J Rheum Dis.  2015 Oct;22(5):293-297. 10.4078/jrd.2015.22.5.293.

Tumor Necrosis Factor-alpha Gene Signature Is Absent in Peripheral Blood Mononuclear Cells of Patients with Granulomatosis Polyangiitis

• Koenig MF
• Park JK

• KMID: 2222841
• DOI: http://doi.org/10.4078/jrd.2015.22.5.293

Abstract

OBJECTIVE
Granulomatosis with polyangiitis (GPA), formally known as Wegener's granulomatosis, is a systemic vasculitis with necrotizing granulomatous inflammation. As treatment directed against tumor necrosis factor (TNF)-alpha failed in GPA, we investigated whether "TNF-alpha signature" (i.e. gene expression profile of TNF-alpha activation) was present in peripheral blood mononuclear cells (PBMCs) of patients with GPA.
METHODS
Gene expression profiling was performed using total RNA from PBMCs of 41 patients with GPA and 23 healthy control subjects using the Illumina microarray technique. Gene set enrichment analysis (GSEA) was performed to detect the presence of TNF-alpha signature using the curated list C2-V3.0 by the Broad Institute. False discovery rate<0.05 was considered statistically significant.
RESULTS
GSEA did not show significant enrichment of any TNF-alpha associated gene sets in GPA. Expression levels of genes up-regulated by TNF-alpha did not differ between healthy control subjects, patients in remission (Birmingham Vasculitis Activity Score [BVAS]=0), and those with active disease (BVAS> or =1). In addition, an unsupervised hierarchical clustering of those genes failed to cluster the samples into healthy control subjects and GPA in remission or with active disease. B cell activation signature was enriched in GPA patients.
CONCLUSION
Absence of a TNF-alpha signature in PBMCs may suggest that TNF-alpha plays a less important role in the pathogenesis of GPA than previously accepted.

Keyword

Tumor necrosis factor-alpha; Granulomatosis with polyangiitis; Gene expression

MeSH Terms

Gene Expression
Gene Expression Profiling
Humans
Inflammation
RNA
Systemic Vasculitis
Transcriptome
Tumor Necrosis Factor-alpha*
Vasculitis
Wegener Granulomatosis
RNA
Tumor Necrosis Factor-alpha

Figure

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  Figure 1. Unsupervised hierarchical clustering of the TNF-α downstream genes failed to cluster the samples into healthy and GPA subjects. Expression pattern of TNF-α downstream genes of controls, inactive, and active GPA did not cluster. GPA: granulomatosis with polyangiitis, TNF: tumor necrosis factor.

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