Type I and II interferon signatures in Sjogren's syndrome pathogenesis: Contributions in distinct clinical phenotypes and Sjogren's related lymphomagenesis

Abstract

Both type I and II interferons (IFNs) have been implicated in the pathogenesis of Sjogren's syndrome (SS). We aimed to explore the contribution of type I and II IFN signatures in the generation of distinct SS clinical phenotypes including lymphoma development. Peripheral blood (PB) from SS patients (n=31), SS patients complicated by lymphoma (n=13) and healthy controls (HC, n=30) were subjected to real-time PCR for 3 interferon inducible genes (IFIGs) preferentially induced by type I IFN, 2 IFIGs preferentially induced by IFNγ as well as for IFNα and IFNγ genes. The same analysis was performed in minor salivary gland tissues (MSG) derived from 31 SS patients, 10 SS-lymphoma patients and 17 sicca controls (SC). In PB and MSG tissues, overexpression of both type I and type II IFIGs was observed in SS patients versus HC and SC, respectively, with a predominance of type I IFN signature in PB and a type II IFN signature in MSG tissues. In SS-lymphoma MSG tissues, lower IFNα, but higher IFNγ and type II IFIG transcripts compared to both SS and SC were observed. In receiver operating characteristic curve analysis, IFNγ/IFNα mRNA ratio in MSG tissues showed the best discrimination for lymphoma development. Discrete expression patterns of type I and II IFN signatures might be related to distinct SS clinical phenotypes. Additionally, IFNγ/IFNα mRNA ratio in diagnostic salivary gland biopsies is proposed as a novel histopathological biomarker for the prediction of in situ lymphoma development in the setting of SS.

Sjögren’s syndrome, should we sign?

“…Taking this into account, it became apparent that both type I and type II IFN-stimulated genes can be upregulated in peripheral blood and salivary gland tissue of pSS patients. [16][17][18] Based on a small set of mRNA transcripts that are preferentially induced by either type I IFN or type II IFN, it was concluded that in the peripheral blood of pSS patients type I IFN-stimulated genes appear to dominate, whereas the opposite is the case in the glandular tissue where type II IFN-stimulated genes are the most pronounced. [17,18] Various approaches and definitions are being used to calculate an IFN score and to assign a type I or type II IFN signature to pSS patients.…”

“…[16][17][18] Based on a small set of mRNA transcripts that are preferentially induced by either type I IFN or type II IFN, it was concluded that in the peripheral blood of pSS patients type I IFN-stimulated genes appear to dominate, whereas the opposite is the case in the glandular tissue where type II IFN-stimulated genes are the most pronounced. [17,18] Various approaches and definitions are being used to calculate an IFN score and to assign a type I or type II IFN signature to pSS patients. Despite these discrepancies is it clear that not all pSS patients upregulate type I and II IFN genes to the same extent and three groups of IFN profiles have been identified in pSS patients: type I IFN dominant, type II IFN dominant, or a mixedtype I/II IFN phenotype.…”

“…Approximately 60% of the pSS patient have a high type I IFN score (signature) in blood based upon the expression of a few (2-5) type I IFN-stimulated genes or whole blood myxovirusresistance protein A levels. [10,14,18] A significant number (slightly less than half of these patients) concomitantly also have a type II IFN signature; only relatively few pSS patients (7%) exhibit only a type II IFN signature. [18] Based upon the expression of a single IFN-induced protein, Hall et al [17] observed that 17% of the patients demonstrated high type I IFN activity in the minor salivary glands, 21% high type II IFN activity, and 21% exhibited a mixed-type I/II IFN profile.…”

“…[10,14,18] A significant number (slightly less than half of these patients) concomitantly also have a type II IFN signature; only relatively few pSS patients (7%) exhibit only a type II IFN signature. [18] Based upon the expression of a single IFN-induced protein, Hall et al [17] observed that 17% of the patients demonstrated high type I IFN activity in the minor salivary glands, 21% high type II IFN activity, and 21% exhibited a mixed-type I/II IFN profile. Thus, there is significant heterogeneity in type I and type II IFN activities between blood versus salivary glands and amongst different individual patients.…”

“…high IFN score) and how and in which tissue this activity has been determined, the emerging picture is that pSS patients with such a signature have a more severe phenotype reflected not only serologically for example by higher serum IgG levels, more (and higher titers of) autoantibodies (rheumatoid factor, ANA, anti-SSA, and anti-SSB antibodies), and lower C3 levels, but also by lower salivary and tear flow rates, and higher disease activity as measured by the ESSDAI scores. [10,[16][17][18] The key question therefore is whether the (operationally defined) type I and/or type II signature reflects merely a more severe variant or more active phase of the disease or identifies a distinct subgroup of patients with a different etiopathogenesis. The absence of an IFN signature in pSS patients does not necessarily imply that IFN (type I/II) does not play a role.…”