or Endo-Eze Quill in teeth with AAP.

PTPN22 represents an important non-HLA gene that has been strongly associated with rheumatoid arthritis (RA) pathogenesis. Several studies have reported a specific genetic variant for PTPN22 (+788 G>A; rs33996649) that might be associated with decreased RA risk in Caucasian population; nevertheless, its specific role in western Mexican population has not been yet described. A case-control study with 443 RA patients and 317 control subjects (CS) was conducted. The genotyping was performed by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) technique and the PTPN22 mRNA expression was determined by SYBR Green-based real-time quantitative-PCR assay. No association between the PTPN22 +788 G>A polymorphism and RA susceptibility in western Mexican population was found when comparing genotype and allelic frequencies between RA patients and CS (G/G vs. G/A: OR 0.55, p = 0.14, 95% CI 0.22-1.32; G vs. A: OR 0.56, p = 0.14, 95% CI 0.23-1.36). The PTPN22 mRNA expression increased 4.6-fold more in RA patients than in CS, and RA patients, carriers of PTPN22 +788 G/A genotype, expressed 15.6-fold more than RA patients carrying the homozygous G/G genotype. Overall, these results showed that the PTPN22 +788 G>A polymorphism is not associated with RA susceptibility in western Mexican population, whereas the presence of G/A genotype is associated with increased PTPN22 mRNA expression in RA patients.

B cell-activating factor (BAFF) promotes the survival, proliferation and maturation of B lymphocytes, which are key elements in the pathogenesis of systemic lupus erythematosus (SLE). This cytokine is encoded on TNFSF13B gene, and diverse single-nucleotide polymorphisms have been associated with susceptibility in different autoimmune disorders. In this study, the relationship of TNFSF13B gene rs9514827T>C, rs1041567T>A and rs9514828C>T polymorphisms, mRNA expression and soluble BAFF levels was investigated in 175 SLE patients and 208 healthy controls (HC). The TNFSF13B polymorphisms were evaluated by PCR-RFLP technique. The TNFSF13B gene expression was quantified through the RT-PCR assays. The soluble BAFF (sBAFF) levels were measured with ELISA test. There were no differences in genotype and allele frequencies for the three TNFSF13B polymorphisms, between SLE patients and HC. SLE patients showed 3.15-fold more TNFSF13B gene expression than HC. The patients who displayed most mRNA expression were those with active disease and the carriers of rs9514828 T variant allele. The sBAFF serum levels were higher in SLE patients compared to HC (2.083 vs. 0.742 ng/mL, p < 0.001). The SLE patients with active disease showed the higher sBAFF serum levels (2.403 ng/mL), mainly patients with lupus nephritis and hematological manifestations. In addition, a correlation of sBAFF with disease activity was found (r = 0.32, p < 0.001). In conclusion, the TNFSF13B gene polymorphisms were not found to be associated with SLE susceptibility in Mexican mestizos. Nevertheless, rs9514828C>T polymorphism seems to increase TNFSF13B gene expression. High BAFF expression is related to active disease, renal and hematological involvement; therefore, it could be considered as follow-up biomarker in SLE patients.

B-cell activating factor (BAFF) is a major cytokine that regulates B-cell survival, maturation and differentiation through its binding with its receptors: BAFF receptor (BAFF-R), transmembrane activator and cyclophilin ligand interactor (TACI) and B-cell maturation antigen (BCMA). These receptors have been demonstrated to be involved in tertiary lymphoid structure formation; however, their role in germinal centers (GCs) has remained elusive. The aim of the present study was to determine the expression profiles of BAFF and its receptors in secondary lymphoid tissues. Tonsils resected due to chronic tonsillitis were used as lymphoid tissues. To confirm the presence of GCs identified based on their typical structure, CD21 antibody staining was employed. The expression of BAFF, BAFF-R, TACI and BCMA was assessed by immunohistochemistry. BAFF was highly expressed in all regions of the follicle, but the highest BAFF expression was detected in the mantle zone (MZ). A high expression of BAFF-R was observed on lymphocytes in the MZ in comparison with the other regions (~80%; P<0.05), which was co-localizated with BAFF (r=0.646; P<0.001), in the MZ. TACI and BCMA exhibited similar expression among the different zones of the GCs, and co-localization with BAFF was observed inside the follicle, mainly in the dark zone. The present results indicate that BAFF is implicated in the maintenance of GCs. BAFF-R overexpression in the MZ, co-localizated with BAFF, suggests that these proteins constitute the principal pathway for the maintenance of the naïve B-cell population. Furthermore, TACI and BCMA have a role in the GC, where processes of B-cell selection, proliferation and differentiation into immunoglobulin-secreting plasma cells occur.

Background: CD40 is a costimulatory molecule for B cells, and CD154 is a marker of CD4+ T cells activation. CD40-CD154 interaction promotes pro-inflammatory cytokines secretion and autoantibodies production. PTPN22 gene encodes LYP protein, an inhibitor of T- and B-cell activation. PTPN22 1858C>T polymorphism confers rheumatoid arthritis (RA) susceptibility. Hence, we evaluate the relationship between 1858C>T polymorphism with CD40 and CD154 expression and IFN-γ secretion in RA patients., Methods: PTPN22 1858C>T polymorphism was genotyped in 315 RA patients and 315 control subjects (CS) using PCR-RFLP method. Later, we selected only ten anti-CCP-positive RA patients, naïve to disease-modifying antirheumatic drugs and ten CS, all with known 1858C>T PTPN22 genotype. The CD40 and CD154 membrane expressions were determined by flow cytometry in peripheral B and T cells, correspondingly., Results: The B cells percentage and mCD40 expression were similar between RA and CS (P > 0.05) and we did not find an association between these variables and the 1858C>T polymorphism. The CD4+ T cells percentage was higher in RA patients than CS (P = 0.003), and in the RA group, the CD4+ T cells percentage and mCD154 expression were higher in the 1858 T allele carriers (P = 0.008 and P = 0.032, respectively). The IFN-γ levels were lower in RA patients carrying the PTPN22 risk allele (P = 0.032)., Conclusion: The PTPN22 1858 T risk allele is associated with increased CD4+ T cells percentage and high mCD154 expression in RA patients, which could favor the pro-inflammatory cytokine release and the establishment of the inflammatory response at the seropositive RA., (© 2018 Wiley Periodicals, Inc.)

Background: Systemic lupus erythematosus (SLE) is the prototype of systemic autoimmune disease, characterized by loss of immune tolerance against self-antigens where autoantibody production is the hallmark of disease. B-cell-activating factor (BAFF) and A proliferation-inducing ligand (APRIL) are cytokines that promote autoreactive cell survival, immunoglobulin-class switching and autoantibody responses in human and mouse SLE models. BAFF and APRIL exert their functions through interactions with their receptors BAFF-R and TACI that are differentially expressed in B lymphocyte subsets, monocytes, dendritic cells and T lymphocytes. BAFF stimulation favors T lymphocyte activation and cytokine production through BAFF-R, which could contribute to the Th1, Th17 and/or Th2 response dysregulation observed in SLE patients., Objective: To evaluate the expression of the cytokines BAFF and APRIL and their association with the receptors BAFF-R and TACI on CD3+ T cells and to evaluate Th1/Th2/Th17 cytokine profile in patients with SLE., Methods: Fifteen healthy controls (HC) and 36 SLE patients were included, and their demographic and clinical data were assessed. The disease activity index (Mex-SLEDAI) and damage index (SLICC) were applied to the SLE patients. BAFF-R and TACI expression on CD3+ T cells were evaluated by flow cytometry. Serum BAFF and APRIL concentrations were measured by enzyme-linked immunosorbent assays (ELISA). Cytokine levels of Th1 (IL-12, IL-2, IFN-γ, TNF-α), Th2 (IL-4, IL-6, IL-10, IL-13) and Th17 (IL-1β e IL-17) were quantified with a multiplex assay (MAGPIX). Statistical analysis was performed using PASW Statistics v.20 and GraphPad Prism v.6 software., Results: No differences in BAFF-R or TACI expression on the CD3+ T cells of SLE and HC were observed. BAFF-R expression correlates inversely with disease activity (r = -0.538, p < 0.01), while TACI correlates with disease activity (r = 0.530, p < 0.05). Serum BAFF and APRIL levels were high in SLE patients and correlated with the disease activity index Mex-SLEDAI (r = 0.621, p < 0.01 and r = 0.416, p < 0.05). SLE patients were found to have significantly higher levels of IL-12, IFN-γ, TNF-α, IL-6, IL-10, IL-13, IL-1β and IL-17 compared to HC (p < 0.05). Cytokines IL-17 (r = 0.526) and TNF-α (r = 0.410) correlate with disease activity (p < 0.05), while APRIL (r = 0.477), IL-10 (r = 0.426) and IFN-γ (r = 0.440) levels were associated with organ damage (p < 0.01). Serum BAFF expression levels correlate with IL-4 (r = 0.424; p < 0.05), IL-6 (r = 0.420; p < 0.05) and IL-10 (r = 0.459; p < 0.01), whereas APRIL levels correlate with IL-2 (r = 0.666; p < 0.01), IL-12 (r = 0.611; p < 0.01) and TNF-α (r = 0.471; p < 0.05) cytokines. A subgroup of SLE patients with high serum BAFF levels (>2 ng/mL) also showed increased APRIL, IL-2, IL-6 and IL-10 levels (p < 0.05). Finally, BAFF, IL-4 and TNF-α serum levels were associated with high titers of antinuclear antibodies., Conclusions: The study demonstrates an imbalance in the Th1/Th2 cytokine profile, with increased proinflammatory cytokines, as well as BAFF and APRIL serum levels. Associations of BAFF with Th2 profile cytokines and disease activity, as well as APRIL with Th1 profile cytokines and organ damage, suggest that BAFF and APRIL generated in the autoimmunity context could through still unknown mechanisms, modulate the microenvironment, and perpetuate the inflammatory response, autoantibody production and organ damage observed in SLE patients., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Primary Sjögren's syndrome (pSS) is an autoimmune disease characterized by destruction of exocrine glands as a result of T and B cells infiltrated in glandular tissue. CD28 and CTLA-4 play a crucial role in T cell activation and inhibition. The aim of this study was to associate CD28 and CTLA4 haplotypes with susceptibility to pSS in patients from western Mexico., Methods: Polymerase chain reaction and restriction fragment length polymorphism were performed to identify CD28 and CTLA4 genotypes in 111 patients with pSS and 138 control subjects (CS). Haplotype analysis was carried out by SHEsis program. Soluble serum levels of CD28 (sCD28) and CTLA-4 (sCTLA-4) were quantified by ELISA kit., Results: The CD28 GC haplotype was associated with low risk to pSS (2.5-folds, P < 0.001). CTLA4 CAG and CGA were identified as genetic risk factor (P < 0.001;OR = 3.82[CI95%:2.022-7.296] and P < 0.001; OR = 11.38[CI95%:3.282-37.69] respectively). No difference in sCD28 and sCTLA-4 were found between patients and CS. However, pSS patients carriers of CD28 IVS3 + 17TC genotype showed high sCD28 (P = 0.039 vs TT carriers in CS). In regard to sCTLA-4, patient who carry CTLA4-319C>T, +49 A>G, and +6230 G>A, or their haplotypes did not show any difference., Conclusion: Our findings suggest that CD28 GC, CTLA4 CAG, and CGA haplotypes are associated with susceptibility to pSS in patients from western Mexico. It seems that genetic control of CD28 and CTLA4 as well as local immune response in glandular tissue may regulate the impact of the gene expression in pSS. It is necessary to confirm this hypothesis in an integrative study., (© 2018 Wiley Periodicals, Inc.)

Prolactin (PRL) is associated with different types of cancer, such as cervical cancer. Recombinant PRL has antiapoptotic effect on cervical cancer cells, and it can also induce cytokine production on macrophages. A 60 kDa variant of PRL is produced by cervical cancer cells. The aim of the present study was to evaluate this variant's bioactivity, to test its effect on cervical cancer cell apoptosis, and to assess its ability to induce cytokine production on THP-1 macrophages. First, 60 kDa PRL was isolated and used to stimulate Nb2 cells. Later, apoptosis was measured after exposure to 60 kDa PRL. Finally, cytokines were measured on THP-1 stimulated supernatants. Our results show that 60 kDa PRL increased Nb2 cell proliferation. Apoptosis was decreased after stimuli with 60 kDa PRL in cervical cancer cells. IL-1β and TNF-α are produced by THP-1 macrophages after stimuli. These results suggest that 60 kDa PRL produced by cervical cancer cells is able to reduce apoptosis in HeLa, SiHa and C-33A cells and induce IL-1β and TNF-α production by THP-1 macrophages.

Background: This study aimed to describe the anatomy of maxillary canines from a Western Mexican sub-population using micro-computed tomography (micro-CT)., Material and Methods: Maxillary canines (n=32) were scanned at 19.6µm voxel resolution. Number and location of canals, the distance between the cemento-enamel junction and apex, occurrence of accessory and lateral canals, presence of oval canals, number of foraminas as well as two- (area, perimeter, roundness, aspect ratio, major and minor diameters) and three-dimensional (volume, surface area, and SMI) analysis were performed. Data of two-dimensional analyses at 5 different apical levels was statistically compared using Kruskal-Wallis tests (α=0.05)., Results: Overall, 31 specimens had one root with a main canal (Vertucci type I). Mean distance from the apex to the cemento-enamel junction was 16.32±2.27. Apical foraminas were present in 14 specimens (43.75%). No statistical differences were found in the two-dimensional analyses between the foramen and the 1 and 2mm apical levels ( P >0.05)., Conclusions: Maxillary canines presenting one root canal were present in a high percentage of cases (96%). The prevalence of long oval canals was <12% at the apical third and at least 37% of the sample showed more than one point of exit in the last apical 3mm. Key words: Maxillary canine, micro-computed tomography, root canal anatomy., Competing Interests: Conflict of interest statement:The authors deny any conflicts of interest related to this study.

Background and Objectives: The protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene encodes an important negative regulator of T-cell activation, lymphoid-specific phosphatase -Lyp- and has been associated with different autoimmune disorders. The PTPN22 -1123G>C polymorphism appears to affect the transcriptional control of this gene, but to date, the biological significance of this polymorphisms on rheumatoid arthritis (RA) risk remains unknown. We evaluate the association of PTPN22 -1123G>C polymorphism with anti-cyclic citrullinated protein antibodies (anti-CCP) and risk for RA in population from Western Mexico., Material and Methods: A transversal analytic study, which enrolled 300 RA patients classified according to ACR-EULAR criteria and 300 control subjects (CS) was conducted. The -1123 G>C polymorphism was genotyped by PCR-RFLP. The anti-CCP antibodies levels were quantified by ELISA kit., Results: We found a higher prevalence of homozygous PTPN22 -1123CC genotype in CS than in RA patients (OR 0.41; 95% confidence interval 0.24-0.71; P=.001), suggesting a potential protective effect against RA. Concerning anti-CCP levels, the CC genotype carriers showed the lowest median levels in RA (P<.05)., Conclusion: The PTPN22 -1123CC genotype is a protector factor to RA in a Mexican-mestizo population and is associated with low anti-CCP antibodies., (Copyright © 2017 Elsevier España, S.L.U. All rights reserved.)

Interleukin 10 (IL-10) is an immunomodulatory cytokinethat plays a central rolein the pathogenesis of autoimmune diseases. Different studies consistently show increased IL-10 serum levels in rheumatoid arthritis (RA) and it appears to be caused by genetic variants. Three polymorphisms situated at positions -1082, -819 and -592 of IL10 gene and its major haplotypes have been associated with regulating IL10 promoter activity. In this study, we evaluated whether IL10 haplotypes are associated with mRNA expression and IL-10 serum levels as well as susceptibility to RA in a Western Mexican population. A total of 240 RA patients and 240 control subjects (CS) were included. Genotyping of IL10 polymorphisms was performed by PCR and PCR-RFLP, respectively. IL10 mRNA expression was determined by real-time PCR and IL-10 serum levels were measured using an ELISA kit. IL10 mRNA expression was 50-fold higher in RA patients than CS (p<0.001), while IL-10 serum levels did not show differences between groups. However, high IL-10 serum levels were positively related to a higherseropositivityfor rheumatoid factor (FR) and anti-CCP antibodies (p<0.05). No significant differences between the distribution of haplotype frequencies were observed between both study groups, but GCC haplotype was associated with higher IL-10 serum levels compared with the ACC and ATA haplotypes in RA patients (p<0.05). In addition, patients carrying ATA and GCC haplotypes showed higher mRNA expression than ACC (5.4-fold and 8.8-fold, respectively) and surprisingly, this trend was reversed in the controls, although it was not significant. In conclusion, our findings suggest that IL10 (GCC, ACC, and ATA) haplotypes may not be a susceptibility marker for RA in a population from Western Mexico. Nevertheless, independently of the presence of these variants, there is an aberrant overexpression of IL10 gene in RA, and it may play an important role in the pathogenesis of RA., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Rheumatoid arthritis (RA) is an autoimmune disease characterized by the presence of antibodies against cyclic citrullinated peptide (anti-CCP), a consequence of the breakdown of immune tolerance. The lymphoid tyrosine phosphatase (Lyp) protein has significant effects on maintenance of peripheral immune tolerance. Two polymorphic variants (-1123G>C and +1858C>T) at PTPN22 gene that encodes this protein have been associated with autoimmune disorders and found in strong linkage disequilibrium in Caucasian population. We evaluated whether PTPN22 haplotypes (-1123G>C/+1858C>T) are associated with anti-CCP antibodies, as well as susceptibility to RA in a Western Mexican population. A total of 315 RA patients and 315 control subjects (CS) were included. The polymorphisms were genotyped by PCR-RFLP and the anti-CCP antibodies were determined by ELISA. The PTPN22 polymorphisms were in strong linkage disequilibrium (D' = 1.00 in CS). The susceptibility haplotype CT was significantly more frequent in RA patients than in CS (OR 2.18, 95% CI 1.15-4.16, p = 0.01). No association between haplotypes and anti-CCP antibodies levels was observed. In conclusion, this study confirmed that -1123G>C and +1858C>T PTPN22 polymorphisms are in strong linkage disequilibrium and the CT haplotype is a susceptibility marker to RA in Western Mexico. However, the PTPN22 haplotypes are not associated with anti-CCP antibodies., Competing Interests: The authors declare that they have no competing interests.

Interleukin 10 (IL-10) is an immunoregulatory cytokine with multiple roles in the immune system. Three single nucleotide polymorphisms at positions -1082 (A>G), -819 (C>T), and -592 (C>A) in the promoter region of the IL10 gene are believed to be associated with different inflammatory, infectious, and autoimmune diseases. These polymorphisms exhibit a strong linkage disequilibrium (LD) and form three principal haplotypes (GCC, ACC, and ATA). The GCC and ATA haplotypes have been associated with high and low levels of IL-10 production, respectively. The aim of this study was to establish the allele and haplotype frequencies of the IL10 polymorphisms in Mestizos from western Mexico. SNPs were analyzed in 340 healthy unrelated Mestizos from western Mexico by polymerase chain reaction-restriction fragment length polymorphism. The studied population presented significant differences, in the distribution of IL10 polymorphisms, from the Asian, African, and European populations. We also observed a strong LD within -1082 A>G, -819 C>T, and -592 C>A (100% pc = 7.735 x 10 -18 ). The haplotypes ACC (45.4%), ATA (22.0%), GTA (14.9%), and GCC (13.9%) were most frequently observed in this population. The haplotype frequencies, however, differed from those reported previously in Mestizos from central Mexico, Asians, Africans, and European Caucasians, suggesting a differential gene flow in the Mexican Mestizo population. This could account for the genetic variability between Mexicans and populations of other ethnicities. The study of these polymorphisms and their haplotypes could help in expanding our knowledge to design future disease-risk studies on the western Mexican population.

Context: Disease Modifying Anti-Rheumatic Drugs (DMARDs) are aimed to interfere with rheumatoid arthritis (RA) progression and reduce the joint damage; however, not all patients respond alike. Killer-cell immunoglobulin-like receptors (KIR) and their ligands, human leucocyte antigen class I (HLA-I), have been associated with RA pathology; therefore, KIR and HLA genes may influence the treatment response., Materials and Methods: We evaluated the association of KIR genotype and their ligands HLA-C genes with the response to DMARDs in RA patients. We included 69 patients diagnosed with RA and 82 healthy individuals as the reference group. KIR and HLA-C genotyping was performed using SSP-PCR. RA patients were assessed at baseline and under treatment at 6 and 12 months; subsequently classified as responders and non-responders in each time period. We evaluated the association between DMARD response and genes using statistical analysis by using Fisher exact test with Bonferroni correction; results were regarded as statistically significant at p < 0.05., Results: Significant difference was observed in gene frequencies of patients and the reference group, KIR2DL2 was associated with RA (p = 0.031, OR = 2.119). We also observed an association between KIR2DS2 and the response to methotrexate (MTX), moreover, the combination KIR2DL2+/KIR2DS2+ was more frequent in responders to MTX (p = 0.043)., Discussion and Conclusions: In our results, responders and non-responders to DMARDs showed KIR2DS2 and KIR2DL2 different gene frequencies, therefore, these genes could be used as response predictors to DMARDs treatment. Thus, these genes were also associated with disease severity, as well as the treatment response possibly by the immunoregulatory function of NK cells.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune inflammatory disease characterized by loss of self-tolerance with hyperactivation of autoreactive T and B cells. Protein tyrosine phosphatase non-receptor type 22 (PTPN22) encodes for lymphoid-specific phosphatase (Lyp), which is a key negative regulator of T lymphocyte activation. The aim of this study was to evaluate the genetic contribution of PTPN22 -1123G>C and +1858C>T polymorphisms and their haplotypes in SLE patients, as well as mRNA expression according to -1123G>C promoter polymorphism and disease activity. One hundred and fifty SLE patients and 150 unrelated healthy controls (HC), both Mexican mestizos, were genotyped by PCR-RFLP technique for the PTPN22 -1123G>C and +1858C>T polymorphisms. PTPN22 mRNA expression levels were determined by real-time PCR from PBMCs of thirty patients with SLE and fifteen HC carrying different genotypes. Distributions of genotype and allelic frequencies were similar between SLE and HC. The most frequent alleles were -1123 G and +1858 C in both groups (69 vs. 66 % and 97 vs. 98 %, in SLE and HC, respectively). However, the recessive model of inheritance analysis showed a lower frequency of -1123 CC genotype in SLE patients (7 vs. 15 %), suggesting a protection effect to develop SLE (OR 0.41, CI 1.10-5.28, p = 0.02). Haplotype analysis showed strong linkage disequilibrium D' = 0.98 for PTPN22 -1123G>C and +1858C>T polymorphisms, but haplotypes were not associated with SLE. The PTPN22 mRNA expression did not show differences among -1123G>C genotypes; nevertheless, a significant negative correlation with disease activity was found (r = -0.64, p < 0.01). SLE inactive patients showed similar PTPN22 mRNA expression levels to healthy controls, whereas in patients with severe flare, the expression was nearly depleted. In conclusion, we found a lack of association of PTPN22 -1123G>C and +1858C>T polymorphisms with the risk of developing SLE in a Mexican population. Moreover, decreased or absent PTPN22 mRNA expression in SLE patients with severe flare suggests that Lyp plays an important regulatory role, and its absence contributes to the inflammatory response and disease activity in SLE. However, further analysis in a prospective study could help us determine its usefulness as a genetic marker of disease activity in SLE.

Primary Sjögren's syndrome is an autoimmune disease affecting the function of exocrine glands. Tumor necrosis factor receptor-1 (TNFR1) is involved in apoptosis through extrinsic pathway initiation. The level of soluble TNFR1 is reported increased in rheumatoid arthritis, systemic lupus erythematosus, and primary Sjögren's syndrome patients. The TNFR1 gene contains a polymorphism that replaced an adenine with a cytosine at the -383 in promoter region position. The TNFR1-383 A˃C polymorphism has been associated with rheumatic diseases. We examined the association between the TNFR1-383 A˃C polymorphism and TNFR1 soluble (sTNFR1) levels and laboratory and clinical characteristics in primary Sjögren's syndrome patients. Eighty-two patients with primary Sjögren's syndrome classified using the American-European criteria and 84 healthy subjects were studied. Sjögren's Syndrome Disease Activity Index (SSDAI) and Sjögren's Syndrome Disease Damage Index were performed for all patients. Genotypic and allelic frequencies were similar in both groups (P = 0.317 and P = 0.329, respectively). sTNFR1 levels were similar in patients and healthy subjects (P = 0.051). High levels of C-reactive protein (P = 0.045) and rheumatoid factor (P = 0.040) in patients with the A˃C genotype were observed. In these patients, the SSDAI score was higher than in A˃A genotype carriers (P = 0.045). This is the first study that to examine the TNFR1-383 A˃C polymorphism in primary Sjögren's syndrome patients. Clinical parameters and SSDAI index were associated in A˃C genotype carriers. However, further studies with a larger sample are necessary to verify the association between primary Sjögren's syndrome and the TNFR1-383 A˃C polymorphism.

Objective: B-cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) signaling pathways regulate B-cell survival through interactions with their receptors BAFF-R, TACI and BCMA. We evaluated the association of these ligands/receptors on B-cell subsets according to clinical manifestations of systemic lupus erythematosus (SLE)., Methods: BAFF and APRIL serum concentrations were measured in 30 SLE patients by enzyme-linked immunosorbent assay. The BAFF-R, TACI and BCMA expression was analyzed on each B cell subset (CD19 + CD27-CD38-/ + naïve; CD19 + CD27 + CD38-/ + memory; CD19 + CD27-CD38 + + immature and CD19 + CD27 + CD38 + + plasma cells) by flow cytometry, and compared among patients with different clinical manifestations as well as healthy controls (HCs)., Results: Serum BAFF and APRIL levels were high in SLE patients and correlated with the Mex-SLEDAI disease activity index (r = 0.584; p = 0.001 and r = 0.456; p = 0.011, respectively). The SLE patients showed an increased proportion of memory and plasma B cells (p < 0.05). BAFF-R, TACI and BCMA expression in SLE patients was decreased in almost all B cell subsets compared to HCs (p < 0.05). A lower BCMA expression was associated with severe disease activity, glomerulonephritis, serositis and hemolytic anemia (p < 0.01). BCMA expression showed a negative correlation with Mex-SLEDAI score (r = -0.494, p = 0.006)., Conclusions: Decreased BCMA expression on peripheral B cells according to severe disease activity suggests that BCMA plays an important regulating role in B-cell hyperactivity and immune tolerance homeostasis in SLE patients., (© The Author(s) 2015.)

Systemic lupus erythematosus (SLE) is the prototype autoimmune rheumatic disease. The etiology of this disease is incompletely understood; however, environmental factors and genetic predisposition are involved. Cytokine-mediated immunity plays a crucial role in the pathogenesis of SLE. We investigate the association of interleukin-10 (IL-10) promoter polymorphisms and their haplotypes in SLE patients from the western Mexico. One hundred and twenty-five SLE patients fulfilling the 1997 ACR criteria and 260 unrelated healthy subjects (HS), both Mexican mestizos, were genotyped for IL-10 -1082A>G, -819C>T, and -592C>A polymorphisms. Haplotypes were inferred using the expectation-maximization algorithm, then allele and haplotype distributions were compared between patients and HS, as well as patients with different clinical variables. We identified at -1082, -819, and -592 four predominant haplotypes ACC (43.70 % in patients vs 46.55 % in HS), ATA (21.45 vs 22.97 %), GCC (16.28 vs 14.21 %), and GTA (14.12 vs 14.12 %). The ATC haplotype was more frequent in SLE respect to HS, suggesting a risk effect (3.23 vs 1.05 %; OR 3.55, CI 1.14-11.11; p = 0.0293). SLE patient carriers of -592 CC genotype as well as the dominant model of inheritance showed higher sIL-10 respect to AA genotype, suggesting that -592 C allele is associated with increased production of the cytokine (p < 0.05). The ACC haplotype had higher IL-10 serum levels and higher values of Mexican version of the Systemic Lupus Erythematosus Disease Activity Index compared with the other haplotype carriers; however, no association was found regarding autoantibodies. Our data suggest that the IL-10 promoter haplotypes play an important role in the risk of developing SLE and influence the production of IL-10 in Mexican population. Nevertheless, further studies are required to analyze the expression of mRNA as well as to investigate the interacting epigenetic factors that could help to define the true contribution of this marker in SLE pathogenesis.

Antibodies against cyclic citrullinated peptides (anti-CCP) are widely used for diagnosis of rheumatoid arthritis (RA). We performed a comparative analysis of antibodies targeting the citrullinating enzyme peptidylarginine deiminase type 4 (anti-PAD4) and mutated citrullinated vimentin (anti-MCV) with anti-CCP autoantibodies in RA patients and examined their relationships with clinical parameters, cytokine profiles and the PADI4 gene. Autoantibodies were examined by enzyme-linked immunosorbent assay (ELISA) in sera of 170 RA patients and 103 controls. Cytokine profiles were measured using a multiplex system. PADI4 polymorphisms (89 G > A, 90 T > C and 92 G > C) were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Anti-PAD4, anti-MCV and anti-CCP autoantibodies were detected in 24, 61 and 74% of RA patients, respectively. Positive correlations were observed between anti-PAD4 and disease duration; anti-CCP and erythrocyte sedimentation rate (ESR); anti-MCV and ESR and C-reactive protein. Anti-MCV antibodies were associated with high disease activity score 28 (DAS-28) in early RA. Concentrations of T helper type 1 (Th1) [tumour necrosis factor (TNF)-α, interleukin (IL)-12, IL-2, IL-1β], Th2 (IL-4, IL-6, IL-10, IL-13) and Th17 (IL-17) cytokines were higher in RA than in controls. Th2 and, to a lesser extent, Th1-related cytokines, showed positive correlations with anti-MCV and anti-CCP. The GTG haplotype in PADI4 was associated with anti-CCP and anti-MCV, but not anti-PAD4 antibodies. In conclusion, anti-PAD4 antibodies are detected mainly in established RA, which is in contrast to the early detection of antibodies against citrullinated peptide/proteins (ACPAs). Among autoantibodies, anti-MCV appear to perform better as markers of disease activity. Furthermore, anti-CCP and anti-MCV are associated genetically with the citrullinating enzyme PAD4 and are related strongly to Th1 and Th2 cytokines, suggesting a feed-forward loop between cytokines and ACPA production., (© 2015 British Society for Immunology.)

Primary Sjögren's syndrome (pSS) is an autoimmune disease characterized by lymphocytic infiltration of salivary and lacrimal glands. Interleukin-10 (IL-10) plays a role in autoimmune diseases by promoting B-cell activation and autoantibodies production. IL10-1082A>G, -819C>T, -592C>A polymorphisms and their haplotypes have been associated with IL-10 production. The aim of this study was to associate IL10 haplotypes with mRNA expression and soluble IL-10 levels with susceptibility to pSS in 111 Mexican patients and 111 healthy subjects (HS). Primary Sjögren's syndrome patients showed high levels of sIL-10 (p=0.0001 vs HS) correlating with anti-Ro and anti-La antibodies (p<0.05). In addition, IL10 mRNA expression in pSS was higher than HS (0.8 vs 0.1, p=0.1537). However, no difference was observed in sIL-10 levels between haplotypes. Patients carriers of GCC haplotype showed higher mRNA expression than ACC+ATA (1.4 vs 0.6, p=0.2424) and high foci number (p=0.04 vs ACC). Our results suggest a strong relationship of IL10 with pSS which is demonstrated by the increased mRNA expression and also high sIL-10 levels positively correlated with autoantibodies. Besides that, the GCC haplotype carriers expressed high mRNA. However, IL10 haplotypes were not associated with sIL-10 in pSS from Western Mexico which suggest that diverse biological factors may regulate the IL10 expression in pSS., (Copyright © 2015 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Aim: The case of a lower molar with apical periodontitis, which had previous root canal treatment and a fractured instrument in the distal root beyond the foramen, is presented., Background: The simultaneous presence of a foreign body (endodontic instrument or material) in periapical tissues and microorganisms in the root canal, are etiological factors in the formation or maintenance of a periapical lesion, and can lead to failure in endodontic treatment., Case Description: This instrument was removed through the staging platform technique, by using ultrasound and an Instrument removal system (IRS) microtube under microscope visual amplification. All the canals were re-instrumented, irrigated with sodium hypochlorite and passive ultrasonic irrigation, removal of smear layer and intracanal medication with calcium hydroxide for 8 days, after which they were filled. The symptoms disappeared and clinical and radiograph 2-year follow-up shows healing of periapical tissues., Conclusion: The combined use of visual magnification microscope, ultrasound and the IRS system by staging platform technique, allowed the removal of an endodontic instrument beyond the foramen, which made it possible to apply a conventional disinfection protocol., Clinical Significance: Endodontic re-treatment by conservative approach of complicated cases it is an option with good clinical prognosis, before apical surgery or extraction.

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&#95;89, PADI4&#95;90 and PADI4&#95;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., (Copyright © 2014 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)

Introduction: During chemomechanical instrumentation, several liquid or paste substances are used to ease the action of the files and to eliminate debris and the smear layer. The aim of this study was to evaluate whether the use of a paste containing EDTA during cleaning and shaping of the root canal helps to eliminate debris., Methods: Twenty root canals in dog teeth were instrumented by a crown-down technique by using nickel-titanium rotary files. In 10 root canals (group A), sodium hypochlorite was used during instrumentation, followed by a final irrigation with 17% liquid EDTA. In another 10 canals (group B), sodium hypochlorite was again used as the irrigating solution, but Glyde File Prep paste was used with every instrument, and a final irrigation with EDTA was also carried out. Two additional teeth were used as positive and 2 as negative controls. The jaws were prepared for histologic evaluation., Results: In group A where Glyde was not used during cleaning and shaping, little or no debris was found in the apical third of the instrumented root canals; however; in group B in which Glyde File Prep paste was used during chemomechanical instrumentation, moderate to high accumulation of debris was observed in the apical third., Conclusions: The use of Glyde File Prep paste during rotary mechanical instrumentation favors the accumulation of debris in the apical third of the root canals. Irrigation with NaOCl and a final flush with EDTA by means of a small-gauge needle with simultaneous aspiration led to less accumulation of debris than in the Glyde File Prep group (P < .05)., (Copyright © 2014 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Primary Sjögren's syndrome (pSS) is a chronic systemic autoimmune disease characterized by lymphocytic infiltration of exocrine glands. Soluble Fas receptor (sFas) has been suggested as a Fas-mediated apoptosis blocker that could impair clonal deletion in infiltrated autoreactive cells. The FAS -670A>G promoter polymorphism has been studied in pSS. However, a relationship between FAS -670A>G promoter polymorphism and sFas levels in pSS had not been found. We examined this relationship in 77 Mexican pSS patients and 84 healthy subjects were included. Genotypes were identified by PCR-RFLP, and Fas soluble levels were quantified by ELISA. No significant differences between allele and genotype frequencies were found between these two groups. The sFas levels in the serum of pSS patients were significantly higher than in controls (9961 vs 8840 pg/mL, respectively). In addition, AA genotype carriers had significantly higher levels of sFas than GG carriers (pSS: 10,763 and 9422 pg/mL; controls: 9712 and 8305 pg/mL, respectively). An additive model analysis between genotypes (AG+GG vs AA) in both groups, demonstrated a significant association between carriers of the A allele and high sFas levels. In conclusion, carrying the double dose of A allele of FAS -670A>G polymorphism is associated with high levels of sFas in pSS, but it is not a susceptibility marker for pSS.

Macrophage migration inhibitory factor (MIF) is an upstream immunoregulatory cytokine associated with the pathogenesis of autoimmune inflammatory diseases. There is evidence that MIF functions in a positive feedback loop with TNF-α that could perpetuate the inflammatory process in systemic lupus erythematosus (SLE). In this case-control study we investigated whether commonly occurring functional MIF polymorphisms are associated with SLE as well as with MIF and TNF-α serum levels in a Mexican-Mestizo population. Genotyping of the -794 CATT5-8 (rs5844572) and -173 G>C (rs755622) MIF polymorphisms was performed by PCR and PCR-RFLP, respectively in 186 SLE patients and 200 healthy subjects. MIF and TNF-α serum levels were determined by ELISA. A significant increase of MIF and TNF-α levels was found in SLE patients. According to a genetic model, we found a significant association of genotypes carrying the -794 CATT7 and -173(∗)C risk alleles with susceptibility to SLE and with a significant increase of TNF-α. In conclusion, MIF gene polymorphisms are associated with SLE susceptibility and with an increase of TNF-α serum levels in a Mexican-Mestizo population., (Copyright © 2014 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Macrophage migration inhibitory factor (MIF) is an upstream pro-inflammatory cytokine that is associated with the pathogenesis of autoimmune inflammatory diseases including rheumatoid arthritis (RA). Two polymorphisms in the upstream region exist in the MIF gene and are associated with RA susceptibility or severity in different populations. In this case-control study, we investigated whether MIF polymorphisms are associated with RA susceptibility or activity in a western Mexican population .The relationship of MIF levels with clinical features of disease also was assessed. Genotyping of the -794 CATT5-8 (rs5844572) and the -173 G>C (rs755622) polymorphisms was performed by PCR and PCR-RFLP respectively on 226 RA patients and 210 healthy subjects. Serum MIF levels were determined by ELISA. We found a significant association between the -794 CATT5-8 6,7 MIF genotype with RA. Moreover, we detected an association between the -794 CATT7 allele with early onset RA. The -794 CATT7 and -173(*)C alleles, which are in linkage disequilibrium, were associated with high disease activity on RA patients. A positive correlation between circulating MIF levels and C-reactive protein, erythrocyte sedimentation rate, rheumatoid factor, anti-citrullinated protein/peptides antibodies and TNFα was detected. MIF levels appear to be associated with disease progression rather than disease activity, which is distinct from the established relationship between disease activity and TNFα levels. In conclusion, the MIF gene and protein are associated with RA in a western Mexican population, with a main contribution onto early onset and early stages of disease., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The influence of genetic factors in rheumatoid arthritis (RA) has been described, including several cytokine genes such as transforming growth factor β (TGF-β) with regulatory effects on lymphocytes, dendritic cells, macrophages, chondrocytes, and osteoblasts, which are important in the RA pathogenesis. The G915C TGF-β1 polymorphism has been associated with soluble TGF-β1 (sTGF-β) serum levels. Thus, we studied the association of G915C (Arg25Pro) TGF-β1 polymorphism with sTGF-β1 serum levels in RA. We enrolled 120 RA patients and 120 control subjects (CS). The G915C TGF-β1 polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, and sTGF-β1 serum levels were quantified using an ELISA kit. The genotype frequency of G915C TGF-β1 polymorphism in RA and CS was G/G (91.7%), G/C (8.3%), C/C (0%) and G/G (85.8%), G/C (14.2%), C/C (0%), respectively, without significant differences. Moreover, the G/G TGF-β1 genotype carriers presented the highest disability index evaluated for the Spanish HAQ-DI score (P < 0.001). In addition, the sTGF-β1 serum levels were higher in RA (182.2 ng/mL) than CS (160.2 ng/mL), there was not significant difference. However, we found a positive correlation between the sTGF-β1 serum levels and the functional class (r = 0.472, P = 0.023). In conclusion, the G915C (Arg25Pro) TGF-β1 polymorphism is not associated with RA, but the sTGF-β1 serum levels are related with the functional class in RA.

Objective: Rheumatoid Arthritis (RA) is an autoimmune and chronic inflammatory disease of unknown etiology. Killer cell immunoglobulin-like receptors are expressed on the surface of natural killer cells and CD28null T-cells, both present in synovial membrane of RA. Therefore we evaluated the associations of KIR genes with RA., Methods: 16 KIR genes were genotyped in 100 healthy subjects (HS) and 100 RA patients from Western Mexico using PCR-SSP. Differences in KIR genotypes and gene frequencies were assessed using the X^{2} test., Results: Gene frequency of KIR2DL3 was lower in RA than in HS (p= 0.0019), whereas KIR2DL2 and KIR2DS2 were higher in RA than HS (p =0.0004 and p = 0.0487, respectively). In addition were identified 38 genotypes (from G1-G38) in both studied groups, and the genotype frequencies of G1, G6 and G14 showed significant differences (p =0.0001, p =0.0208 and p =0.0300, respectively)., Conclusions: The presence of KIR2DL2, KIR2DS2 and absence of KIR2DL3 are associated with RA. Moreover, two genotypes BX are associated with RA. These results suggest that KIRs can be involved in RA susceptibility.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the presence of autoantibodies against nuclear autoantigens as well as cytoplasmic and circulating proteins. Recent studies have demonstrated mechanisms responsible for modulation of the immune response by the plasminogen activator inhibitor-1 (PAI-1). Furthermore, the endogenous PAI-1 has shown to promote a Th2 immune response. We assessed the -844 G>A and HindIII C>G PAI-1 polymorphisms in SLE. In a case-control study of 71 SLE patients classified according to ACR criteria and 71 healthy subjects (HS). The A allele of -844 PAI-1 polymorphism showed a significant difference in SLE patients (41%) when compared with HS (27%) [P = 0.01; OR = 1.8, 95%, CI = 1.1-3.0]. In addition, the -844 G>A PAI-1 polymorphism was associated with increased risk for SLE in a dominant genetic model (G/G vs. G/A + A/A; OR = 2.3, 95% CI = 1.14-4.44). Also, anti-RNP positive antibodies in SLE were associated with G/G -844 PAI-1 genotype. The HindIII polymorphism did not show any differences. The haplotype analysis showed that the AC haplotype confers susceptibility to SLE (OR = 3.1, 95% CI, 1.45-6.52; P = 0.003). The AC haplotype of the -844 and HindIII PAI-1 polymorphism might be an additional susceptibility factor to SLE in Mexicans.