ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1467

Do G-CSF and Neutrophils Contribute to the Pathophysiology of Rheumatoid Arthritis?

Gabrielle Goldberg1, Simon Chatfield2,3, Jane Murphy1, Ee Shan Pang1, Yunshun Chen4, Gordon Smyth4, Milica Ng5, Michael Wilson5, Clare O'Neill3, Samantha Busfield5, Arna Andrews5 and Ian P. Wicks3,6,7, 1Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia, 2Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia, 3Rheumatology, The Royal Melbourne Hospital, Melbourne, Australia, 4Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia, 5Research, CSL Limited, Melbourne, Australia, 6Inflammation, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia, 7Medical Biology, The University of Melbourne, Melbourne, Australia

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: , ,

Session Information

Title: Rheumatoid Arthritis - Human Etiology and Pathogenesis

Session Type: Abstract Submissions (ACR)

Background/Purpose

Rheumatoid arthritis (RA) is characterised by a persistent, but poorly understood interplay between innate and adaptive immunity. Neutrophils are the predominant cell type in inflamed RA synovial fluid (SF). Granulocyte colony‑stimulating factor (G-CSF) is a key regulator of neutrophil production, function and survival.

Methods

In this study peripheral blood (PB) neutrophil phenotype and function were analysed according to disease activity (DAS28 scores and other clinical parameters) in RA patients (n=50-60).

Results

We found significant correlations between disease activity and PB neutrophil percentage (r=0.26, p≤0.05), as well as between neutrophil activation state (CD62L, CD11b) and the expression of receptors for factors regulating neutrophil production and function. For example, CD62L vs G-CSF-R (r=0.58, p≤0.0001); CD62L vs CD35 (r=-0.37, p≤0.01); CD62L vs CXCR2 (r=0.42, p≤0.01); CD62L vs CXCR1 (r=0.46, p≤0.001). To further explore the role of neutrophils and G-CSF in RA, transcriptional profiling using RNASeq was performed comparing: PB neutrophils isolated from healthy donors (HD) and RA patients (n=5); neutrophils isolated from paired PB and SF samples of RA patients (n=3); neutrophils or white blood cells from HDs stimulated with G-CSF in vitro (n=4). 194 genes were differentially expressed (DE) in RA neutrophils (logFC≥1; adjusted p≤0.05) when compared to HDs. Over 50 of those genes were also differentially expressed when neutrophils were stimulated with G-CSF in vitro.  There were 1724 DE genes (logFC≥1; adjusted p≤0.05) when comparing PB and SF neutrophils from RA patients. Bioinformatic interrogation using Ingenuity Pathway Analysis software demonstrated that G-CSF was a likely regulator (p=9.83 x 10-21) of these differences.

Conclusion

These data provide evidence that neutrophils and G-CSF contribute to the pathogenesis of RA. G-CSF may therefore represent a potential therapeutic target in the treatment of RA and other inflammatory diseases where there is a pathogenic contribution from neutrophils.

Disclosure:

G. Goldberg,

CSL Limited,

2;

S. Chatfield,
None;

J. Murphy,
None;

E. S. Pang,
None;

Y. Chen,
None;

G. Smyth,
None;

M. Ng,

CSL Limited,

3;

M. Wilson,

CSL Limited,

3;

C. O’Neill,
None;

S. Busfield,

CSL Limited,

3;

A. Andrews,

CSL Limited,

3;

I. P. Wicks,

CSL Limited,

2.

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