Variants in the autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland.

Fine mapping and bioinformatic analysis of the genetic risk association in Sjögren's Disease (SjD) and Systemic Lupus Erythematosus (SLE) identified five common SNPs with functional evidence in immune cell types: rs4938573, rs57494551, rs4938572, rs4936443, rs7117261. Functional interrogation of nuclear protein binding affinity, enhancer/promoter regulatory activity, and chromatin-chromatin interactions in immune, salivary gland epithelial, and kidney epithelial cells revealed cell type-specific allelic effects for all five SNPs that expanded regulation beyond effects on and expression. Mapping the local chromatin regulatory network revealed several additional genes of interest, including .

Mitochondrial Dysfunction and Fatigue in Sjögren's Disease.

Objectives: Sjögren's disease (SjD) is a common exocrine disorder typified by chronic inflammation and dryness, but also profound fatigue, suggesting a pathological basis in cellular bioenergetics. In healthy states, damaged or dysfunctional mitochondrial components are broken down and recycled by mitophagy, a specialized form of autophagy. In many autoimmune disorders, however, evidence suggests that dysfunctional mitophagy allows poorly functioning mitochondria to persist and contribute to a cellular milieu with elevated reactive oxygen species.

Dysregulated long non-coding RNA in Sjögren's disease impacts both interferon and adaptive immune responses.

Objective: Sjögren's disease (SjD) is an autoimmune disease characterised by inflammatory destruction of exocrine glands. Patients with autoantibodies to Ro/SSA (SjD) exhibit more severe disease. Long non-coding RNAs (lncRNAs) are a functionally diverse class of non-protein-coding RNAs whose role in autoimmune disease pathology has not been well characterised.

Addressing the clinical unmet needs in primary Sjögren's Syndrome through the sharing, harmonization and federated analysis of 21 European cohorts.

For many decades, the clinical unmet needs of primary Sjögren's Syndrome (pSS) have been left unresolved due to the rareness of the disease and the complexity of the underlying pathogenic mechanisms, including the pSS-associated lymphomagenesis process. Here, we present the HarmonicSS cloud-computing exemplar which offers beyond the state-of-the-art data analytics services to address the pSS clinical unmet needs, including the development of lymphoma classification models and the identification of biomarkers for lymphomagenesis. The users of the platform have been able to successfully interlink, curate, and harmonize 21 regional, national, and international European cohorts of 7,551 pSS patients with respect to the ethical and legal issues for data sharing.

Defective Efferocytosis in a Murine Model of Sjögren's Syndrome Is Mediated by Dysfunctional Mer Tyrosine Kinase Receptor.

Sjögren's syndrome (SjS) is a chronic autoimmune disease primarily involving the exocrine glands in which the involvement of the innate immune system is largely uncharacterized. Mer signaling has been found to be protective in several autoimmune diseases but remains unstudied in SjS. Here, we investigated the role of Mer signaling in SjS.

Transcriptomic and Network Analysis of Minor Salivary Glands of Patients With Primary Sjögren's Syndrome.

Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease characterized primarily by immune-mediated destruction of exocrine tissues, such as those of the salivary and lacrimal glands, resulting in the loss of saliva and tear production, respectively. This disease predominantly affects middle-aged women, often in an insidious manner with the accumulation of subtle changes in glandular function occurring over many years. Patients commonly suffer from pSS symptoms for years before receiving a diagnosis.

Sjögren's Syndrome Minor Salivary Gland CD4 Memory T Cells Associate with Glandular Disease Features and have a Germinal Center T Follicular Helper Transcriptional Profile.

To assess the types of salivary gland (SG) T cells contributing to Sjögren's syndrome (SS), we evaluated SG T cell subtypes for association with disease features and compared the SG CD4 memory T cell transcriptomes of subjects with either primary SS (pSS) or non-SS sicca (nSS). SG biopsies were evaluated for proportions and absolute numbers of CD4 and CD8 T cells. SG memory CD4 T cells were evaluated for gene expression by microarray.

Epidemiological profile and north-south gradient driving baseline systemic involvement of primary Sjögren's syndrome.

Objective: To characterize the systemic phenotype of primary Sjögren's syndrome at diagnosis by analysing the EULAR-SS disease activity index (ESSDAI) scores.

Methods: The Sjögren Big Data Consortium is an international, multicentre registry based on worldwide data-sharing cooperative merging of pre-existing databases from leading centres in clinical research in Sjögren's syndrome from the five continents.

Results: The cohort included 10 007 patients (9352 female, mean 53 years) with recorded ESSDAI scores available.

Unique Sjögren's syndrome patient subsets defined by molecular features.

Objective: To address heterogeneity complicating primary SS (pSS) clinical trials, research and care by characterizing and clustering patients by their molecular phenotypes.

Methods: pSS patients met American-European Consensus Group classification criteria and had at least one systemic manifestation and stimulated salivary flow of ⩾0.1 ml/min.

Genetics in Sjögren's syndrome: where we are and where we go.

Sjögren's syndrome is a complex autoimmune disease that involves dysregulation of immune responses that preferentially target exocrine glands. Systemic manifestations vary and may involve nearly every organ system. Genetic studies to date are in their infancy relative to other autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, each with more than 100 genetic associations now established.

Systemic manifestations of primary Sjögren's syndrome out of the ESSDAI classification: prevalence and clinical relevance in a large international, multi-ethnic cohort of patients.

Objectives: To analyse the frequency and characterise the systemic presentation of primary Sjögren's syndrome (SS) out of the ESSDAI classification in a large international, multi-ethnic cohort of patients.

Methods: The Big Data Sjögren Project Consortium is an international, multicentre registry based on world-wide data-sharing and cooperative merging of pre-existing clinical SS databases from leading centres in clinical research in SS from the five continents. A list of 26 organ-by-organ systemic features not currently included in the ESSDAI classification was defined according to previous studies; these features were retrospectively recorded.

Reproducibility of Ocular Surface Staining in the Assessment of Sjögren Syndrome-Related Keratoconjunctivitis Sicca: Implications on Disease Classification.

Objective: The objective of this study was to assess the performance and reproducibility of the two currently used ocular surface staining scores in the assessment of keratoconjunctivitis sicca in Sjögren syndrome (SS) research classification.

Methods: In a multidisciplinary clinic for the evaluation of sicca, we performed all tests for the American European Consensus Group (AECG) and the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria, including the van Bijsterveld score (vBS) and the Ocular Staining Score (OSS), in 994 participants with SS or with non-SS sicca. We analyzed the concordance between the scores, the diagnostic accuracy and correlation with clinical variables, and interrater and intrasubject reproducibility.

American Indians Have a Higher Risk of Sjögren's Syndrome and More Disease Activity Than European Americans and African Americans.

Objective: To describe the clinical and serologic manifestations of Sjögren's syndrome (SS) in ethnic groups of the US.

Methods: This was a cross-sectional study of 648 patients with primary SS: 20 African American (AA), 164 American Indian (AI), 426 European American (EA), and 38 patients of other races evaluated in a multidisciplinary Sjögren's International Collaborative Clinical Alliance research clinic.

Results: AA subjects comprised 3.

Sjögren Syndrome without Focal Lymphocytic Infiltration of the Salivary Glands.

Objective: Primary Sjögren syndrome (SS) is characterized by a focal lymphocytic infiltrate in exocrine glands. We describe patients who lacked this key feature.

Methods: We evaluated patients with sicca in a comprehensive clinic at which medical, dental, and ophthalmological examinations were performed.

Genetics and epigenetics in primary Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is considered to be a multifactorial disease, where underlying genetic predisposition, epigenetic mechanisms and environmental factors contribute to disease development. In the last 5 years, the first genome-wide association studies in pSS have been completed. The strongest signal of association lies within the HLA genes, whereas the non-HLA genes IRF5 and STAT4 show consistent associations in multiple ethnicities but with a smaller effect size.

How immunological profile drives clinical phenotype of primary Sjögren's syndrome at diagnosis: analysis of 10,500 patients (Sjögren Big Data Project).

Objectives: To evaluate the influence of the main immunological markers on the disease phenotype at diagnosis in a large international cohort of patients with primary Sjögren's syndrome (SjS).

Methods: The Big Data Sjögren Project Consortium is an international, multicentre registry created in 2014. As a first step, baseline clinical information from leading centres on clinical research in SjS of the 5 continents was collected.

Genetic fine mapping of systemic lupus erythematosus MHC associations in Europeans and African Americans.

Genetic variation within the major histocompatibility complex (MHC) contributes substantial risk for systemic lupus erythematosus, but high gene density, extreme polymorphism and extensive linkage disequilibrium (LD) have made fine mapping challenging. To address the problem, we compared two association techniques in two ancestrally diverse populations, African Americans (AAs) and Europeans (EURs). We observed a greater number of Human Leucocyte Antigen (HLA) alleles in AA consistent with the elevated level of recombination in this population.

Antibodies to periodontogenic bacteria are associated with higher disease activity in lupus patients.

Objectives: Microbial infections and mucosal dysbiosis influence morbidity in patients with systemic lupus erythematosus (SLE). In the oral cavity, periodontal bacteria and subgingival plaque dysbiosis provide persistent inflammatory stimuli at the mucosal surface. This study was undertaken to evaluate whether exposure to periodontal bacteria influences disease parameters in SLE patients.

A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus.

Systemic lupus erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1-STAT4 locus is one of the first and most highly replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk.

Genetic variants at the 16p13 locus confer risk for eosinophilic esophagitis.

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus triggered by immune hypersensitivity to food. Herein, we tested whether genetic risk factors for known, non-allergic, immune-mediated diseases, particularly those involving autoimmunity, were associated with EoE risk. We used the high-density Immunochip platform, encoding 200,000 genetic variants for major auto-immune disease.