Cytokine Gene Expression and Autoantibody Production in Sjögren's Syndrome of MRL/lpr Mice

Sjögren’s syndrome (SS) is a chronic systemic autoimmune disease that affects predominately salivary and lacrimal glands. SS can occur alone or in combination with another autoimmune disease like systemic lupus erythematosus (SLE). Here we report that TLR7 signaling drives the development of SS since TLR8-deficient (TLR8ko) mice that develop lupus due to increased TLR7 signaling by dendritic cells, also develop an age-dependent secondary pathology similar to associated SS. The SS phenotype in TLR8ko mice is manifested by sialadenitis, increased anti-SSA and anti-SSB autoantibody production, immune complex deposition and increased cytokine production in salivary glands, as well as lung inflammation. Moreover, ectopic lymphoid structures characterized by B/T aggregates, formation of high endothelial venules and the presence of dendritic cells are formed in the salivary glands of TLR8ko mice. Interestingly, all these phenotypes are abrogated in double TLR7/8-deficient mice, suggesting that the SS phenotype in TLR8-deficient mice is TLR7-dependent. In addition, evaluation of TLR7 and inflammatory markers in the salivary glands of primary SS patients revealed significantly increased TLR7 expression levels compared to healthy individuals, that were positively correlated to TNF, LT-α, CXCL13 and CXCR5 expression. These findings establish an important role of TLR7 signaling for local and systemic SS disease manifestations, and inhibition of such will likely have therapeutic value.

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An integrative multi-omics approach in Sjögren’s Syndrome identifies novel genetic drivers with regulatory function and disease-specificity

10.1101/2020.09.14.20192211 ◽

2020 ◽

Author(s):

María Teruel ◽

Guillermo Barturen ◽

Manuel Martínez-Bueno ◽

Miguel Barroso ◽

Olivia Castelli ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Sjögren’S Syndrome ◽

Genetic Variants ◽

Sjögren's Syndrome ◽

Expression Patterns ◽

Sjogren’S Syndrome ◽

Sjogren's Syndrome ◽

Regulatory Function ◽

Sjögren‘S Syndrome

ABSTRACTPrimary Sjögren’s syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study we identified vast coordinated hypomethylation and overexpression effects, that also exhibit increased variability, in many already known IFN-regulated genes. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of novel genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified new genetic variants associated with SS that mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, DNA methylation, gene expression and SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population.

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STAT4, TRAF3IP2, IL10, and HCP5 Polymorphisms in Sjögren’s Syndrome: Association with Disease Susceptibility and Clinical Aspects

Journal of Immunology Research ◽

10.1155/2019/7682827 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8 ◽

Cited By ~ 6

Author(s):

Serena Colafrancesco ◽

Cinzia Ciccacci ◽

Roberta Priori ◽

Andrea Latini ◽

Giovanna Picarelli ◽

...

Keyword(s):

Sjögren’S Syndrome ◽

Sjögren's Syndrome ◽

Sjogren’S Syndrome ◽

Sjogren's Syndrome ◽

Variant Allele ◽

Clinical Aspects ◽

Autoantibody Production ◽

Focus Score ◽

Risk Alleles ◽

Sjögren‘S Syndrome

Sjögren’s syndrome (SS) is a chronic autoimmune condition characterized by autoantibody production, sicca syndrome, and periepithelial lymphocytic lesions in target tissues. A predisposing genetic background is likely, and, to date, several polymorphisms in non-HLA genes have been explored with interesting results. We investigated the association between the STAT4, TRAF3IP2, HCP5, and IL10 polymorphisms and SS susceptibility and their possible role in the modulation of clinical and laboratory features. 195 consecutive patients with SS were enrolled and clinical and laboratory data were collected. 248 age- and sex-matched healthy subjects were used as controls. Genotyping was performed by allelic discrimination assays. A case-control association study and a phenotype-genotype correlation analysis were performed. A genetic risk profile was developed considering the risk alleles. Both the variant alleles of rs7574865 in the STAT4 gene and rs3099844 in the HCP5 gene were significantly more prevalent in patients than in controls (OR=1.91 and OR=2.44, respectively). The variant allele of rs3024505 of IL10 resulted to be a susceptibility allele (OR=1.52), while the variant allele of rs1800872 seemed to confer a protective effect for the development of the disease (OR=0.65). A risk genetic profile showed a higher probability to develop the disease in subjects with at least three risk alleles; subjects with 4 risk alleles were not observed in the controls. HCP5 rs3099844 was associated with anti-SSA (P=0.006, OR=3.07) and anti-SSB (P=0.005, OR=2.66) antibodies, severity of focus score (P=0.03, OR=12), and lymphoma development (P=0.002, OR=7.23). Patients carrying the STAT4 rs7574965 variant allele had a higher risk of monoclonal component and leukopenia (P=0.002, OR=7.6; P=0.048, OR=2.01, respectively). We confirmed the association of SS with the STAT4 and IL10 genes and we describe a novel association with HCP5. In particular, we describe an association of this specific SNP of HCP5 not only with disease development but also with autoantibody production and focus score suggesting a potential contribution of this variant to a more severe phenotype.

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MicroRNA in Sjögren’s Syndrome: Their Potential Roles in Pathogenesis and Diagnosis

Journal of Immunology Research ◽

10.1155/2018/7510174 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 14

Author(s):

M. Reale ◽

C. D’Angelo ◽

E. Costantini ◽

M. Laus ◽

A. Moretti ◽

...

Keyword(s):

B Cells ◽

Sjögren’S Syndrome ◽

Sjögren's Syndrome ◽

Lymphocytic Infiltration ◽

Sjogren’S Syndrome ◽

Sjogren's Syndrome ◽

Exocrine Glands ◽

Autoantibody Production ◽

Systemic Autoimmunity ◽

Sjögren‘S Syndrome

Sjögren’s syndrome (SS) or sicca syndrome was described by Swedish ophthalmologist Sjögren in the year 1933 for the first time. The etiology of the SS is multifunctional and includes a combination of genetic predisposition and environmental as well as epigenetic factors. It is an autoimmune disease characterized by features of systemic autoimmunity, dysfunction, and inflammation in the exocrine glands (mainly salivary and lacrimal glands) and lymphocytic infiltration of exocrine glands. In fact, the involvement of lacrimal and salivary glands results in the typical features of dry eye and salivary dysfunction (xerostomia). Only in one-third of the patients also present systemic extraglandular manifestations. T cells were originally considered to play the initiating role in the autoimmune process, while B cells were restricted to autoantibody production. In recent years, it is understood that the roles of B cells are multiple. Moreover, autoantibodies and blood B cell analysis are major contributors to a clinical diagnosis of Sjögren’s syndrome. Recently, there has been rising interest in microRNA implication in autoimmunity. Unfortunately, to date, there are only a few studies that have investigated their participation in SS etiopathogenesis. The purpose of this work is to gather the data present in the literature to clarify this complex topic.

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