Gene expression profiling of minor salivary glands clearly distinguishes primary Sjögren's syndrome patients from healthy control subjects

Abstract

Objective. To identify gene expression signatures in minor salivary glands (MSGs) from patients with primary Sjögren's syndrome (SS).Methods. A 16K complementary DNA microarray was used to generate gene expression profiles in MSGs obtained from 10 patients with primary SS and 10 control subjects. The data were analyzed by 2 different strategies, one strict primary analysis and one subanalysis that allowed for inclusion of genes with no signal in more than 3 samples from each group. The results were validated by quantitative reverse transcriptasepolymerase chain reaction techniques.Results. We found a distinct difference in gene expression levels in MSGs, enabling a simple class prediction method to correctly classify 19 of the 20 samples as either patient or control, based on the top 5 differentially expressed genes. The 50 most differentially expressed genes in the primary SS group compared with the control group were all up-regulated, and a clear pattern of genes involved in chronic inflammation was found. CXCL13 and CD3D were expressed in >90% of primary SS patients and in <10% of the controls. Lymphotoxin ␤, as well as a number of major histocompatibility complex genes, cytokines, and lymphocyte activation factors, manifested its role in the pathogenesis of SS. Numerous type I interferon genes related to virus infection were found among the top 200 genes, with increased expression in primary SS. Interestingly, the expression of carbonic anhydrase II, which is essential in saliva production and secretion, and the apoptosis regulator Bcl-2-like 2 were down-regulated in primary SS patients.Conclusion. We have identified distinct gene expression profiles in MSGs from patients with primary SS that provide new knowledge about groups of genes that are up-regulated or down-regulated during disease, constituting an excellent platform for forthcoming functional studies.

The unexpected role of lymphotoxin β receptor signaling in carcinogenesis: from lymphoid tissue formation to liver and prostate cancer development

“…Moreover, tertiary lymphoid organs also frequently appear in autoimmune diseases such as Sjo¨gren's syndrome (Hjelmervik et al, 2005), chronic obstructive pulmonary disease, rheumatoid arthritis (RA) (Young et al, 1984;Takemura et al, 2001), Graves' disease (Armengol et al, 2003;Aust et al, 2004) or multiple sclerosis (Prineas 1979;Serafini et al, 2004). In most of these diseases, elevated expression of LT or its target genes has been detected, supporting LT's role in lymphoid neogenesis (Drayton et al, 2006).…”

The type I interferon system in systemic lupus erythematosus

“…This IFN␣-inducing capacity of pSS sera was associated with both lymphocytic foci in the labial salivary glands and several extraglandular disease manifestations (e.g., dermatologic, hematologic, and pulmonary involvement). Gene expression profiles of minor salivary gland biopsy specimens also show an up-regulation of type I IFNregulated genes (105). Skin biopsy specimens obtained from patients with psoriasis display increased expression of mRNA for both IFN␣ and IFN-induced proteins as well as an infiltration of NIPCs/PDCs (46,106).…”

The CGGGG insertion/deletion polymorphism of the IRF5 promoter is a strong risk factor for primary Sjögren's syndrome

“…The results of recent studies of pathogenic mechanisms in primary SS have supported the notion that the interferon (IFN) pathway plays a role through an IFN signature, both in peripheral blood mononuclear cells (PBMCs) and in salivary glands (1,2). Moreover, plasmacytoid dendritic cells, the professional cells that secrete IFN␣, are present in salivary glands, the target organ of the autoimmune process (2).…”