Gene expression profiling reveals a downregulation in immune-associated genes in patients with AS

Duan, Ran; Leo, Paul; Bradbury, L.; Brown, Matthew A.; Thomas, Gethin

doi:10.1136/ard.2009.111690

Cited by 47 publications

(53 citation statements)

References 48 publications

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“…Previous microarray studies in AS have generally not included sex-matched patients and controls, while those that balanced the sex of patients and controls did not independently analyze males and females (26)(27)(28)(29). These studies demonstrate mild hierarchal clustering of AS patients and controls, as in the current study, supporting the heterogeneity of the disease at the transcription level.…”

Section: Discussionsupporting

confidence: 68%

Sexual Dimorphism in the Th17 Signature of Ankylosing Spondylitis

Gracey

Yao

Green

et al. 2016

Arthritis & Rheumatology

145

101

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ObjectiveTo identify an immunologic basis for the male sex bias in ankylosing spondylitis (AS).MethodsCohorts of male and female patients with AS and age‐ and sex‐matched healthy control subjects were selected, and the levels of serum cytokines (interferon‐γ [IFNγ], tumor necrosis factor α, interleukin‐17A [IL‐17A], and IL‐6) were examined by enzyme‐linked immunosorbent assay, the frequencies of Th1 and Th17 cells were assessed by flow cytometry, and whole blood gene expression was analyzed using both microarray and NanoString approaches.ResultsThe frequency of IL‐17A and Th17 cells, both of which are key factors in the inflammatory Th17 axis, was elevated in male patients with AS but not in female patients with AS. In contrast, AS‐associated alterations in the Th1 axis, such as the frequency of IFNγ and Th1 cells in serum, were independent of a patient's sex. Results of microarray analysis supported an altered Th17 axis in male patients, with a specific increase in IL17RA. In addition, male and female patients with AS displayed shared gene expression patterns, while male patients with AS had additional alterations in gene expression that were not seen in female patients with AS. The differential sex‐related immune profiles were independent of HLA–B27 status, clinical disease activity (as measured by the Bath Ankylosing Spondylitis Disease Activity Index), or treatment (with nonsteroidal antiinflammatory drugs or biologic agents), implicating intrinsic sexual dimorphism in AS.ConclusionThe results of this study demonstrate distinct sexual dimorphism in the activation status of the immune system in patients with AS, particularly in the Th17 axis. This dimorphism could underlie sex‐related differences in the clinical features of AS and could provide a rationale for sex‐specific treatment of AS.

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Section: Discussionsupporting

confidence: 68%

Sexual Dimorphism in the Th17 Signature of Ankylosing Spondylitis

Gracey

Yao

Green

et al. 2016

Arthritis & Rheumatology

145

101

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“…Very few genes altered in AS with most of those being up-regulated including NR4A2 which was downregulated in our study. 145 The Gu et al study was undertaken in a Chinese patient cohort which might explain the different findings to our Caucasian cohort study. Table 2 summarises the most interesting genes identified through whole genome expression profiling studies in wellpowered studies.…”

mentioning

confidence: 96%

“…143 A subset of 1428 genes was differentially expressed in response to treatment and downregulation of 4 inflammation-associated genes, including LIGHT, whose downregulation has also been associated with RA suggesting this gene maybe generally associated with inflammatory processes, 144 was confirmed. Only recently however have large-scale whole genome expression profiling studies on the complete PBMC population been undertaken in AS or SpA by ourselves 145 and David Yu's group at UCLA. 146 Using Illumina's HT-12 whole genome arrays we compared expression profiles of PBMCs from 18 active AS patients (confirmed by Modified New York Criteria) and 18 age-and gender-matched controls identifying a 452-gene signature delineating AS and control samples with 94% accuracy.…”

Section: Circulating Cell Studiesmentioning

confidence: 99%

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The genomics and genetics of ankylosing spondylitis

Kenna¹,

Davidson²,

Thomas³

2011

AGG

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Abstract:The spondyloarthropathies are a group of arthritides which specifically target the spine and pelvis with ankylosing spondylitis (AS) being the most prevalent and debilitating of these conditions. Unique to AS is the progression to excessive uncontrolled bone formation following an initial inflammatory phase that can result in joint fusion and significant disability. Spondyloarthritis is estimated to affect 1%-2% of the population, twice as many as rheumatoid arthritis and thus constitutes a significant health problem. Currently AS pathogenesis is very poorly understood but recent large-scale genetics and gene expression profiling studies have identified some of the underlying mechanisms and pathways contributing to the disease. Genome-wide association studies have identified a number of candidate genes associated with AS sharing the same pathways which are now being targeted for therapeutic intervention. However, although such approaches can identify genes contributing to the disease process and are very informative as to disease aetiopathogenesis, they cannot profile the actual changes in gene/cell activity at any point in the disease process or possibly more importantly at specific sites. Such information is generated using expression profiling. A number of expression profiling studies have been undertaken in AS, looking at both circulating cells and tissues from affected joints. Although some common genes/pathways have been identified, overall the results to date have been somewhat disappointing due to differences in experimental design and tissue source as well as the low power of the studies. More recent better powered studies have shown some potential in developing gene expression profiling as a diagnostic tool in AS. True future success will rely on larger genetic and genomic studies and the combination of these datasets in eQTL studies requiring significant collaborative efforts. Such larger-scale approaches will also generate sufficient power to target specific disease stages and sites.

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“…A proinflammatory profile in peripheral blood monocyte cells (PBMCs), from undifferentiated spondyloarthritis (uSpA) and AS, is indicated by an increased expression of RGS1, NR4A2, HBEGF and SOCS3, in both groups (Gu et al, 2009). However, other reports suggest decreased immune responsiveness such as a "reverse IFN signature" (Smith et al, 2008), and immunosuppressive phenotypes (Duan et al, 2010, Pimentel-Santos et al, 2011. The main reason for these differences in the transcriptomic profiles, between the first study and the 3 later studies, is unknown but differences in patients and methodologies may contribute.…”

Section: Proinflammatory Vs Immunosuppressive Signaturesmentioning

confidence: 90%