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

Zana Brkic, Naomi I Maria, Cornelia G van Helden-Meeuwsen, Joop P van de Merwe, Paul L van Daele, Virgil A Dalm, Manon E Wildenberg, Wouter Beumer, Hemmo A Drexhage, Marjan A Versnel, Zana Brkic, Naomi I Maria, Cornelia G van Helden-Meeuwsen, Joop P van de Merwe, Paul L van Daele, Virgil A Dalm, Manon E Wildenberg, Wouter Beumer, Hemmo A Drexhage, Marjan A Versnel

Abstract

Objective: To 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).

Methods: Expression 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.

Results: An 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.

Conclusions: The 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.

Figures

Figure 1
Figure 1
(A) Gene expression of 11 interferon (IFN) type I inducible genes in patients with primary Sjögren's syndrome (pSS) (n=69) and healthy controls (HC) (n=44). To compare means the Mann–Whitney U test was applied. (B) Heat map showing gene expression of five interferon (IFN) type I inducible genes in monocytes of patients with pSS (n=69) and HC (n=44). On the left the patients with pSS are depicted and subdivided into IFN type I signature-positive patients and IFN type I signature-negative patients. On the right the HC are depicted. Red colour indicates high gene expression. (C) Distribution of IFN scores in IFN type I signature-positive and -negative patients and HC. IFN type I-positive cases are depicted in red. Blue lines depict medians. (D) Heat map showing gene expression of IFN type I inducible genes in monocytes of patients with pSS (n=24) at two different time points (average period between two measurements 3.6±2.5 years). (E) No significant differences detected between two time points using the dependent t test.
Figure 2
Figure 2
(A) EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) scores in interferon (IFN) type I signature-positive and -negative patients with primary Sjögren's syndrome (pSS) (n=38). (B) IFN scores in patients with pSS positive or negative for anti-SSA (both Ro52 and Ro60) and anti-SSB (n=69). (C) Rheumatoid factor levels in IFN type I signature-positive and -negative patients with pSS (n=50). (D) IgG levels in IFN type I signature-positive and -negative patients with pSS (n=68). (E) C3 levels in IFN type I signature-positive and -negative patients with pSS (n=46). (F) Absolute lymphocyte levels in IFN type I signature-positive and -negative patients with pSS (n=42). (G) Absolute neutrophil levels in IFN type I signature-positive and -negative patients with pSS (n=41). Independent t test was used to compare means in E–G, where horizontal bars represent the means. Mann–Whitney U test was used to compare means in A–D, where horizontal bars represent the medians. In B medians and IQR are depicted; ** represents p value

Figure 3

(A) B cell activating factor…

Figure 3

(A) B cell activating factor (BAFF) mRNA expression in monocytes in patients with…

Figure 3
(A) B cell activating factor (BAFF) mRNA expression in monocytes in patients with primary Sjögren's syndrome (pSS) (n=69) and healthy controls (HC) (n=44). BAFF mRNA expression was determined by real time quantitative-PCR. (B) Correlation between interferon (IFN) type I score and BAFF mRNA expression in monocytes in patients with pSS (n=69). (C) Induction of BAFF mRNA expression in THP-1 cells by incubation with 50% serum of IFN type I signature-positive patients with pSS (n=9) and IFN type I signature-negative patients with pSS (n=7) in the presence of a blocking IFN type I receptor antibody. Expression is relative compared with the mean expression in HC (n=8). (D) BAFF protein levels in serum of patients with pSS (n=68) and HC (n=42) measured by ELISA. (E) Correlation between serum BAFF protein and IFN scores in patients with pSS (n=68). (F) Correlation between serum BAFF protein and BAFF mRNA expression in monocytes of patients with pSS (n=68). The correlation coefficients (r) and p values are shown. For correlations Spearman's ρ correlation test was used and to compare means the Mann–Whitney U test was used.
Figure 3
Figure 3
(A) B cell activating factor (BAFF) mRNA expression in monocytes in patients with primary Sjögren's syndrome (pSS) (n=69) and healthy controls (HC) (n=44). BAFF mRNA expression was determined by real time quantitative-PCR. (B) Correlation between interferon (IFN) type I score and BAFF mRNA expression in monocytes in patients with pSS (n=69). (C) Induction of BAFF mRNA expression in THP-1 cells by incubation with 50% serum of IFN type I signature-positive patients with pSS (n=9) and IFN type I signature-negative patients with pSS (n=7) in the presence of a blocking IFN type I receptor antibody. Expression is relative compared with the mean expression in HC (n=8). (D) BAFF protein levels in serum of patients with pSS (n=68) and HC (n=42) measured by ELISA. (E) Correlation between serum BAFF protein and IFN scores in patients with pSS (n=68). (F) Correlation between serum BAFF protein and BAFF mRNA expression in monocytes of patients with pSS (n=68). The correlation coefficients (r) and p values are shown. For correlations Spearman's ρ correlation test was used and to compare means the Mann–Whitney U test was used.

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