Heterogeneity in peripheral blood cells

Since RA is a systemic disease, several investigators study gene expression levels in peripheral blood cells to address the question, whether disease heterogeneity is detectable from gene expression levels in peripheral blood cells (Tab. 1, Fig. 1).

Comparison of the gene expression profiles of peripheral blood mononuclear cells (PBMC) between 14 RA patients and seven healthy controls using DNA-microarrays containing ~10K genes, revealed only nine genes that were differentially expressed [25]. These genes also reflected changes in the immune/inflammatory responses in RA patients, including the calcium-binding protein S100A8 and S100A10, which were expressed at higher levels in RA patients. The aspect of heterogeneity was addressed by principle component analysis, from which analysis it was clear that there is at least a greater variability in gene expression in RA patients than in controls. Subsequent analysis to identify differences between RF positive and RF negative RA patients yielded no differences in this study.

Gene expression profiling in whole blood cells from RA patients revealed significant variation between RA patients that allows stratification of patients on the basis of distinct molecular characteristics (Tineke van der Pouw-Kraan, Carla Wijbrandts, Paul-Peter Tak en Cornelis Verweij, unpublished observations). Analysis of the differentially expressed gene clusters using gene set analysis, such as PLAGE (www.cbcb.duke.edu/pathways/) and Panther (www.panther.appliedbiosys-tems.com), indicated that distinct inflammatory processes are active in different subsets of patients. So far the clinical relevance of the molecular differences remains to be established.

Olsen et al. identified different gene expression levels in PBMC from early arthritis (disease duration less than 2 years ), and established RA patients (with an aver-

Figure 1

Heterogeneity between rheumatoid synovia is reflected in cultured fibroblast-like synoviocytes (FLS) derived from the synovia.

A) Heterogeneity among FLS, and synovial tissue gene expression profiles. Hierarchical clustering of expression profiles from synovial tissues (left) and corresponding FLS (right) from 10 patients with rheumatoid arthritis (RA). Each row represents a single gene; each column represents an individual patient sample. Red bands indicate relative expression greater than the median of all samples (ratio >1), green bands indicate an expression level lower than the median (ratio <1), black bands indicate equal expression levels (ratio near 1), and grey bands indicate missing or excluded data. We selected genes whose transcripts varied in abundance by at least two-fold from their median level in at least two samples. B) Subclassification of synovial tissues matches the subclassification of FLS. Correlation between subclasses of FLS and corresponding synovial tissue samples.

Figure 1

Heterogeneity between rheumatoid synovia is reflected in cultured fibroblast-like synoviocytes (FLS) derived from the synovia.

A) Heterogeneity among FLS, and synovial tissue gene expression profiles. Hierarchical clustering of expression profiles from synovial tissues (left) and corresponding FLS (right) from 10 patients with rheumatoid arthritis (RA). Each row represents a single gene; each column represents an individual patient sample. Red bands indicate relative expression greater than the median of all samples (ratio >1), green bands indicate an expression level lower than the median (ratio <1), black bands indicate equal expression levels (ratio near 1), and grey bands indicate missing or excluded data. We selected genes whose transcripts varied in abundance by at least two-fold from their median level in at least two samples. B) Subclassification of synovial tissues matches the subclassification of FLS. Correlation between subclasses of FLS and corresponding synovial tissue samples.

age disease duration of 10 years) [26]. From 4,300 analysed genes, nine genes were expressed at three-fold higher levels, and 44 genes were expressed at three-fold lower levels in the early RA group compared to the late RA patients. The genes expressed at higher levels in early RA include colony stimulating factor 3 receptor, cleavage stimulation factor, and TGF-P receptor II, which affect B-cell function. Genes involved in immune/inflammatory processes and genes related to cell proliferation and neoplasia were expressed at lower levels in early arthritis. Comparison between the genes that were expressed at higher levels in early RA and influenza-induced genes indicated that about a quarter of the early arthritis genes overlapped with the influenza-induced genes. This finding led the authors to suggest that the early arthritis signature may partly reflect the response to an unknown infectious agent.

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