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.

Background/Objectives: A case-control study was conducted to determine the association of the −238 G>A and −308 G>A TNF-alpha (TNFA) promoter polymorphisms with mRNA and protein expression in 180 Systemic Lupus Erythematosus (SLE) patients and 186 control subjects (CS) from western Mexico. Methods: Genotyping was performed using the PCR-RFLP method. TNFA mRNA expression was assessed by real-time quantitative PCR, and soluble TNF-α (sTNF-α) levels were quantified by ELISA. For comparison groups, Chi-square, Mann–Whitney U, or Kruskal–Wallis tests were used. Spearman’s rank correlation coefficient determined the correlation between variables. The Area Under the Curve was used to determine the diagnosing performance of sTNF-α. Results: No differences were found in the genotype distribution of −238 G>A and −308 G>A TNFA polymorphisms between SLE patients and CS. However, the −238A allele was associated with increased SLE susceptibility (OR 1.18 CI 95% 1.02–3.50, p = 0.037). Also, logistic regression analysis showed that LN risk was significantly higher in carriers of the −308A allele (OR 3.11 IC95% 1.15–6.43; p = 0.002). On the other hand, the TNFA mRNA expression was 3.3-fold higher in SLE compared to CS. SLE patients with −308 GG genotype showed higher TNFA mRNA expression compared to GA+AA genotype carriers (p < 0.01). Regarding sTNFa levels, SLE patients showed higher concentration than CS, mainly in lupus nephritis (LN), with a weak negative correlation with estimated Glomerular Filtration Rate and an acceptable accuracy for diagnosing SLE and LN, with areas under the curve of 0.61 and 0.65, respectively. Conclusions: The −238 A allele and −308 A allele of the TNFA gene are linked to a higher risk of susceptibility to SLE and LN in the western Mexican population. Additionally, SLE patients exhibited increased TNF-alpha gene expression and sTNF-α, particularly in LN, demonstrating acceptable diagnostic performance.

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.

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 (r² = 0.499, p = 0.008) and levels of anti-SSA/Ro and anti-SSB/La autoantibodies (r² = 0.200, p = 0.03 and r² = 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.

Sjögren’s disease (SjD) is an autoimmune condition marked by exocrine gland damage, lymphocytic infiltration, and autoantibody production. Recently, extrafollicular B cells have been implicated in autoimmune diseases, yet their specific role and characteristics within SjD remain largely unknown. Therefore, we aim to evaluate the distribution of atypical memory B cells (aMBCs) in patients with SjD and correlate them with clinical features. Forty SjD patients and 34 healthy subjects (HS) were included. Identification of aMBCs (CXCR5 ⁻ CD11c ⁺ ) subsets was performed, then expression of CD21 and CD38 were assessed in aMBCs subpopulations. SjD patients exhibited a systemic expansion of extrafollicular B cells, including aNAV, DP NAV, and DN2, DN3, and DN4 populations ( P < 0.001). ANCOVA revealed that DN2 expansion is uniquely independent of chronological aging ( P = 0.006). Analyzed CD19 ⁺ B cells using high-dimensional t-SNE and biaxial gating showed that aMBCs displayed heightened CD38 expression, signaling an activated phenotype primed for plasma cell differentiation. Furthermore, inverse correlations between DP NAV and USM frequencies and clinical scores (clinESSDAI, SSDDI) suggest possible sequestration within salivary glands or functional exhaustion. This pathogenic signature, manifesting as early as the naïve stage, underscores the aNAV-DN2 axis as a central hallmark of B-cell dysregulation in SjD.