Research ArticleArticle

Activation of the Interferon Pathway in Peripheral Blood of Patients with Sjögren’s Syndrome

OSAMU KIMOTO, JIN SAWADA, KUMIKO SHIMOYAMA, DAISUKE SUZUKI, SATOKI NAKAMURA, HIDEHARU HAYASHI and NORIYOSHI OGAWA
The Journal of Rheumatology February 2011, 38 (2) 310-316; DOI: https://doi.org/10.3899/jrheum.100486

Abstract

Objective. DNA microarray analysis and quantitative real-time polymerase chain reaction (PCR) were performed to identify key target genes in peripheral blood from patients with Sjögren’s syndrome (SS).

Methods. DNA microarray analysis was performed in 19 patients with SS (all women) and 10 healthy controls (5 men and 5 women) using a low-density DNA microarray system with 778 genes. For confirmation, the expression of upregulated genes was analyzed by quantitative real-time PCR in another 37 SS patients (35 women and 2 men) and 9 healthy controls (8 women and 1 man). Relationships between gene signatures and various clinical measures, such as disease duration, symptoms and signs, complications, immunological findings, and salivary and lacrimal functions, were analyzed.

Results. Interferon-α (IFN-α)-inducible protein 27 (IFI27) showed the most significant difference between SS patients and controls in the microarray screening. We performed quantitative RT-PCR for IFI27. IFI27 gene expression level was increased in patients with SS compared with controls (p < 0.01) by real-time PCR, supporting our observations from the microarray data. The level of IFI27 was significantly correlated with serum IgG levels (r = 0.462, p < 0.01) and ß2-microglobulin (r = 0.385, p < 0.05), soluble interleukin 2 receptor (r = 0.473, p < 0.01), erythrocyte sedimentation rate (r = 0.333, p < 0.05), and antinuclear antibody titer (speckled pattern; r = 0.445, p < 0.01).

Conclusion. Our results suggest that upregulation of IFN-inducible genes in SS patients is a systemic phenomenon, and IFN may play an important role in the pathogenesis of SS. The expression level of IFI27 could be an effective and specific biomarker associated with SS.

Sjögren’s syndrome (SS) is characterized by autoimmune exocrinopathy preferentially involving the salivary and lacrimal glands, which causes dry mouth (xerostomia) and dry eyes (xerophthalmia). Extraglandular manifestations are present at varying frequencies and include arthralgia/arthritis, Raynaud’s phenomenon, lymphadenopathy, and vasculitis, as well as lung and kidney involvement. Patients with systemic autoimmune disorders other than primary SS, especially rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and dermatomyositis (DM), may also fulfill the criteria for SS and are then defined as secondary SS. The etiology of SS remains unclear, but studies suggest that pathogenesis is associated with both genetic predispositions and environmental factors1,2.

Recently, gene expression analyses have provided an important perspective on unknown biological phenomena. Microarray analysis for diagnostic and prognostic biomarker signatures was first developed in the field of cancer. Blood profiling studies were extended rapidly to other diseases, and characteristic signatures were reported in patients with autoimmune diseases, including SS, SLE, DM, and RA3,4. Global profiling of gene expression in peripheral blood mononuclear cells (PBMC) indicated the upregulation of interferon (IFN)-inducible genes in patients with SLE compared with healthy controls5. Pathological overproduction of type I IFN has been noted in SLE and DM6,7,8. Further, the magnitude of overexpression of IFN-inducible genes is greater and is correlated with disease activity in SLE and DM5,9. In another study, the IFN expression signature was correlated with disease activity of patients with pediatric lupus10.

It recently became apparent that SS is also associated with activation of the type I IFN pathway. cDNA microarray analysis revealed that numerous type I IFN-inducible genes were highly expressed in SS salivary glands11,12,13. Further, the IFN pathway and inflammation-related genes, including the Toll-like receptor (TLR) family, T-cell receptor, STAT-1, and IP-10, are overexpressed in the SS salivary gland11,12,14,15. IFN production is detected in both sera and salivary gland biopsy specimens16,17. These findings suggest that IFN-related genes could be useful biomarkers in SS. However, it would be better to use more easily accessible materials than salivary glands for screening.

We examined whether expression levels of these genes are correlated with severity of the disease. We attempted to identify potential biomarkers associated with SS using peripheral blood of Japanese patients with SS.

MATERIALS AND METHODS

Patients and controls

Blood was obtained from 19 SS patients (all women), 10 healthy controls (5 men and 5 women), and 10 disease controls (10 patients with RA) for DNA microarray analysis. Of the 19 SS patients, 5 had secondary SS [SLE 1, scleroderma (SSc) 4] and 2 had been treated with low-dose corticosteroids. For real-time polymerase chain reaction (PCR), another 37 SS patients (35 women and 2 men; no overlap with the microarray group) and 9 healthy controls (8 women and 1 man) were analyzed. Of the 37 patients with SS, 9 had secondary SS (RA 5, mixed connective tissue disease 2, SSc 2) and 8 had been treated with corticosteroids. The profiles of SS patients and controls are shown in Tables 1 and 2. Healthy volunteers with no history of serious illness during the previous 6 months were also recruited as controls. Written informed consent was obtained from all participants. This study was performed in accord with the guidelines of the Independent Ethical Committee of Hamamatsu University School of Medicine, which are consistent with the Declaration of Helsinki on Ethical Principles for Medical Research Involving Human Subjects.

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Table 1.

Clinical features of 19 patients with SS (all women) and 10 healthy controls (5 men and 5 women) examined by DNA microarray analysis.

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Table 2.

Clinical features of 37 patients with SS (35 women and 2 men) and 9 healthy controls (8 women and 1 man) analyzed by quantitative real-time PCR.

All SS patients fulfilled the 1999 revised Japanese criteria for classification of SS18. All RA patients fulfilled the American College of Rheumatology 1987 revised criteria for RA19.

cDNA microarray analysis

Total RNA was isolated from 2.5 ml whole blood with a PAXgene Blood RNA Kit (Qiagen, Hilden, Germany) according to the manufacturer’s instructions. We prepared a low-density DNA microarray for mRNA expression profiling in whole blood. Genes for this microarray were selected from the public database of SAGE results (Department of Molecular Preventive Medicine, School of Medicine, The University of Tokyo [Japanese]; http://133.11.248.12) from activated blood cells, such as T cells, dendritic cells, monocytes, and macrophages. Microarray analysis was performed using a DNA microarray system (Genomessage V2, GEO accession no. GPL5460; Japan Genome Solutions, Tokyo, Japan) with 778 genes. Reference RNA was established from a mixture of whole-blood RNA samples from healthy volunteer donors. Competitive hybridization of Cy3-labeled reference and Cy5-labeled sample cDNA on the microarray was carried out with chamber systems (Agilent Technologies, Palo Alto, CA, USA). The Cy5/Cy3 ratio for each mRNA signal was calculated. The relationships of gene signature with various clinical measures, such as disease duration, symptoms and signs, complications, immunological findings, and salivary and lacrimal functions, were analyzed.

RNA extraction and cDNA synthesis for real-time PCR

Total RNA was isolated from 2.5 ml whole blood with a PAXgene Blood RNA Kit. Quality of RNA was confirmed from the ratio of absorbance at 260 nm to that at 280 nm (A260/A280 ratio), and RNA samples with a ratio > 1.8 were used for quantitative PCR. Samples were quantified based on the A260, and 1000 ng RNA was used as the template for reverse transcription. cDNA was synthesized using a first-strand cDNA Synthesis Kit for RT-PCR (Roche Diagnostics GmbH, Mannheim, Germany).

Quantitative real-time PCR

Relative quantification with real-time PCR was performed using the LightCycler® 2.0 system (Roche Diagnostics). The primer sequences were as follows: IFN-α-inducible protein 27 (IFI27): 5′-TCA CCT CAT CAG CAG TGA-3′ (forward) and 5′-CAT CTT GGC TGC TAT GGA-3′ (reverse); G3PDH: 5′-TCC CAT CAC CAT CTT CCA-3′ (forward) and 5′-CAT CAC GCC ACA GTT TCC-3′ (reverse). After an initial denaturation step at 95°C for 10 min, PCR was performed with 40 cycles of denaturation at 95°C for 5 s, annealing at 56°C for 5 s, and extension at 72°C for 20 s. G3PDH was used as an internal standard. All samples were automatically quantified simultaneously during the amplification process by comparison to the standard curve and expressed as a ratio relative to the reference sample.

Statistical analysis

Data were analyzed using SPSS (v 11.0.1; SPSS Inc., Chicago, IL, USA) for Windows. Mann-Whitney U test was carried out to compare IFI27 gene expression levels between patients and controls. Linear regression analysis and correlation analysis using Spearman’s correlation coefficients were performed to estimate associations between mRNA expression levels and clinical variables in the patient group. Statistical significance was defined as p < 0.05.

RESULTS

cDNA microarray analysis

To identify the putative SS-specific genes in whole peripheral blood of SS patients compared to controls, we performed DNA microarray analysis. Genes that were upregulated by 1.6-fold or more in patients with primary SS relative to controls (the top 30) are shown in Table 3. Among the 10 most highly upregulated genes, at least 6 (60%) were IFN-α/ß-inducible genes. Table 4 shows the genes (top 30) that were upregulated by 1.4-fold or more in patients with secondary SS compared to controls. Similar to patients with primary SS, among the 10 most highly upregulated genes, at least 6 (60%) were IFN-α/ß-inducible genes. A comparison of transcript levels for patients with primary SS and secondary SS and controls revealed that genes induced by IFN-α/ß had the largest fold difference. The magnitude of upregulation was generally higher in primary SS than in secondary SS. In RA patients, among the 10 most highly upregulated genes, 3 (30%) were IFN-α/ß-inducible genes (Table 5). All IFN-inducible genes were upregulated less than 1.8-fold compared to controls. The gene expression pattern of SS was different from that of RA. IFN-inducible genes were upregulated in primary and secondary SS. IFI27 showed the most significant difference between SS patients and healthy controls in microarray screening. In RA patients, IFI27 was slightly upregulated (1.35-fold) compared to healthy controls. IFI27 expression was much higher in SS compared to RA (35.6 ± 31.4 vs 1.35 ± 0.55 fold). These findings suggest that IFI27 could be used as an SS-specific gene marker.

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Table 3.

Genes showing upregulated expression in peripheral blood from patients with primary SS relative to healthy controls (top 30). The average fold change is shown based on normalized microarray fluorescence data of SS patients compared to controls.

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Table 4.

Genes showing upregulated expression in peripheral blood from patients with secondary SS relative to controls (top 30).

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Table 5.

Top 10 genes showing upregulated expression in peripheral blood from 10 patients with RA relative to 10 controls, by microarray analysis.

Confirmation of microarray findings by real-time PCR analysis

Based on microarray analysis, to further investigate the significance of IFI27 in SS, we examined IFI27 gene expression levels by real-time PCR. The mean IFI27 relative expression levels in SS patients was 137.2 ± SD 250.2 and that in healthy controls was 9.1 ± 22.7. Quantitative real-time PCR showed that IFI27 gene expression levels were significantly increased in patients with SS compared with healthy controls (p < 0.01), supporting our microarray data. Further, the relative IFI27 expression levels in primary SS, secondary SS, and healthy controls were 111.1 ± 212.3, 218.6 ± 346.0, and 9.1 ± 22.7, respectively. IFI27 gene expression levels were significantly increased in patients with primary SS (p < 0.01) and secondary SS (p < 0.05) compared with healthy controls (Figure 1).

Figure 1.
Figure 1.

Relative expression of IFI27 in primary SS was 111.1 ± 212.3, in secondary SS 218.6 ± 36.0, and in healthy controls 9.1 ± 22.7. IFI27 gene expression was significantly increased in patients with primary (*p < 0.01) and secondary Sjögren’s syndrome (**p < 0.05) compared with controls (Mann-Whitney U test).

Association between IFI27 expression and clinical variables

The expression level of IFI27 was significantly correlated with serum IgG level (r = 0.462, p < 0.01; Figure 2). Moreover, IFI27 expression was correlated with serum ß2-microglobulin (r = 0.385, p < 0.05), soluble interleukin 2 (IL-2) receptor (r = 0.473, p < 0.01), erythrocyte sedimentation rate (ESR; r = 0.333, p < 0.05), and antinuclear antibody (ANA) titer (speckled pattern; r = 0.445, p < 0.01; Table 6). Other manifestations, such as severity of dry mouth and dry eye, rash, arthritis, hematological involvement, occurring currently or previously, were not associated with IFI27 expression.

Figure 2.
Figure 2.

Linear regression analysis showed a significant positive correlation between relative expression of IFI27 and serum IgG levels in patients with Sjögren’s syndrome (r2 = 0.1316, p < 0.0274).

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Table 6.

IFI27 expression was correlated with serum IgG, ß2-microglobulin (ß2MG), soluble interleukin 2 receptor (sIL-2R), erythrocyte sedimentation rate (ESR), and antinuclear antibody (ANA) titer. Correlation analyses using Spearman’s correlation coefficients were performed to estimate associations between mRNA expression levels and clinical variables in the SS patient group.

DISCUSSION

In SS, disease activity cannot be easily defined due to its nonspecific symptoms and the lack of both sensitive and specific biomarkers. Serum IgG, soluble IL-2 receptor, ß2-microglobulin, anti-Ro/SSA, and anti-La/SSB have been found at elevated concentrations in sera from patients with SS, but none individually was sufficiently sensitive or specific to use for evaluation of disease activity20,21,22. To monitor disease activity and to apply more appropriate treatment, there is increasing interest in the identification of bio-markers for SS.

Our study showed that IFN-inducible genes reveal the most significant difference between SS patients and healthy controls in microarray screening, and IFI27 is expressed at the highest level in the peripheral blood of SS patients. The level of IFI27 was significantly correlated with various clinical measures. The number of patients in our experimental groups was too small to discuss the differences between primary and secondary SS. Although IFI27 is reported to be upregulated in patients with SLE and DM7, IFI27 is not the most upregulated gene in these diseases. Moreover, we showed that IFI27 expression is much higher in SS compared to RA. These findings suggest that IFI27 could serve as an SS-specific biomarker.

Plasmacytoid dendritic cells (pDC) are the main producers of type I IFN. Viruses may initiate the production of IFN; continuous IFN-α synthesis is caused by immune complexes that activate pDC to prolong IFN-α production at the tissue level in patients with SS17. As pDC are detectable in the salivary glands of patients with SS, they are considered an important source of type I IFN14. The systemic type I IFN signature in patients with SS may be linked to higher systemic pDC activation23. Genes involved in IFN signaling are upregulated in labial salivary gland cells of primary SS13,24. In response to immunological stimuli such as apoptotic cells or viruses, hyperactive pDC may cause SS in those who have susceptibility for developing auto immune disorders like Bcl-2 antagonist killer 1 (BAK1) polymorphisms13,24.

IFN-inducible genes, such as IP-10, Mig, I-TAC, STAT1α, and STAT1ß, are highly expressed in the salivary gland tissues of patients with SS11,25,26,27. Type I IFN stimulation of DC has been reported to increase the production of B cell-activating factor (BAFF) belonging to the tumor necrosis factor (TNF) family23,28. BAFF is known to promote B cell survival and Ig class-switching29,30. In the SS salivary gland, infiltrating inflammatory cells strongly express BAFF protein31. As a result, the elevated serum IgG concentration may be a reflection of enhanced IFN-α activity. Indeed, in our study, the level of serum IgG correlated with expression levels of IFI27. These findings suggest that the IFN pathway is important in the pathogenesis of SS. The mechanism of IFN pathway upregulation remains to be elucidated in future studies.

SS and SLE share some clinical and immunological features, including the presence of infiltrating pDC in target organs and activation of IFN pathways. In SLE, the serum concentration of IFN-α is correlated with both disease activity and severity as well as clinical manifestations such as fever and rashes28,32,33. One of the major differences between the 2 diseases is the organ specificity of SS. Our data showed that the expression level of IFI27 was not correlated with the sicca symptoms. These observations suggest that expression of IFN-inducible genes may be not only a dynamic component of the SS disease process, but also a relatively stable characteristic. Nine (29%) of 37 patients with SS showed IFI27 gene levels that were significantly increased (above 100-fold); and 6 (66.7%) of the 9 cases were complicated by interstitial nephritis, aplastic anemia, mononeuritis multiplex, primary biliary cirrhosis, liver dys-function, and hypothyroidism, respectively. Longitudinal analysis of subsets of patients with SS based on IFN-inducible gene levels is necessary to determine whether IFN-inducible genes affect disease progression.

Anti-IFN-α monoclonal antibody can neutralize over-expression of type I IFN-inducible genes in whole blood and lesional skin from SLE patients, and has profound effects on signaling pathways, including BAFF, TNF-α, and IL-10, which may be located downstream of IFN-α28. Corticosteroid therapy has previously been shown to downregulate IFN-inducible gene expression10. In this study, 8 (21.6%) SS patients received oral corticosteroid therapy (average prednisolone 9.4 mg/day). One, with interstitial nephritis, received 30 mg/day prednisolone. The remaining 7 patients were treated with low-dose prednisolone (2–10 mg/day) as maintenance therapy. The expression of IFI27 was not correlated with the steroid dose. Our data suggest that anti-IFN-α agents may be useful in SS patients who show elevated serum IgG, ß2-microglobulin, soluble IL-2 receptor, ESR, and ANA titer. Treatment of SS with anti-TNF agents has not been successful to date. Interestingly, etanercept was not effective for SS because etanercept exacerbates overexpression of IFN-α and BAFF34.

Our data suggest an important role of the IFN pathway in the pathogenesis of SS. IFI27 could be an effective and specific biomarker related to disease activity or disease progression in SS. The IFN pathway could be a novel therapeutic target in SS in the future.

Acknowledgment

The authors thank the patients and healthy volunteers who participated in this study.

Footnotes

  • Supported by a grant from the Japanese Ministry of Education, Culture, Sports, Science and Technology.

  • Accepted for publication September 20, 2010.

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