Systemic Lupus Erythematosus in Children and Young People.

PURPOSE OF REVIEW: Juvenile-onset systemic lupus erythematosus ((j)SLE) is an autoimmune/inflammatory disease that results in significant damage and disability. When compared to patients with disease onset in adulthood, jSLE patients exhibit increased disease activity, damage and require more aggressive treatments. This manuscript summarises age-specific pathogenic mechanisms and underscores the need for age group-specific research, classification and treatment. RECENT FINDINGS: Genetic factors play a significant role in the pathophysiology of jSLE, as > 7% of patients develop disease as a result of single gene mutations. Remaining patients carry genetic variants that are necessary for disease development, but require additional factors. Increased 'genetic impact' likely contributes to earlier disease onset and more severe phenotypes. Epigenetic events have only recently started to be addressed in jSLE, and add to the list of pathogenic mechanisms that may serve as biomarkers and/or treatment targets. To allow meaningful and patient-oriented paediatric research, age-specific classification criteria and treatment targets require to be defined as currently available tools established for adult-onset SLE have limitations in the paediatric cohort. Significant progress has been made in understanding the pathophysiology of jSLE. Meaningful laboratory and clinical research can only be performed using age group-specific tools, classification criteria and treatment targets.

[Influence of epigenetic in Sjögren's syndrome]. / Épigénome et syndrome de Gougerot-Sjögren.

Sjögren's syndrome (SS) is a systemic autoimmune epithelitis with a major female incidence, and characterized by a dry syndrome, impaired quality of life, visceral involvement, and lymphoma for the most aggressive cases. During this process, epithelial cells acquire the capacity to produce cytokines, chemokines, and autoantigens which can in turn be presented to the immune system. Consequently, this epithelitis is accompanied by lymphocytic infiltrations leading to the formation of pseudo-follicles in which self-reactive B lymphocytes are present. The recent integration of genomic and especially of epigenomic data, which make it possible to analyze the different cellular partners, opens new perspectives and allows to a better understanding of this complex and still incurable disease.

Epigenetic modifications in salivary glands from patients with Sjögren's syndrome affect cytokeratin 19 expression.

Sjögren's syndrome (SS) is a chronic autoimmune epithelitis, and several lines of experiments indicate that multifactorial factors contribute to salivary gland epithelial cells (SGEC) dysfunctions including a combination of environmental factors, lymphocytic infiltrations, genetic predispositions as well as epigenetic defects. Such statement is reinforced by the observation that global DNA methylation (5MeCyt) is altered in minor salivary glands from pSS patients and that such defect is associated cytokeratin 19 (KRT19) overexpression. An epigenetic deregulation of the KRT19 gene was further tested by treating the human salivary gland (HSG) cell line with the DNA demethylating agent 5-azacytidin, and with the histone acetylase inhibitor trichostatin A. Blocking DNA methylation, but not histone acetylation, with 5-azacytidin was associated with KRT19 overexpression at both transcriptional and protein level. Next, analysis of the CpG genome-wide methylome array in the KTR19 locus from long term cultured SGEC obtained from 8 pSS patients revealed a more reduced DNA methylation level in those patients with defective global DNA methylation. Altogether, our data, therefore, suggest that alteration of DNA methylation in SGEC may contribute to pSS pathophysiology in part by controlling the expression of KRT19.

Defective DNA methylation in salivary gland epithelial acini from patients with Sjögren's syndrome is associated with SSB gene expression, anti-SSB/LA detection, and lymphocyte infiltration.

The pathogenesis of primary Sjögren's syndrome (pSS) is complex, in part due to DNA methylation abnormalities. This study was undertaken to evaluate the importance of global DNA methylation ((5m)C) as determined in minor salivary glands (MSG) from well characterized pSS patients. Twenty-two pSS patients and ten controls were selected, and MSG were stained with anti-(5m)C, anti-(5m)C/anti-cytokeratin (KRT)19, or with anti-SSB/La antibodies (Ab). The DNA methylation status at the SSB gene promoter P1 and P1' was evaluated by methylation-sensitive restriction enzymes (MSRE) coupled with PCR. The effect of the DNA demethylating drug 5 azacytidine (5-Aza) was tested in the human salivary gland (HSG) cell line. In pSS, the reduction of global DNA methylation ((5m)C) was associated with lymphocyte infiltration, the emergence of (5m)C(low) and KRT19(high) acini, and the detection of circulating anti-SSB/La Ab, but not with disease activity (ESSDAI). Next, treating HSG cells with 5-Aza was effective in inducing SSB expression. Finally in pSS patients positive for anti-SSB/La Ab, we further observed DNA demethylation at the SSB gene promoter P1 with consequent SSB overexpression at both the transcriptional and protein levels in salivary gland epithelial cells. In conclusion, our results highlight the importance of DNA methylation in the pathophysiology of pSS and to the emergence of anti-SSB/La Ab.