Background/Purpose

Spondyloarthritis (SpA) etiology is largely multifactorial with a genetic component dominated by the long-known strong association with the HLA-B27 allele. This allele, however, is not sufficient for the disease to occur. Whereas dendritic cells are believed to play a key role in SpA pathogenesis, the precise mechanisms underlying disease development and particularly the role of HLA-B27 remain poorly understood. To shed light on the genes involved, we carried out a transcriptome analysis of dendritic cells from patients and healthy controls, also accounting for HLA-B27.

Methods

Transcriptomic profiles of monocyte-derived dendritic cells (MD-DCs) were obtained from 23 HLA-B27+ SpA patients, and from 44 controls (23 HLA-B27+ and 21 HLA-B27-). MD-DCs were stimulated or not with endotoxin for 6 or 24 hrs. We used the Affymetrix Human Gene 1.0 ST platform. Analysis of differentially expressed (DE) genes was conducted with LIMMA considering both the disease and the HLA-B27 status (p-value < 5%), followed by quantitative gene set enrichment analyses (quSAGE) and functional pathway annotation.

Results

We performed three comparisons to identify DE genes related to HLA-B27 or SpA status, thus generating three lists: A, including 800 DE genes between HLA-B27+ SpA patients and HLA-B27- healthy controls; B, including 673 DE genes between HLA-B27+ controls and HLA-B27- controls; and C, including 466 DE genes between HLA-B27+ patients and HLA-B27+ controls. Subtracting A–B left 656 genes, of which 68 are in list C, thus yielding a robust list of genes affected by SpA and filtering out irrelevant genes affected by HLA-B27. The most significantly DE gene was procollagen C-endopeptidase enhancer 2 (PCOLCE2), which was overexpressed in patients compared to both HLA-B27- (Fold Change = 2.35, P = 9×10-4) and HLA-B27+ (FC = 3.57, P = 2.7×10-6) controls. This gene codes for an enhancer of bone morphogenic protein-1 (BMP1) that facilitates the cleavage of procollagen and apolipoproteins. QuSAGE and functional annotation revealed that DE genes and gene sets associated with SpA were mainly related to lipid biosynthesis, autophagy, and ribosomal units.

Conclusion

Our study identified a list of MD-DC genes and functions that differ between SpA and controls after controlling for HLA-B27 and involve major pathways, including lipid synthesis, autophagy and ribosomal function. The most striking DE gene, PCOLCE2 is known to interact physically with BMP1, an enzyme that is implicated in ossification and cartilage formation. BMP1 loss-of-function mutations can cause osteogenesis imperfecta. Thus, it is conceivable that a mechanism of gain-of-function of BMP1 signalling pathway could be implicated in the SpA pathogenic process.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/multiway-transcriptomic-analysis-of-monocyte-derived-dendritic-cells-discriminates-effects-of-disease-and-of-hla-b27-in-spondyloarthritis/