Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren's syndrome.

Sjögren's syndrome is a common autoimmune disease (affecting ∼0.7% of European Americans) that typically presents as keratoconjunctivitis sicca and xerostomia. Here we report results of a large-scale association study of Sjögren's syndrome. In addition to strong association within the human leukocyte antigen (HLA) region at 6p21 (Pmeta = 7.65 × 10(-114)), we establish associations with IRF5-TNPO3 (Pmeta = 2.73 × 10(-19)), STAT4 (Pmeta = 6.80 × 10(-15)), IL12A (Pmeta = 1.17 × 10(-10)), FAM167A-BLK (Pmeta = 4.97 × 10(-10)), DDX6-CXCR5 (Pmeta = 1.10 × 10(-8)) and TNIP1 (Pmeta = 3.30 × 10(-8)). We also observed suggestive associations (Pmeta < 5 × 10(-5)) with variants in 29 other regions, including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2 and PHIP, among others. These results highlight the importance of genes that are involved in both innate and adaptive immunity in Sjögren's syndrome.

Systems analysis of primary Sjögren's syndrome pathogenesis in salivary glands identifies shared pathways in human and a mouse model.

INTRODUCTION: Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease with complex etiopathogenesis. Despite extensive studies to understand the disease process utilizing human and mouse models, the intersection between these species remains elusive. To address this gap, we utilized a novel systems biology approach to identify disease-related gene modules and signaling pathways that overlap between humans and mice. METHODS: Parotid gland tissues were harvested from 24 pSS and 16 non-pSS sicca patients and 25 controls. For mouse studies, salivary glands were harvested from C57BL/6.NOD-Aec1Aec2 mice at various times during development of pSS-like disease. RNA was analyzed with Affymetrix HG U133+2.0 arrays for human samples and with MOE430+2.0 arrays for mouse samples. The images were processed with Affymetrix software. Weighted-gene co-expression network analysis was used to identify disease-related and functional pathways. RESULTS: Nineteen co-expression modules were identified in human parotid tissue, of which four were significantly upregulated and three were downregulated in pSS patients compared with non-pSS sicca patients and controls. Notably, one of the human disease-related modules was highly preserved in the mouse model, and was enriched with genes involved in immune and inflammatory responses. Further comparison between these two species led to the identification of genes associated with leukocyte recruitment and germinal center formation. CONCLUSION: Our systems biology analysis of genome-wide expression data from salivary gland tissue of pSS patients and from a pSS mouse model identified common dysregulated biological pathways and molecular targets underlying critical molecular alterations in pSS pathogenesis.

A current perspective on Sjögren's syndrome.

Sjögren's syndrome is a common autoimmune disorder characterized by dry mouth and dry eyes. Symptoms and signs are chronic and can be severe. The diagnosis of Sjögren's syndrome can be confusing and time-consuming. The management can also be a significant challenge for the clinicians. However, recent genomic and proteomic developments are unlocking the mystery of the disease process as well as contributing to our ability to define, diagnose, and develop new treatment modalities for patients with this complex disorder.

Genetics and genomics of Sjögren's syndrome: research provides clues to pathogenesis and novel therapies.

PURPOSE: Although the key inciting events that drive the progression from autoantibodies to clinical disease remain to be clarified, new light has been shed on the factors contributing to disease susceptibility and the role of genetic factors in determining Sjögren's syndrome (SS) disease phenotypes. The purpose of this article is to provide an update on the role of genetic markers in the susceptibility to and pathogenesis of SS. This article also discusses how genomic and proteomic technology can help in the design of specific therapeutics. KEY FINDINGS: Recent evidence suggests that inflammatory genes associated with interferon pathways, and specific regulatory genes that control the maturation and proliferation of B cells, contribute to the pathogenesis of SS. Both gene expression profiling technology and gene association studies have been used to identify these key biological pathways. Molecularly, defined subsets of pSS patients are also being revealed by these studies. Previously, identified gene loci that predispose to multiple autoimmune disorders have been confirmed supporting the paradigm of "general" autoimmune disease genes. Association of SS with many additional susceptibility loci are likely to be established through ongoing genome-wide association scans (GWAS). Clues from genetic studies suggest that targeting B cells will prove to be an effective way of reducing the systemic manifestations of pSS and are supported by early clinical trials. SUMMARY: Genome-wide technologies are likely to identify new genes and molecular pathways in the pathogenesis of SS that will be useful not only to identify patients at risk for SS, but also to identify subsets of patients at risk for variable levels of disease severity. In the future, these studies could identify novel biomarkers that will lead to significant advances in management by providing the means to tailor therapeutic strategies to individual patients.

Therapeutic doses of radiation alter proliferation and attachment of osteoblasts to implant surfaces.

Osseointegration of implants in irradiated bone is inadequate. The effect of radiation on cell-implant material interaction has not been adequately studied. The goal of this study was to investigate the effects of ionizing radiationon the proliferation, differentiation, and attachment of osteoblasts to commercially pure titanium (cpTi). Human fetal osteoblasts (hFOB) were irradiated either before or after plating in tissue culture (TC) dishes with or without cpTi disks. Radiation was single dose of 10 cGy, 25 cGy, 50 cGy, 1 Gy, 2 Gy, 4 Gy or 8 Gy. Cell proliferation was determined by counting trypsinized cells on 7 days after irradiation. Attachment of irradiated hFOB was measured indirectly by counting cells 2 and 6 h after plating. Differentiation was evaluated by alkaline phosphatase activity. Compared with nonirradiated sham controls, higher doses of radiation significantly reduced cell attachment and proliferation. Both proliferation and attachment were significantly lower on cpTi compared with TC. Attachment decreased based on the length of postirradiation period. Although differentiation was significantly enhanced by a dose of 8 Gy, proliferation was lowest. These initial studies show that effects of therapeutic doses of radiation on osteoblasts varied depending on the surface, time-elapsed, and amount of radiation.