Insights in to the pathogenesis of axial spondyloarthropathy based on gene expression profiles

Sharma, Srilakshmi M; Choi, Dongseok; Planck, Stephen R.; Harrington, Christina A.; Austin, Carrie R.; Lewis, J. A.; Diebel, Tessa N.; Martin, Tammy M.; Smith, Justine R.; Rosenbaum, James T.

doi:10.1186/ar2855

Cited by 51 publications

(52 citation statements)

References 28 publications

(29 reference statements)

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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: 63%

Sexual Dimorphism in the Th17 Signature of Ankylosing Spondylitis

Gracey

Yao

Green

et al. 2016

Arthritis & Rheumatology

143

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: 63%

Sexual Dimorphism in the Th17 Signature of Ankylosing Spondylitis

Gracey

Yao

Green

et al. 2016

Arthritis & Rheumatology

143

101

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“…139 A role for the innate system in AS has long been postulated due to the proposed link between an as yet unknown pathogen and disease onset. 140 SPARC, a bone matrix protein, was also upregulated in two of the studies 136,137 which suggests dysregulation of the bone matrix which might contribute to the joint ankylosis.…”

Section: Circulating Cell Studiesmentioning

confidence: 93%

“…Two kits have been specifically developed for transcriptomic studies in whole blood with the blood collected into an RNA preservative which stabilises the RNA allowing shipping/initial storage at room temperature with minimal degradation (PAXgene from Qiagen Three whole genome expression profiling studies have been published using whole blood in spondylarthropy all using the PAXgene technology. [135][136][137] Sharma et al compared healthy controls and spondyloarthropy patients but used a slightly unusual approach. Rather than analysing a main sample group by microarray then confirming candidate genes by qPCR in a second cohort, they split the sample groups into a discovery and a validation set and microarrayed both groups and compared differentially expressed genesets.…”

Section: Circulating Cell Studiesmentioning

confidence: 99%

“…Rather than analysing a main sample group by microarray then confirming candidate genes by qPCR in a second cohort, they split the sample groups into a discovery and a validation set and microarrayed both groups and compared differentially expressed genesets. 137 However, the control and patient groups had significant imbalances in their gender mix, as well as no joint disease scores being ascertained making interpretation difficult. Both Assassi et al and Pimental-Santos et al focussed on AS, using patients with confirmed AS according to the Modified New York Criteria, with Assassi also comparing their datasets with those from systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) patients.…”

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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“…64 Finally, a recent study also found a TREM-1 upregulation in peripheral blood cells from patients suffering from spondylarthropathy. 65 Thus, while TREM-1 role in acute inflammation, especially during sepsis, is today better understood, its function during chronic rheumatic diseases only begins to be elicited.…”

Section: Effects Of the Trem-1 Pathway Modulation During Inflammatorymentioning

confidence: 99%