Precise probes of type II interferon activity define the origin of interferon signatures in target tissues in rheumatic diseases

Abstract

Elucidating the molecular pathways active in pathologic tissues has important implications for defining disease subsets, selecting therapy, and monitoring disease activity. The development of therapeutics directed at IFN-α or IFN-γ makes the discovery of probes that report precisely on the activity of different IFN pathways a high priority. We show that, although type I and II IFNs induce the expression of a largely overlapping group of molecules, precise probes of IFN-γ activity can be defined. Used in combination, these probes show prominent IFN-γ effects in Sjögren syndrome (SS) tissues. In contrast, dermatomyositis muscle shows a dominant type I IFN pattern. Interestingly, heterogeneity of IFN signatures exists in patients with SS, with some patients demonstrating a predominant type I pattern. The biochemical patterns largely distinguish the target tissues in patients with SS from those with dermatomyositis and provide a relative weighting of the effects of distinct IFN pathways in specific biopsies. In SS, type I and II IFN effects are localized to the same epithelial cells, surrounded by inflammatory cells expressing IFN-γ–induced proteins, suggesting reinforcing interactions. Precise probes of the different IFN pathways active in tissues of complex rheumatic diseases will be critical to classify disease, elucidate pathogenesis, and select therapy.

Blockade of Interferon‐γ Normalizes Interferon‐Regulated Gene Expression and Serum CXCL10 Levels in Patients With Systemic Lupus Erythematosus

“…Type I and type II IFNs signal through distinct receptors (IFNα receptor and IFNγ receptor, respectively), but their signaling pathways overlap with variable and, at times, opposing functional effects 11, 12, 13. Recent investigations of synovial tissue from subjects with rheumatic diseases have identified specific gene transcripts and proteins that may be useful for distinguishing between the 2 IFN pathways 14, 15. Data supporting a pathogenic role for IFNγ in SLE include findings from murine models of SLE 16, 17, 18, 19, 20 and from in vitro studies of blood from SLE patients 21, 22.…”

Endoplasmic reticulum stress causes autophagy and apoptosis leading to cellular redistribution of the autoantigens Ro/Sjögren's syndrome-related antigen A (SSA) and La/SSB in salivary gland epithelial cells

“…IFN 'signature' is evident in minor salivary gland biopsies from these patients [23,24]. Interestingly, Smith et al have shown that ER stress significantly augments type I IFN immune response in the setting of pathogen challenge, such as viral infection or endogenous damage [25,26].…”

Sjögren’s syndrome, should we sign?

“…[15] Although the initial evidence accredited the importance of type I IFNs in pSS, more recent data indicate that not only type I IFN genes, but also type II IFN genes are involved. Hall et al [16] observed that the majority of genes induced by IFNα (type I IFN) are also induced by IFNγ (type II IFN) and that only few genes are exclusively induced by IFNα. 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.…”

“…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.…”

“…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.…”