Activation of IFN pathways and plasmacytoid dendritic cell recruitment in target organs of primary Sjögren’s syndrome

Abstract

Gene expression analysis of target organs might help provide new insights into the pathogenesis of autoimmune diseases. We used global gene expression profiling of minor salivary glands to identify patterns of gene expression in patients with primary Sjögren’s syndrome (pSS), a common and prototypic systemic autoimmune disease. Gene expression analysis allowed for differentiating most patients with pSS from controls. The expression of 23 genes in the IFN pathways, including two Toll-like receptors (TLR8 and TLR9), was significantly different between patients and controls. Furthermore, the increased expression of IFN-inducible genes, BAFF and IFN-induced transmembrane protein 1, was also demonstrated in ocular epithelial cells by quantitative RT-PCR. In vitro activation showed that these genes were effectively modulated by IFNs in salivary gland epithelial cells, the target cells of autoimmunity in pSS. The activation of IFN pathways led us to investigate whether plasmacytoid dendritic cells were recruited in salivary glands. These IFN-producing cells were detected by immunohistochemistry in all patients with pSS, whereas none was observed in controls. In conclusion, our results support the pathogenic interaction between the innate and adaptive immune system in pSS. The persistence of the IFN signature might be related to a vicious circle, in which the environment interacts with genetic factors to drive the stimulation of salivary TLRs.

A possible mechanism for endogenous activation of the type I interferon system in myositis patients with anti–Jo‐1 or anti–Ro 52/anti–Ro 60 autoantibodies

“…The IFN␣ in the muscle tissue of these patients did not seem to be produced locally by BDCA-2-positive cells, since these were only seen as scattered cells in a few DM patients. The IFN␣ in DM patients may therefore be produced not only in muscles, but also in other organs, as previously observed (e.g., in the skin of SLE patients and in salivary glands of primary SS patients) (14,(31)(32)(33).…”

Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjögren's syndrome

“…3,4 This is interesting as an activation of the type I interferon (IFN) system in patients with primary SS has been shown convincingly. Thus, IFN-a production 5 and the presence of plasmacytoid dendritic cells 6 in minor salivary gland biopsies have been shown. Gene expression profiling of minor salivary glands have shown upregulation of type I IFN-inducible genes, which is called an IFN signature.…”

“…Gene expression profiling of minor salivary glands have shown upregulation of type I IFN-inducible genes, which is called an IFN signature. 6,7 In addition, sera from primary SS patients together with material from apoptotic or necrotic cells induce IFN-a production in peripheral blood mononuclear cells in vitro, and this IFN-inducing ability of primary SS patient serum correlates with the presence of anti-SS-A/SS-B antibodies. 5 High serum IFN activity had also been shown in a proportion of anti-SS-A antibody-positive patients with primary SS or SLE.…”

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). Similar findings have been reported in systemic lupus erythematosus, with the same IFN signature observed in both PBMCs and the kidney (3).…”