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B cell-activating factor (BAFF) is an essential cytokine in primary Sjogren’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

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by elevated levels of pro-inflammatory cytokines, such as interleukin (IL)-6, IL-17, and macrophage migration inhibitory factor (MIF). MIF induces IL-17 secretion and MIF promoter polymorphisms influence the expression of selected downstream mediators. The aim of this study was to investigate the relationship between known functional MIF haplotypes and Th17-related cytokine secretion profile in peripheral blood mononuclear cells (PBMC) from control subjects (CS) and RA patients stimulated with lipopolysaccharide (LPS) and recombinant human MIF (rhMIF). The −794 CATT5-8 and −173G > C polymorphisms of the MIF gene were determined by conventional PCR and PCR-RFLP, respectively. The most frequent haplotypes of the MIF polymorphism and PBMC were identified from three subjects homozygous for each haplotype and in both study groups, the PBMC were obtained and stimulated with LPS or rhMIF. The secretion of cytokines related to the Th17 profile was determined by a multiplex immunoassay (MAGPIX). LPS stimulation induced the secretion of cytokines related to the Th17 profile in PBMC from CS and RA patients, whereas, rhMIF only stimulated this response in PBMC from RA patients. PBMC from CS carriers of the MIF 7C haplotype showed more IL-17A, IL-17F, IL-22, and IL-23 secretion than non-7C carriers after LPS stimulation. In the case of rhMIF stimulation, the PBMC from CS carriers of the 7C haplotype secreted more IL-17A and IL-23 than non-7C carriers. In conclusion, genetic variants of the MIF promoter modulate the secretion of cytokines related to the Th17 profile in PBMC from CS inducing a differential response in comparison to PBMC from RA patients.

Background Rheumatoid arthritis (RA) and periodontitis (P) are chronic inflammatory diseases characterized by joint and radiographic bone loss, respectively. IL‐23 and IL‐17 have an essential role in the immunopathogenesis of RA, and P. IL‐23 stimulates Th17 cells through which produces IL‐17, IL‐21, and RANKL. IL‐17 stimulates fibroblasts to produce RANKL, which initiates bone loss in the joints in RA and the periodontal tissue in periodontitis. The aim of this study was to determine the expression pattern of IL‐23/IL‐17 axis and soluble receptors isoforms sIL‐23R and sIL‐17RA of patients with RA presenting P (RAP). Material and methods Healthy subjects (HS) (n = 42), patients with P (n = 40), RA (n = 20), and patients with RAP (n = 40) were included. Plasma samples were obtained to evaluate the IL‐23, IL‐17A, sIL‐23R, and sIL‐17RA by ELISA technique. A nonparametric Mann‐Whitney U test was used to compare the differences between groups. A Chi‐square was used to compare gender, grade and stage of periodontitis, and DAS28‐ESR between the groups. Spearman's rank correlation coefficient was used to study the association between the molecules and clinical parameters. Results IL‐23 levels were increased in the RAP group, and lower sIL‐23R levels were found in the RAP groups. However, IL‐17A was lower in the P and RAP group but not in RA patients. RAP group showed a decrease IL‐17A levels in advanced stages of the periodontal disease. Conclusion These results suggest that IL‐23 and IL‐17A tend to downregulate their expression patterns when patients present both rheumatoid arthritis and periodontitis., Blood sample was taken to obtain plasma from all study participants. IL‐23, IL‐23R, IL‐17A, and IL‐17RA were detected with ELISA technique. Results: (a) The sIL‐23R levels were found lower in the RAP group and IL‐23 levels were increased. (b) IL‐17A was lower in the P and RAP group but not in RA patients. According to the chronicity of periodontitis, RAP group showed a decreased IL‐17A levels in advanced stages of the periodontal disease.

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., Principal component analysis of 14 cytokines was realized to determine the cytokine groups in primary Sjögren´s syndrome patients. The mild group was characterized by less severity of the disease with low cytokine levels and fewer clinical parameters; the moderate group included patients with intermediate severity, presented higher cytokine levels than the mild group but less than severe group. Patients of the severe group showed higher severity, higher cytokine levels, and clinical parameters.

Melatonin is a pleiotropic molecule that, after a short-term sleep deprivation, promotes the proliferation of neural stem cells in the adult hippocampus. However, this effect has not been observed in long-term sleep deprivation. The precise mechanism exerted by melatonin on the modulation of neural stem cells is not entirely elucidated, but evidence indicates that epigenetic regulators may be involved in this process. In this study, we investigated the effect of melatonin treatment during a 96-hour sleep deprivation and analyzed the expression of epigenetic modulators predicted by computational text mining and keyword clusterization. Our results showed that the administration of melatonin under sleep-deprived conditions increased the MECP2 expression and reduced the SIRT1 expression in the dentate gyrus. We observed that let-7b, mir-132, and mir-124 were highly expressed in the dentate gyrus after melatonin administration, but they were not modified by sleep deprivation. In addition, we found more Sox2+/5-bromo-2′-deoxyuridine (BrdU)+ cells in the subgranular zone of the sleep-deprived group treated with melatonin than in the untreated group. These findings may support the notion that melatonin modifies the expression of epigenetic mediators that, in turn, regulate the proliferation of neural progenitor cells in the adult dentate gyrus under long-term sleep-deprived conditions. All procedures performed in this study were approved by the Animal Ethics Committee of the University of Guadalajara, Mexico (approval No. CI-16610) on January 2, 2016.

Obesity and nutrients intake deficiencies may contribute to the clinical manifestations and inflammatory processes in systemic lupus erythematosus (SLE). The aim of this study was to assess the relationship between nutritional status and dietary intake with clinical variables in Mexican-mestizo SLE patients. A cross-sectional study was conducted in 130 female SLE patients, classified by the 1997 SLE American College of Rheumatology (ACR) criteria, the clinical activity was evaluated by the Mexican-Systemic Lupus Erythematosus-Disease Activity Index (Mex-SLEDAI), body mass index (BMI) by the World Health Organization (WHO) criteria, the energy calculation and nutritional intake were performed by Nutritionist Pro Diet software. SLE patients with excess weight (BMI &gt, 25 kg/m2) showed a higher score of clinical activity (Mex-SLEDAI = 2, p = 0.003), higher clinical activity prevalence (40.9%, p = 0.039) and a significant association for high clinical activity (odds ratio (OR) = 2.52, 95% confidence interval (CI) = 1.08&ndash, 5.9, p = 0.033), in comparison with patients without excess weight (BMI &lt, 25 kg/m2). In particular, the excess weight increased the Mex-SLEDAI score (&beta, coefficient = 1.82, R2 = 0.05, p = 0.005). Also, the SLE patients presented a high prevalence (%) of deficient consumption (cut-off point: &lt, 67% of dietary adequacy) of vitamin E (100%), iodine (96%), omega 3 (93.44%), biotin (78%), vitamin K (73.33%), iron (67%), vitamin D (63.3%), potassium (59%), folic acid (56.67%), pantothenic acid (43.3%), vitamin A (41.67%) and zinc (32%). In conclusion, in SLE patients the excess weight was associated with increased clinical activity and to the presence of deficiencies in some essential nutrients ingested.

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

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.

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 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.

This study was designed to investigate whether genetic polymorphisms of the Wnt/β-catenin signaling pathway and its interactions are involved in the development of knee osteoarthritis (KOA). Patients with KOA (n = 131) and healthy individuals (n = 190) with different ancestry from two Mexican populations (Mexico City and Guadalajara City) were analyzed. Twenty-five SNPs from thirteen genes (WISP1, DKK1, SOST, FRZB, LRP1, LRP4, LRP5, LRP6, GSKB, ADAMTS5, GDF5, FMN2 and COL11A1) involved in the Wnt/β-catenin signaling pathway were genotyped. Genetic and allelic frequencies and gene–gene interactions were performed for this study. After adjusting for age, sex, BMI and admixture, significant associations were found for five SNPs in Mexico City: LRP6 rs12314259 (G/G genotype OR 0.22, P = 0.029; and G allele OR 0.48, P = 0.022), SOST rs851054 (C/T genotype OR 0.42, P = 0.027; and T allele OR 0.62, P = 0.026), FMN2 rs986690 (G/A genotype OR 0.42, P = 0.034; and A allele OR 0.50, P = 0.015), FRZB rs409238 (A/G genotype, OR 2.41, P = 0.022), and COL11A1 rs2615977 (A/C genotype OR 2.39, P = 0.024); no associations for Guadalajara City were found. With respect to gene–gene interactions, the pairwise interactions of WISP1–COL11A1, COL11A1–FRZB, FRZB–SOST and WISP1–FMN2 make it possible to visualize the synergistic or antagonistic effect of their genotypes or alleles in both populations. These results suggest that gene–gene interactions in the Wnt/β-catenin signaling pathway play a role in the etiology of KOA.

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

To investigate the association of sICAM-1 and sVCAM-1 with ICAM1 721G>A and VCAM1 1238G>C polymorphisms and rheumatoid arthritis (RA) clinical activity, sixty RA patients and 60 healthy non-related subjects (HS) matched for age and sex were recruited. Soluble adhesion molecules were determined by ELISA technique. Rheumatoid factor (RF), C reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) were measured by routine methods. Disability and clinical activity was measured with Spanish-HAQ-DI and DAS28 scores, respectively. The ICAM1 and VCAM1 polymorphism were identified using the PCR-RFLP procedure. Inter-group comparison showed increased levels of sICAM-1 and sVCAM-1 in RA patients (284 and 481 ng/mL) versus HS (132 and 280 ng/mL); in the RA group, significant correlations between sVCAM-1 and RF (r= 0.402), ESR (r= 0.426), Spanish-HAQ-DI (r= 0.276), and DAS28 (r= 0.342) were found, whereas sICAM-1 only correlated with RF (r= 0.445). In RA patients, a significant association with the 721A allele of ICAM1 polymorphism (p= 0.04), was found. In addition, the allele impact (G/A+A/A) of this polymorphism was confirmed, (p= 0.038, OR = 2.3, C.I. 1.1–5.0). sVCAM-1 and sICAM-1 serum levels reflected the clinical status in RA, independently of the ICAM1 and VCAM1 polymorphism. However, the ICAM1 721A allele could be a genetic marker to RA susceptibility.

Cardiovascular diseases and type 2 diabetes are the major causes of mortality in Mexico. Metabolic syndrome (MS) is a cluster of factors that increase the risk to develop such diseases. Previous studies have shown that MS is associated with high tumor necrosis factor (TNF‐α) levels. In fact, TNF‐α has been proposed to be a useful marker for clinical diagnosis of inflammation at an early stage. Therefore, we analyzed TNF‐α concentrations in Mexican individuals with or without MS and related these levels to the associated MS components. Clinical, anthropometric, and biochemical data were analyzed in 41 healthy and 39 MS individuals. Individuals were similarly grouped by age and gender.The serum TNF‐α levels measured bya highly sensitive enzyme‐linked immunosorbent assay (ELISA) kit were increased significantly in MS subjects compared with healthy individuals (P

Autoantibodies to RNA helicase A (RHA) were reported as a new serological marker of systemic lupus erythematosus (SLE) associated with early stage of the disease. Anti-RHA and other autoantibodies in Mexican SLE patients and their correlation with clinical and immunological features were examined.Autoantibodies in sera from 62 Mexican SLE patients were tested by immunoprecipitation of 35S-labeled K562 cell extract and enzyme-linked immunosorbent assay (anti-U1RNP/Sm, ribosomal P, beta2GPI, and dsDNA). Anti-RHA was screened based on the immunoprecipitation of the 140-kDa protein, the identity of which was verified by Western blot using rabbit anti-RHA serum. Clinical and immunological characteristics of anti-RHA-positive patients were analyzed.Anti-RHA was detected in 23% (14/62) of patients, a prevalence higher than that of anti-Sm (13%, 8/62). Prevalence and levels of various autoantibodies were not clearly different between anti-RHA (+) vs. (-) cases, although there was a trend of higher levels of anti-RHA antibodies in patients without anti-U1RNP/Sm (P = 0.07). Both anti-RHA and -Sm were common in cases within one year of diagnosis; however, the prevalence and levels of anti-RHA in patients years after diagnosis did not reduce dramatically, unlike a previous report in American patients. This suggests that the high prevalence of anti-RHA in Mexican patients may be due to relatively stable production of anti-RHA.Anti-RHA was detected at high prevalence in Mexican SLE patients. Detection of anti-RHA in races in which anti-Sm is not common should be clinically useful. Racial difference in the clinical significance of anti-RHA should be clarified in future studies.

Introduction Systemic lupus erythematosus is characterized by production of autoantibodies to RNA or DNA–protein complexes such as small nuclear ribonucleoproteins (snRNPs). A role of Epstein–Barr virus in the pathogenesis has been suggested. Similar to Epstein–Barr virus, cytomegalovirus (CMV) infects the majority of individuals at a young age and establishes latency with a potential for reactivation. Homology of CMV glycoprotein B (UL55) with the U1snRNP-70 kDa protein (U1–70 k) has been described; however, the role of CMV infection in production of anti-snRNPs is controversial. We investigated the association of CMV serology and autoantibodies in systemic lupus erythematosus. Methods Sixty-one Mexican patients with systemic lupus erythematosus were tested for CMV and Epstein–Barr virus serology (viral capsid antigen, IgG, IgM) and autoantibodies by immunoprecipitation and ELISA (IgG and IgM class, U1RNP/Sm, U1–70 k, P peptide, rheumatoid factor, dsDNA, β2-glycoprotein I). Results IgG anti-CMV and IgM anti-CMV were positive in 95% (58/61) and 33% (20/61), respectively, and two cases were negative for both. Clinical manifestation and autoantibodies in the IgM anti-CMV(+) group (n = 20) versus the IgM anti-CMV(-)IgG (+) (n = 39) group were compared. Most (19/20) of the IgM anti-CMV(+) cases were IgG anti-CMV(+), consistent with reactivation or reinfection. IgM anti-CMV was unrelated to rheumatoid factor or IgM class autoantibodies and none was positive for IgM anti-Epstein–Barr virus–viral capsid antigen, indicating that this is not simply due to false positive results caused by rheumatoid factor or nonspecific binding by certain IgM. The IgM anti-CMV(+) group has significantly lower levels of IgG anti-U1RNP/Sm and IgG anti-U1–70 k (P = 0.0004 and P = 0.0046, respectively). This finding was also confirmed by immunoprecipitation. Among the IgM anti-CMV(-) subset, anti-Su was associated with anti-U1RNP and anti-Ro (P < 0.05). High levels of IgG anti-CMV were associated with production of lupus-related autoantibodies to RNA or DNA–protein complex (P = 0.0077). Conclusions Our findings suggest a potential role of CMV in regulation of autoantibodies to snRNPs and may provide a unique insight to understand the pathogenesis.