Dataset Information

Haplotypes of FOXP3 genetic variants are associated with susceptibility, autoantibodies, and TGF-?1 in patients with systemic lupus erythematosus.

ABSTRACT: 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-?1 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-?1 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-?1 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.

SUBMITTER: Stadtlober NP

PROVIDER: S-EPMC7940633 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Haplotypes of FOXP3 genetic variants are associated with susceptibility, autoantibodies, and TGF-β1 in patients with systemic lupus erythematosus.

Stadtlober Nicole Perugini NP Flauzino Tamires T da Rosa Franchi Santos Lorena Flor LF Iriyoda Tatiana Mayumi Veiga TMV Costa Neide Tomimura NT Lozovoy Marcell Alysson Batisti MAB Dichi Isaias I Reiche Edna Maria Vissoci EMV Simão Andréa Name Colado ANC

Scientific reports 20210308 1

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-β1 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-β1 were determined u ...[more]

PMID: 33686190

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Project description:IntroductionThe pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE) is widely unknown, and the role of autoantibodies is still undetermined.MethodsTo identify brain-reactive autoantibodies possibly related to NPSLE, immunofluorescence (IF) and transmission electron microscopy (TEM) on rat and human brains were performed. ELISA was used to reveal the presence of known circulating autoantibodies, while western blot (WB) was applied to characterize potential unknown autoantigen(s).ResultsWe enrolled 209 subjects, including patients affected by SLE (n=69), NPSLE (n=36), Multiple Sclerosis (MS, n=22), and 82 age- and gender-matched healthy donors (HD). Autoantibody reactivity by IF was observed in almost the entire rat brain (cortex, hippocampus, and cerebellum) using sera from NPSLE and SLE patients and was virtually negative in MS and HD. NPSLE showed higher prevalence (OR 2.4; p = 0.047), intensity, and titer of brain-reactive autoantibodies than SLE patients. Most of the patient sera with brain-reactive autoantibodies (75%) also stained human brains. Double staining experiments on rat brains mixing patients' sera with antibodies directed against neuronal (NeuN) or glial markers showed autoantibody reactivity restricted to NeuN-containing neurons. Using TEM, the targets of brain-reactive autoantibodies were located in the nuclei and, to a lesser extent, in the cytoplasm and mitochondria. Given the high degree of colocalization between NeuN and brain-reactive autoantibodies, we assumed NeuN was a possible autoantigen. However, WB analysis with HEK293T cell lysates expressing or not expressing the gene encoding for NeuN protein (RIBFOX3) showed that patients' sera carrying brain-reactive autoantibodies did not recognize the NeuN corresponding band size. Among the panel of NPSLE-associated autoantibodies (e.g., anti-NR2, anti-P-ribosomal protein, antiphospholipid) investigated by ELISA assay, only the anti-β2-glycoprotein-I (aβ2GPI) IgG was exclusively found in those sera containing brain-reactive autoantibodies.ConclusionIn conclusion, SLE and NPSLE patients possess brain-reactive autoantibodies but with higher frequency and titers found in NPSLE patients. Although many target antigens of brain-reactive autoantibodies are still undetermined, they likely include β2GPI.

Project description:The mitochondrion supplies energy to the cell and regulates apoptosis. Unlike other mammalian organelles, mitochondria are formed by binary fission and cannot be directly produced by the cell. They contain numerous copies of a compact circular genome that encodes RNA molecules and proteins involved in mitochondrial oxidative phosphorylation. Whereas, mitochondrial DNA (mtDNA) activates the innate immune system if present in the cytosol or the extracellular milieu, it is also the target of circulating autoantibodies in systemic lupus erythematosus (SLE). However, it is not known whether mitochondrial RNA is also recognized by autoantibodies in SLE. In the present study, we evaluated the presence of autoantibodies targeting mitochondrial RNA (AmtRNA) in SLE. We quantified AmtRNA in an inducible model of murine SLE. The AmtRNA were also determined in SLE patients and healthy volunteers. AmtRNA titers were measured in both our induced model of murine SLE and in human SLE, and biostatistical analyses were performed to determine whether the presence and/or levels of AmtRNA were associated with clinical features expressed by SLE patients. Both IgG and IgM classes of AmtRNA were increased in SLE patients (n = 86) compared to healthy controls (n = 30) (p < 0.0001 and p = 0.0493, respectively). AmtRNA IgG levels correlated with anti-mtDNA-IgG titers (r s = 0.54, p < 0.0001) as well as with both IgG and IgM against β-2-glycoprotein I (anti-β2GPI; r s = 0.22, p = 0.05), and AmtRNA-IgG antibodies were present at higher levels when patients were positive for autoantibodies to double-stranded-genomic DNA (p < 0.0001). AmtRNA-IgG were able to specifically discriminate SLE patients from healthy controls, and were negatively associated with plaque formation (p = 0.04) and lupus nephritis (p = 0.03). Conversely, AmtRNA-IgM titers correlated with those of anti-β2GPI-IgM (r s = 0.48, p < 0.0001). AmtRNA-IgM were higher when patients were positive for anticardiolipin antibodies (aCL-IgG: p = 0.01; aCL-IgM: p = 0.002), but AmtRNA-IgM were not associated with any of the clinical manifestations assessed. These findings identify mtRNA as a novel mitochondrial antigen target in SLE, and support the concept that mitochondria may provide an important source of circulating autoantigens in SLE.

Project description:ObjectiveThe presence of urinary autoantibodies in patients with systemic lupus erythematosus (SLE) has been confirmed by several studies; however, the significance of their presence in urine remains unclear. This study aims to further investigate the association between urine autoantibodies and disease activity as well as organ involvement in SLE.MethodsThis cross-sectional study included 89 SLE patients. Data collected included anti-nuclear antibody (ANA), anti-ENA antibodies, and anti-dsDNA antibody levels in both serum and urine, complement (C) 3, C4 levels in serum, SLE disease activity index-2000 (SLEDAI-2000), renal domains of SLEDAI (RSLEDAI) and non-renal SLEDAI (NRSLEDAI).ResultsThe rate of positive urine ANA (uANA) was 33.3% (29/87) among the enrolled patients. Compared to the uANA negative group, the positive group exhibited significantly higher SLEDAI-2000 scores (7.85 ± 5.88 vs. 18.69 ± 6.93, p < 0.001), RSLEDAI scores [0 (0, 4.0) vs. 12.0 (8.0, 16.0), p < 0.001], and NRSLEDAI [4 (2.0, 8.0) vs. 6.0 (4.0, 9.5), p = 0.038]. Patients with positive urine anti-Sm antibody demonstrated significantly elevated SLEDAI-2000 scores compared to those who were negative (25.0 ± 8.80 vs. 10.09 ± 6.63, p < 0.001). Similarly, they also had higher RSLEDAI [16.0 (12.0, 16.0) vs. 4.0 (0, 8.0), p < 0.001] and NRSLEDAI [9.5 (6.0, 13.5) vs. 4.0 (3.0, 8.0), p = 0.012], as well as a greater prevalence of renal involvement compared to their negative counterparts (100% vs. 58.2, p = 0.022). There was a positive correlation between uANA titer and both SLEDAI-2000 (rs = 0.663, p < 0.001) and RSLEDAI (rs = 0.662, p < 0.001). The serum anti-dsDNA antibody level did not exhibit a significant correlation with RSLEDAI (rs = 0.143, p = 0.182). Conversely, the urine anti-dsDNA antibody level demonstrated a significant positive correlation with RSLEDAI (rs = 0.529, p < 0.001).ConclusionUrine ANA is associated with both global SLEDAI and RSLEDAI scores. Urine anti-Sm antibody is associated with an increased incidence of renal involvement in SLE. The urine anti-dsDNA antibody level, rather than the serum anti-dsDNA antibody level, exhibits a significant association with RSLEDAI in SLE.

Dataset Information

Haplotypes of FOXP3 genetic variants are associated with susceptibility, autoantibodies, and TGF-?1 in patients with systemic lupus erythematosus.

Publications

Haplotypes of FOXP3 genetic variants are associated with susceptibility, autoantibodies, and TGF-β1 in patients with systemic lupus erythematosus.

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