Sjögren’s syndrome is a tissue-specific autoimmune disease that affects exocrine tissues, especially salivary glands and lacrimal glands. It is one of the most common autoimmune disorders in the U.S., with an estimated prevalence of 2–4 million people. The autoimmune-mediated damage of the salivary and lacrimal glands in Sjögren’s syndrome leads to a decrease in the production of saliva and tears and to the development of dry mouth and dry eyes. Without the lubricating and protective functions of saliva and tears, the oral and ocular surfaces are subject to infections and discomfort, leading to a significantly reduced quality of life
Development of Sjögren’s syndrome requires a complex interplay between a number of genetic, hormonal and environmental factors, most of which have not been defined. Genetic linkages, especially involving major histocompatibility complex (MHC) genes, have been reported for Sjögren’s syndrome but it is not clear if, or how, the associated genes are involved in the development of the disease
]. Additional non-MHC genes have also been linked with the development of Sjögren’s syndrome.
In addition to genetic predisposition, some studies suggest that infection of a genetically-susceptible individual by a virus or other pathogen might trigger the development of an autoimmune disease
]. The proposed mechanisms include activation of the innate immune system, release of self antigens from damaged or apoptotic tissues, and molecular mimicry that results in activation of T cells and/or B cells that react with tissue antigens
Both the innate and the adaptive immune systems are involved in the pathogenesis of Sjögren’s syndrome. The type I interferon (IFN) pathway, which plays an important role in the innate immune response to viruses, is also thought to play an important role in the development of Sjögren’s syndrome and other autoimmune disorders, including SLE
]. Moreover, type I IFNs can activate the adaptive immune system directly, by binding to IFN receptors on antigen presenting cells, T cells and B cells, or indirectly, by inducing the production and release of cytokines and chemokines that bind to these cells.
Autoantibodies to intracellular antigens, notably the nuclear proteins SSA/Ro and SSB/La, are found in the sera of many patients with Sjögren’s syndrome. These autoantibodies are thought to develop when intracellular antigens, some of which have undergone proteolytic cleavage that reveals new antigenic epitopes, become “visible” to the immune system in membrane blebs on the surface of apoptotic cells
]. Alternatively, antigenic epitopes from bacteria and viruses, including Epstein-Barr virus (EBV) and coxsackie virus, may act as molecular mimics that trigger the development of antibodies that cross react with similar epitopes on target tissue autoantigens
]. Although autoantibodies to intracellular antigens are useful in the diagnosis of Sjögren’s syndrome, it is not clear if they play a direct role in the development of salivary gland and lacrimal gland damage and hypofunction. In contrast, autoantibodies to the M3 muscarinic acetylcholine receptor (M3R) have been directly implicated in salivary gland hypofunction in the nonobese diabetic (NOD) mouse model of Sjögren’s syndrome
]. Importantly, function-inhibiting anti-M3R autoantibodies are found in the sera of many patients with Sjögren’s syndrome
Current therapy for Sjögren’s syndrome usually consists of palliative treatment that relieves the symptoms of dry eye and dry mouth, but fails to modify the underlying disease. Novel disease-modifying treatment strategies, based on recent immunological insights in Sjögren's syndrome and other autoimmune diseases, have met with mixed results
]. For example, in recent clinical trials, treatment of Sjögren's syndrome patients with a B cell-depleting anti-CD20 monoclonal antibody (rituximab) led to significant improvement of the stimulated whole saliva flow rate and a reduction in parotid gland inflammation
]. In contrast, TNFα inhibitors have been ineffective in the treatment of Sjögren's syndrome. Detailed studies on the immune response in Sjögren’s syndrome patients treated with one of the inhibitors (etanercept) revealed an increase in the circulating levels of TNFα
]. These results suggest that TNFα may not play a pivotal role in the disease and that other therapeutic targets must be identified.
Despite a large body of evidence gathered over the past 60 years, significant gaps still exist in our understanding of Sjögren’s syndrome. Recent gene expression and proteomic studies have identified many genes and pathways that may play a role in the pathogenesis of Sjögren’s syndrome
]. However, validation of these data will require significant additional effort. As an initial step in this validation, we have compiled the published data on Sjögren’s syndrome that is not derived from gene expression or proteomic studies. No such unifying database currently exists. Through data curation, the existing data have been uniformly formatted to allow systematic retrieval and comparisons to newly generated gene expression data. As an example of its functionality, the Sjögren's Syndrome Knowledge Base (SSKB) was analyzed for biological functions and pathways that are likely to play a role in the disease.