MxA as a clinically applicable biomarker for identifying systemic interferon type I in primary Sjögren's syndrome

Abstract

ObjectiveTo establish an easy and practical assay for identifying systemic interferon (IFN) type I bioactivity in patients with primary Sjögren's syndrome (pSS). The IFN type I signature is present in over half of the pSS patients and identifies a subgroup with a higher disease activity. This signature is currently assessed via laborious expression profiles of multiple IFN type I-inducible genes.MethodsIn a cohort of 35 pSS patients, myxovirus-resistance protein A (MxA) was assessed as a potential biomarker for type I IFN activity, using an enzyme immunoassay (EIA) on whole-blood and flow cytometric analyses (fluorescence-activated cell sorting, FACS) of isolated CD14 monocytes. In addition, potential biomarkers such as CD64, CD169 and B cell-activating factor (BAFF) were simultaneously analysed in CD14 monocytes using FACS. The IFNscore, a measure for total type I IFN bioactivity, was calculated using expression values of the IFN type I signature genes—IFI44, IFI44L, IFIT3, LY6E and MX1—in CD14 monocytes, determined by real-time quantitative PCR.ResultsIFNscores correlated the strongest with monocyte MxA protein (r=0.741, p<0.001) and whole-blood MxA levels (r=0.764, p<0.001), weaker with CD169 (r=0.495, p<0.001) and CD64 (r=0.436, p=0.007), and not at all with BAFF protein. In particular, whole blood MxA levels correlated with EULAR Sjögren's Syndrome Disease Activity Index scores and numerous clinical pSS parameters. Interestingly, patients on hydroxychloroquine showed reduced MxA levels (EIA, p=0.04; FACS p=0.001).ConclusionsThe MxA assays were excellent tools to assess IFN type I activity in pSS, MxA-EIA being the most practical. MxA levels associate with features of active disease and are reduced in hydroxychloroquine-treated patients, suggesting the clinical applicability of MxA in stratifying patients according to IFN positivity.

Safety of treatments for primary Sjögren’s syndrome

“…[63] Moreover, a recent report has shown that HCQ impairs systemic interferon alpha (IFNα) production in pSS, which is hypothesized to play an important role in the pathogenesis of pSS. [64] It has been shown, however, that administration of HCQ did not resolve sicca signs and symptoms or extraglandular manifestations in pSS patients. [65,66] In both trials in pSS, serious AEs rarely occurred.…”

Sjögren’s syndrome, should we sign?

“…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 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.…”

“…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.…”

“…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.…”

Avaliação da imunidade antiviral no lavado nasal de pacientes com imunodeficiência comum variável em vigência de rinossinusites virais

“…É induzida exclusivamente por IFN tipo I e tipo III como uma resposta específica a infecções virais e seus níveis basais em indivíduos saudáveis e imunotolerantes são baixos (250,251) .…”