Prevalence of interferon type I signature in CD14 monocytes of patients with Sjögren's syndrome and association with disease activity and BAFF gene expression

Abstract

ObjectiveTo determine the prevalence of upregulation of interferon (IFN) type I inducible genes, the so called ‘IFN type I signature’, in CD14 monocytes in 69 patients with primary Sjögren's syndrome (pSS) and 44 healthy controls (HC) and correlate it with disease manifestations and expression of B cell activating factor (BAFF).MethodsExpression of IFI44L, IFI44, IFIT3, LY6E and MX1 was measured using real time quantitative PCR in monocytes. Expression values were used to calculate IFN type I scores for each subject. pSS patients positive for the IFN type I signature (IFN score≥10) and patients negative for the signature (IFN score<10) were then compared for clinical disease manifestations and BAFF expression. A bioassay using a monocytic cell line was performed to study whether BAFF mRNA expression was inducible by IFN type I activity in serum of patients with pSS.ResultsAn IFN type I signature was present in 55% of patients with pSS compared with 4.5% of HC. Patients with the IFN type I signature showed: (a) higher EULAR Sjögren's Syndrome Disease Activity Index scores; higher anti-Ro52, anti-Ro60 and anti-La autoantibodies; higher rheumatoid factor; higher serum IgG; lower C3, lower absolute lymphocyte and neutrophil counts; (b)higher BAFF gene expression in monocytes. In addition, serum of signature-positive patients induced BAFF gene expression in monocytes.ConclusionsThe monocyte IFN type I signature identifies a subgroup of patients with pSS with a higher clinical disease activity together with higher BAFF mRNA expression. Such patients might benefit from treatment blocking IFN type I production or activity.

HIV-1–Mediated BAFF Secretion in Macrophages Does Not Require Endosomal TLRs, Type-I IFN, and Nef, but Depends on the Cellular Phenotype Status

“…Increased BAFF levels seen in certain chronic autoimmune disorders and chronic inflammatory diseases were reported to be associated with an elevated type-I IFN response (51)(52)(53). Moreover, we reported that HIV-1-directed release of type-I IFN by pDCs plays a determinant role in BAFF production by monocytes (30).…”

Increase of Intracellular BAFF in B Cells of Sjögren’s Patients Is Not Affected by Decrease of BAFFR

“…There are consistent reports that monocytes are contributing to the elevated of BAFF in SjS patients (8). Serum level of BAFF in SjS patients correlates with BAFF mRNA expression (2). Peripheral blood monocytes of SjS patients produce significantly higher amount of sBAFF in vitro both spontaneously and after stimulation with interferon γ (22).…”

Sjögren’s syndrome, should we sign?

“…[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 blood from pSS patients [12][13][14] indicates that IFN activity is clearly not only restricted to the target tissue itself, but is a more systemic feature of the disease. Possibly, continued activation of type I IFN production by triggers such as virus, autoantigen, and immune complexes in combination with a special genetic background and lack of proper control and regulation may be responsible for the observed overproduction of type I IFN in pSS patients.…”

“…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.…”

“…Indeed, although in a small group of patients the IFN signature was reported to be longitudinally stable over time (3.6 ± 2.5 years), the signature seems to change in a number of patients during this period. [14] Long-term cohort studies with larger numbers of pSS patients are urgently needed to see whether the IFN signature changes over time, whether and how it is associated with various serological and clinical disease parameters, and whether treatment can affect the signature. To compare signatures from different studies a unifying definition of the signature is warranted.…”