TGFB1 +869 T > C (rs1800470) variant is independently associated with susceptibility, laboratory activity, and TGF-ß1 in patients with systemic lupus erythematosus.

The aim of this study was to evaluate the association of the +869 T > C (rs1800470) and -509 C > T (rs1800469) TGFB1 variants, individually or in haplotypes structure, with susceptibility, autoantibodies, disease activity, and TGF-ß1 plasma levels in patients with systemic lupus erythematosus (SLE). The study included 203 patients with SLE and 165 healthy controls. TGFB1 variants were determined by real-time polymerase chain reaction (qPCR). Plasma levels of TGF-ß1 were determined using immunofluorimetric assay. The TGFB1 + 869 CC genotype was associated with SLE susceptibility (OR: 1.710, 95%CI: 1.020-2.866, p = 0.042) and with reduction of C4 (p = 0.040) and TGF-ß1 levels (p = 0.044). In addition, patients with TGFB1 + 869 TC and CC genotypes and positive anti-dsDNA had lower TGF-ß1 levels than those with TT (p = 0.004). TGFB1 -509 TT genotype was associated with reduced levels of C4 (p = 0.032). There was no association between haplotypes and clinical and laboratory parameters. Our data demonstrated that the TGFB1 + 869 T > C variant could be used as a genetic marker for SLE susceptibility and both variants as predictors of laboratory activity. This is the first study to demonstrate that TGF-ß1 levels could be modulated by the interaction between TGFB1 + 869 C allele, in homozygosity, or heterozygosity, and the presence of anti-dsDNA.

Haplotypes of FOXP3 genetic variants are associated with susceptibility, autoantibodies, and TGF-ß1 in patients with systemic lupus erythematosus.

The aim of this study was to evaluate the association of rs2232365 (-924 G > A) and rs3761548 (-3279 C > A) FOXP3 variants with systemic lupus erythematosus (SLE) susceptibility, TGF-ß1 plasma levels, autoantibodies, and LN nephritis, and SLE disease activity index (SLEDAI). The study included 196 SLE female patients and 157 female controls. FOXP3 variants were determined with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Plasma levels of TGF-ß1 were determined using immunofluorimetric assay. The AA genotype [OR: 2.650, CI 95%(1.070-6.564), p = 0.035] and A allele [OR: 2.644, CI 95%(1.104-6.333), p = 0.029] were associated with SLE diagnosis in the -3279 C > A. The A/A haplotype was associated with SLE [OR: 3.729, CI 95%(1.006-13.820), p = 0.049]. GCGC haplotype patients had higher TGF-ß1 levels (p = 0.012) than other haplotypes. Patients with -924 AA genotype showed higher frequency of anti-dsDNA (p = 0.012) and anti-U1RNP (p = 0.036). The A/C haplotype had higher SLEDAI score [OR: 1.119, CI 95%(1.015-1.234), p = 0.024] and ACAC haplotype higher frequency of anti-dsDNA [OR: 3.026, CI 95%(1.062-8.624), p = 0.038], anti-U1RNP [OR: 5.649, CI 95%(1.199-26.610), p = 0.029] and nephritis [OR: 2.501, CI 95%(1.004-6.229), p = 0.049]. Our data demonstrate that the G/C haplotype provides protection for SLE. While the presence of allele A of both variants could favor autoimmunity, disease activity, and LN.

Increased lipid and protein oxidation and lowered anti-oxidant defenses in systemic lupus erythematosus are associated with severity of illness, autoimmunity, increased adhesion molecules, and Th1 and Th17 immune shift.

This study investigated nitro-oxidative stress in patients with systemic lupus erythematosus (SLE) in association with disease activity, immune-inflammatory biomarkers, and adhesion molecules. Two-hundred-four patients with SLE and 256 healthy volunteers were enrolled in this case-control study, which measured nitro-oxidative stress biomarkers, including lipid peroxides (LOOH), advanced oxidation protein products (AOPPs), nitric oxide metabolites (NOx), sulfhydryl (-SH) groups, products of deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) oxidative degradation, and total radical-trapping anti-oxidant parameter (TRAP). Also measured were anti-nuclear antibodies (ANAs), antibodies against double-stranded DNA (dsDNA), plasma levels of diverse cytokines, C-reactive protein, and adhesion molecules. LOOH (p < 0.001) and AOPP (p < 0.001) were significantly higher, while TRAP was significantly lower (p < 0.001) in SLE patients than in controls. AOPP and LOOH were significantly and positively associated with SLE disease activity index (SLEDAI) scores, anti-nuclear antibodies, and antibodies against double-stranded DNA (anti-dsDNA) levels, while TRAP was significantly and inversely correlated with SLEDAI, ANA, and dsDNA antibody levels. There were significant positive associations between AOPP and LOOH and immune-inflammatory markers, indicating T helper (Th)-17 and Th1 bias and Th1 + Th17/Th2 ratio (p = 0.002 and p = 0.001, respectively). AOPP and LOOH (positively) and TRAP (inversely) were associated with adhesion molecule expression. A model predicting SLE was computed showing that, using LOOH, AOPP, NOx, adhesion molecules, and body mass index, 94.2% of the patients were correctly classified with a specificity of 91.5%. Increased nitro-oxidative stress takes part in the (auto)immune pathophysiology of SLE and modulates severity of illness and adhesion molecule expression.

C-reactive protein +1444CT (rs1130864) genetic polymorphism is associated with the susceptibility to systemic lupus erythematosus and C-reactive protein levels.

The T rare allele of +1444CT (rs1130864) polymorphism of C-reactive protein (CRP) has been associated with increased CRP levels in some inflammatory conditions, but its role on systemic lupus erythematosus (SLE) susceptibility and on CRP levels in SLE patients remains uncertain. The objective of the study was to evaluate the association between the rs1130864 CRP polymorphism with SLE susceptibility, disease activity, and CRP levels in SLE Brazilian patients. The study enrolled 176 SLE patients and 137 controls. SLE disease activity was assessed using the SLE Disease Activity Index (SLEDAI). The rs1130864 CRP polymorphism was determined using polymerase chain reaction and restriction fragment length polymorphism. SLE patients presented higher body mass index (p = 0.046) and CRP levels (p = 0.017) than controls. The genotype and allele frequencies of patients differed from controls [CC vs. CT = odds ratio (OR) 1.730, 95% confidence interval (CI) 1.068-2.803, p = 0.035; CC vs. TT = OR 3.667, 95% CI 1.410-9.533, p = 0.009; C vs. T = OR 1.883, 95% CI 1.299-2.728, p = 0.001)]. Patients carrying the T allele presented higher CRP levels (p = 0.009), were more frequent Caucasians (p = 0.018), and with no use of immunosuppressive treatment (p = 0.004) than those carrying the C allele. However, the SLEDAI and anti-double-stranded DNA positivity did not differ from those carrying T vs. C allele (p = 0.595 and p = 0.243, respectively). The rs1130864 CRP polymorphism was associated with SLE susceptibility and CRP levels, but not with disease activity, suggesting that this polymorphism may play a role in the pathophysiology of SLE through increasing the CRP that, probably, plays an inflammatory role in SLE pathophysiology.

Cytokines in systemic lupus erythematosus: far beyond Th1/Th2 dualism lupus: cytokine profiles.

The aims of this study were to delineate cytokine profiles of systemic lupus erythematosus (SLE), construct prediction models for diagnosis and disease activity using those profiles, and to examine the associations between TNFB Ncol polymorphism, body mass index (BMI) and vitamin D levels with cytokine levels. Two hundred SLE patients and 196 healthy controls participated in this case-control study. Plasma cytokines levels of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-1ß, IL- 4, IL-6, IL-10, IL-12 and IL-17 were measured and cytokines profiles were computed. IL-6, IL-12, IL-17, IFN-γ and IL-10 levels were significantly higher in SLE, while IL-4 was lower in SLE. The Th1/Th2 and Th1+Th17/Th2 profiles were significantly higher in SLE than in healthy controls, whereas there were no significant differences in the proinflammatory cytokine profile (TNFα+IL-6+IL-1ß). In total, 90.4% of all subjects were correctly classified using Th1+Th17 profile and IL-10 (positively associated) and IL-4 (negatively associated) as predictor variables (sensitivity=66.7% and specificity=96.9%). In all, 20.9% of the variance in the SLE Disease Activity Index was predicted by the Th1+Th17/Th2 ratio, IL-10 and BMI (all positively) and proinflammatory profile (inversely associated). B1/B1 genotype is accompanied by increased IL-17 and Th17/Th2 ratio, while B1/B2 genotype is accompanied by higher IL-4 and IFNγ values. 25-OH vitamin D was inversely associated with IFN-γ levels. SLE is accompanied by Th1, Th17 and Treg profile and lowered IL-4 production. Lowered vitamin D levels and B1/B1 genotype, but not BMI, contribute to changes in cytokines profiles. Future treatments should target Th1, Th2 and Th17 profiles rather than inflammatory cytokines.