Epigenetic dysregulation in salivary glands from patients with primary Sjögren's syndrome may be ascribed to infiltrating B cells.

Sjögren's syndrome (SS) is an autoimmune exocrinopathy characterized by an epithelium injury with dense lymphocytic infiltrates, mainly composed of activated T and B cells. Present at the interface of genetic and environmental risk factors, DNA methylation is suspected to play a key role in SS. To clarify this point, global DNA methylation was tested within salivary gland epithelial cells (SGEC), peripheral T cells and B cells from SS patients. Global DNA methylation was reduced in SGEC from SS patients, while no difference was observed in T and B cells. SGEC demethylation in SS patients was associated with a 7-fold decrease in DNA methyl transferase (DNMT) 1 and a 2-fold increase in Gadd45-alpha expression. The other DNA methylation/demethylation partners, tested by real time PCR (DNMT3a/b, PCNA, UHRF1, MBD2, and MBD4), were not different. Interestingly, SGEC demethylation may be attributed in part to the infiltrating B cells as suspected in patients treated with anti-CD20 antibodies to deplete B cells. Such hypothesis was confirmed using co-culture experiments with human salivary gland cells and B cells. Furthermore, B cell-mediated DNA demethylation could be ascribed to an alteration of the PKC delta/ERK/DNMT1 pathway. As a consequence, part of the SGEC dysfunction in SS may be linked to epigenetic modifications, thus opening new therapeutic perspectives in SS.

Anti-Saccharomyces cerevisiae antibodies in patients with systemic lupus erythematosus.

Anti-Saccharomyces cerevisiae antibodies (ASCA) had been known to be specific for Crohn's disease but it has been found in many other autoimmune diseases like systemic lupus erythematosus (SLE). Furthermore, cross-reactive epitopes on ß2-glycoprotein I (ß2GPI) and Saccharomyces cerevisiae were found in SLE patients. The aims of this study were to evaluate the frequency of ASCA in patients with SLE and to compare it with that of anti-ß2GPI antibodies (aß2GPI). Sera of 116 patients with SLE were analyzed in this retrospective study. All patients fulfilled at least 4 criteria of the 1997 American College of Rheumatology updated criteria for the classification of SLE. Sera of 160 blood donors were included as normal controls. ASCA IgA and IgG and aß2GPI antibodies were determined by enzyme-linked immunosorbent assays. The frequency of ASCA (IgG and/or IgA) was significantly higher in SLE patients than in control group (31.9 vs. 3.7 %, p < 10(-6)). ASCA IgG and ASCA IgA were more frequent in SLE patients than in control group (29.3 vs. 3.1 %, p < 10(-6) and 12.1 vs. 0.6 %, p = 10(-4), respectively). The mean level of ASCA IgG was higher than that of ASCA IgA (9.5 vs. 6.4 U/ml) but the difference was not statistically significant. The frequencies of aß2GPI (IgG and/or IgA) and aß2GPI IgA were significantly higher than those of ASCA (IgG and/or IgA) and ASCA IgA (54.3 vs. 31.9 %, p = 5 × 10(-4) and 50.9 vs. 12.1 %, p < 10(-6), respectively). Increased ASCA IgG was observed in patients with SLE, suggesting a role of environmental stimuli in its pathogenesis.

Anti-Saccharomyces cerevisiae antibodies are elevated in Graves' disease but not in Hashimoto's thyroiditis.

BACKGROUND: Anti-Saccharomyces cerevisiae antibodies (ASCA) had been known to be specific for Crohn's disease, but they had also been found in many other autoimmune diseases. AIM: The aim of this study was to evaluate the prevalence of ASCA in patients with autoimmune thyroid disease (AITD). PATIENTS AND METHODS: One hundred and ninety-seven patients with AITD and 160 healthy controls were included in the study. One hundred and nineteen patients had Graves' disease (GD) and 78 patients had Hashimoto's thyroiditis (HT). ASCA IgG and IgA were determined by ELISA. RESULTS: ASCA IgG were significantly more frequent in patients with GD than in control group (11.8% vs. 3.1%, p = 0.002). In HT, the frequency of ASCA IgG was similar to that of the control group (3.8% and 3.1% respectively). The frequency of ASCA IgA was similar in GD (0.8%), HT (2.6%), and the control group (3.1%). In all GD patients, the frequency of ASCA IgG was significantly higher than that of ASCA IgA (11.8% vs. 0.8%, p = 0.001). These results were also true even in male and female groups (10.4% vs. 1.3%, p = 0.01 and 14.3% vs. 0%, p = 0.01, respectively). ASCA IgG levels were significantly higher in GD patients (6.7 ± 11.1 vs. 2.2 ± 2.8, p = 3 × 10(-6)) and in HT patients (4.2 ± 4.7 vs. 2.2 ± 2.8, p = 0.0002) than those in the control group. ASCA IgA levels were comparable among patients with GD, HT, and the control group. In GD patients, the mean titer of ASCA IgG was significantly higher than that of ASCA IgA (6.7 ± 11.1 vs. 3.6 ± 4.2, p = 0.005). CONCLUSION: Patients with GD had a higher frequency of ASCA IgG than controls.

Altered patterns of epigenetic changes in systemic lupus erythematosus and auto-antibody production: is there a link?

The prominent feature of immunological defects in systemic lupus erythematosus (SLE) is the production of autoantibodies (auto-Abs) to nuclear antigens including DNA, histones and RNP. In addition, there is growing evidence that epigenetic changes play a key role in the pathogenesis of SLE. Autoreactive CD4(+) T cells and B cells in patients with SLE have evidence of altered patterns of DNA methylation as well as post-translational modifications of histones and ribonucleoproteins (RNP). A key question that has emerged from these two characteristic features of SLE is whether the two processes are linked. New data provide support for such a link. For example, there is evidence that hypomethylated DNA is immunogenic, that anti-histone auto-Abs in patients with SLE bind epigenetic-sensitive hot spots and that epigenetically-modified RNP-derived peptides can modulate lupus disease. All in all, the available evidence indicates that a better understanding of dysregulation in epigenetics in SLE may offer opportunities to develop new biomarkers and novel therapeutic strategies.

Systemic lupus erythematosus in the elderly.

Onset of the disease above the age of 65 years is unusual. This study was undertaken to determine retrospectively the clinical and laboratory features in SLE patients aged over 65 years. It is a retrospective study about 18 elderly patients with SLE out of 342 diagnosed between 1994 and 2009 in the center of Tunisia. All patients had at least 4 of 11 revised ACR criteria of SLE. The frequency of SLE in the elderly was 5.3%. The median age was 70 years (range 66 and 78 years). The sex ratio F/M was 5. The most frequent clinical signs were anemia (83.3%), arthralgia (55.5%), arthritis (38.9%), and malar rash (33.3%). The proteinuria and the neuropsychiatric troubles were present in 27.8% of cases. The pericarditis was present in 16.7% of cases. Antibodies to double stranded DNA (anti-dsDNA) were detected in 66.7%, anti-nucleosome in 50%, anti-SSA and anti-RNP in 27.8%, anti-Sm in 22%, and anti-SSB in 11%. Elderly patients with SLE exhibit distinct clinical and biological manifestations from the classic form. Thus, greater attention should be given for this particular subgroup of SLE patients to avoid delays in diagnosis or misdiagnosis.

Thyroid-related autoantibodies in Tunisian patients with type 1 diabetes.

AIM: To evaluate, retrospectively, the frequency of antithyroid antibodies (ATA) in patients with type 1 diabetes (T1D). MATERIALS AND METHODS: Antithyroperoxidase antibodies (TPO-Ab), antithyroglobulin antibodies (TG-Ab), and antithyroid-stimulating hormone receptor antibodies (TSHR-Ab) were determined by enzyme-linked immunosorbent assay. Sera of 312 patients (166 children and 146 adults) with T1D were analyzed. Sera of 276 healthy subjects (87 children and 189 blood donors) served as controls. RESULTS: Out of 312 patients with T1D, 44 (14%) had ATA (TPO-Ab or TG-Ab or TSHR-Ab). The frequency of ATA in patients with T1D was significantly higher than in the control group (14% vs. 2.8%; p<10(-5)). ATA were significantly more frequent in adult patients with T1D than in the blood donor group (20% vs. 1.6%; p<10(-8)). The frequency of ATA in adult patients was significantly higher than in pediatric patients (20% vs. 9%; p=0.006). The frequency of TPO-Ab and TG-Ab was significantly higher in patients with T1D than in the control group (13.5% vs. 2%; p<10(-8) and 7% vs. 2.2%, p=0.008), respectively. Out of 312 patients with T1D, only one had TSHR-Ab. The simultaneous presence of three autoantibodies was found in one patient with T1D. CONCLUSION: ATA were frequent in patients with T1D. Serological screening of autoimmune thyroid disease is suggested in patients with T1D.

DNA methylation modulates HRES1/p28 expression in B cells from patients with Lupus.

Systemic lupus erythematosus (SLE) disease is an autoimmune disease of unknown aetiology that affects predominantly women of child bearing age. Since previous studies, including ours, have demonstrated that CD4+ T cells and B cells from SLE patients are defective in their ability to methylate their DNA upon antigen stimulation, the aim of this study was to investigate whether DNA demethylation affects the transcription of HRES-1 in B cells. HRES-1 is the prototype of Human Endogenous Retrovirus (HERV) overexpressed in SLE. We have observed that SLE B cells were characterized by their incapacity to methylate the HRES-1 promoter, both in unstimulated and in anti-IgM stimulated B cells. In turn, HRES-1/p28 expression was increased in SLE B cells after B cell receptor engagement, but not in controls. In SLE B cells the Erk/DNMT1 pathway was defective. In addition, blocking the autocrine-loop of IL-6 in SLE B cells with an anti-IL-6 receptor monoclonal antibody restores DNA methylation and control of HRES-1/p28 expression became effective. As a consequence, a better understanding of HERV dysregulation in SLE reinforces our comprehension of the disease and opens new therapeutic perspectives.

The contribution of epigenetics in Sjögren's Syndrome.

Sjögren's syndrome (SS) is a chronic autoimmune epithelitis that combines exocrine gland dysfunctions and lymphocytic infiltrations. While the pathogenesis of SS remains unclear, its etiology is multifunctional and includes a combination of genetic predispositions, environmental factors, and epigenetic factors. Recently, interest has grown in the involvement of epigenetics in autoimmune diseases. Epigenetics is defined as changes in gene expression, that are inheritable and that do not entail changes in the DNA sequence. In SS, several epigenetic mechanisms are defective including DNA demethylation that predominates in epithelial cells, an abnormal expression of microRNAs, and abnormal chromatin positioning-associated with autoantibody production. Last but not least, epigenetic modifications are reversible as observed in minor salivary glands from SS patients after B cell depletion using rituximab. Thus epigenetic findings in SS open new perspectives for therapeutic approaches as well as the possible identification of new biomarkers.

Performance of anti-deamidated gliadin peptides antibodies in celiac disease diagnosis.

OBJECTIVES: To assess the usefulness of anti-deamidated gliadin peptides antibodies (a-DGP), in the diagnostic of celiac disease (CD). PATIENTS AND METHODS: One hundred and three untreated CD patients (67 children and 36 adults) and 36 celiac patients under gluten-free diet were studied. Two hundred and seventy-four subjects served as controls (114 healthy blood donors, 80 healthy children and 80 patients with primary biliary cirrhosis). a-DGP (IgG and IgA) and anti-tissue transglutaminase antibodies (AtTG) were detected by enzyme-linked immunosorbent assay (Elisa). Anti-endomysium antibodies (AEA) were detected by indirect immunofluorescence on human umbilical cord. RESULTS: The sensitivitiy of IgG and IgA a-DGP were 94% and 97% respectively, compared to 96% for AEA and AtTG. The specificity of a-DGP was 93.6% for IgG and 92% for IgA. The specificity of AEA and AtTG were 100%. The frequency of IgG and IgA a-DGP was significantly higher in patients with CD than in control group (94% vs. 4.4%, P<10(-7); 97% vs. 8%, P<10(-7)). The frequency of IgG a-DGP was the same in children and adult (94%). The frequency of IgA a-DGP were similar in children and adults (95.5% vs. 100%). CONCLUSION: Our study shows that a-DGP increases neither the sensitivity nor the specificity of AEA and AtTG.

Anti-Saccharomyces cerevisiae antibodies are frequent in type 1 diabetes.

Anti-Saccharomyces cerevisiae antibodies (ASCA) have been described in many autoimmune diseases in which there is an increased intestinal permeability. Also in type 1 diabetes (T1D), there is an increased intestinal permeability. Since no data are available about ASCA in T1D, we evaluated, retrospectively, the frequency of ASCA in this disease. ASCA, IgG, and IgA, were determined by ELISA in sera of 224 T1D patients in which coeliac disease has been excluded and 157 healthy control group. The frequency of ASCA (IgG or IgA) was significantly higher in T1D patients than in the control group (24.5% vs. 2.5%, p < 10(-7)). The same observation was found in children and in adult patients when we compare them to healthy children and blood donors group respectively. Compared to children, adult patients with T1D showed significantly higher frequencies of ASCA of any isotype (38% vs. 13.7%, p < 10(-4)), both ASCA IgG and IgA (12% vs. 1.6%, p = 0.002), ASCA IgG (35% vs. 9.8%, p < 10(-5)) and ASCA IgA (15% vs. 5.6%, p = 0.001). The frequency of ASCA was statistically higher in females of all T1D than in males (30.8% vs.17.7%, p = 0.03), in girls than in boys (22% vs.6.2%, p = 0.017), and significantly higher in men than in boys (35.7% vs. 6.2%, p < 10(-4)). The frequency of ASCA IgG was significantly higher than that of ASCA IgA in all T1D patients (21% vs. 9.8%, p < 0.002), in all females (26.5% vs. 10.2%, p < 0.002), in women (37.9% vs. 12%, p < 0.001). The frequency of ASCA was significantly higher in all long-term T1D than in an inaugural T1D (29% vs. 14.5%, p = 0.019). The same observation was found in adults (45.8% vs. 17.8%, p = 0.01). In long-term T1D patients, ASCA were significantly more frequent in adults than children (45.8% vs. 14.5%, p < 10(-4)). The frequency of ASCA IgG was significantly higher in long-term T1D than in an inaugural T1D (25.2% vs. 11.6%, p = 0.03). Patients with T1D had a high frequency of ASCA.