Sjögren’s syndrome, should we sign?

Type I interferons (IFNs) play a significant role in the pathogenesis of primary Sjögren’s syndrome (pSS). Derailed IFN production may contribute to overactivation of the innate and adaptive immune system, finally leading to B-cell hyperactivity, autoimmunity, and dysfunctioning of the glandular tissue. In pSS patients many IFN-stimulated genes and proteins are overexpressed, resulting in a so-called IFN signature. Although initially mainly type I inducible genes were believed to be overexpressed in pSS patients, more recent evidence indicates that also type II IFN genes can be overrepresented. Not all pSS patients seem to exhibit an IFN signature and the key question that remains to be answered is whether the presence of a type I and/or type II IFN signature reflects merely a more severe variant or more active phase of the disease or that it identifies a distinct subgroup of patients with a different etiopathogenesis. Type I IFNs have been implicated in the pathogenesis of several systemic autoimmune diseases, including pSS. [1] pSS is characterized by a chronic inflammatory process of the salivary glands and lacrimal glands, leading to the dominant complaints of dry mouth and dry eyes. The disease is, however, certainly not restricted to exocrine glands as reflected by complaints of fatigue and pain and a wide range of extraglandular manifestations, explaining the diverse clinical presentation of pSS patients. Type I IFN comprises a large group of subtypes of IFNs of which IFNα and IFNβ are the most studied proteins. These subtypes share similar functions. Type I IFNs are prevalently induced by the binding of (viral) DNA/RNA to transmembrane pattern recognition receptors (Toll-like receptors (TLRs) in particular TLR3, TLR7, and TLR9) or to cytosolic sensors (e.g. RIG-1, MDA-5). Most body cells, including epithelial cells of exocrine glands, can produce IFNβ, whereas plasmacytoid dendritic cells (pDCs) are specialized to produce large amounts of IFNα, but also produce other subtypes; pSS patients express higher serum levels of type I IFN (IFNα) compared to healthy controls. [2] Other studies, however, detected serum IFNα only in a small proportion of pSS patients. [3] IFNα producing pDCs are found in the glandular infiltrates from pSS patients. [3,4] Not only microbial-derived nucleic acids, but also autologous nucleic acids and immune complexes composed of autoantibodies directed to RNA binding proteins are strong stimulants of IFNα production by pDCs in pSS patients. [3] These autoantigens (mostly SSA/SSB) are possibly derived from the intrinsically activated epithelial cells. [5] In turn, IFNs can upregulate the expression of these autoantigens by the epithelial cells. Furthermore, B-cells from patients with pSS can stimulate directly the secretion of IFNα by pDCs. [6] IFN production is regulated by various IFN regulatory factors (IRFs) and type I IFN production by pDCs is dependent on the transcription factors IRF5 and IRF7. [7] The importance of IRF5 in pSS is illustrated by genome-wide association studies that identified a polymorphism in IRF5 associated with pSS. [8] Another pSS-associated gene polymorphism is stat4, a transcription factor involved in the signaling of type I IFN, after binding to its receptor the type I IFN receptor (IFNAR). This receptor is widely expressed by many different cell types and binds all isoforms of type I IFNs. [9] IFNAR signaling results in the transcription of several genes that renders the cells with a kind of antiviral state, in order to protect the body from viral infections. Many other genes that are stimulated by type I IFN modulate both innate and adaptive immune responses, for example by increased antigen presentation, cytokine and chemokine production, and stimulation of effector Tand B-cell responses. Indeed, most evidence for a crucial role of (type I) IFN in pSS comes from studies analyzing mRNA transcripts and protein expression levels of genes stimulated by IFN. Measuring the expression of IFN-inducible genes also overcomes the problem that there are several type I IFN subtypes, as a result of which assessment of a single subtype I IFN does not provide clues about the overall type I IFN activity. [10] Initial microarray analysis of mRNA extracted from minor salivary gland tissue of pSS patients revealed an upregulated expression of many IFN-stimulated genes, the so-called IFN signature, compared to nonpSS sicca patients. [4,11] The finding that the increased expression of many (type I) IFN-stimulated genes can also been observed in circulating monocytes, peripheral blood mononuclear cells, and whole EXPERT REVIEW OF CLINICAL IMMUNOLOGY, 2016 VOL. 12, NO. 4, 365–367 http://dx.doi. org/10.1586/1744666X.2016. 1130624