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

Abstract

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.

Figure 1

Model of Sjogren's syndrome pathogenesis

Figure 2

Peripheral Blood Gene expression profile of pSS Gene expression profile of seropositive pSS patients differs from seronegative patients. Hierarchical clustering analysis of 106 differentially over expressed genes between 36 pSS patients (indicated by blue bars), 11 seronegative patients (indicated by gray bars) and 22 controls (indicated by orange bars). The purple bars on the right side of the CLUSTERTREEVIEW diagram indicate the IFN signature gene cluster. Each row represents an individual gene. Red signifies genes that are upregulated relative to controls. Green indicates genes downregulated compared to controls, black indicates genes that are not significantly different from controls.

Figure 3

Differences in risk factors, immune events, and longitudinal disease course in seropositive and seronegative Sjogren's syndrome subsets