Session Information
Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's - Pathogenesis, Animal Models and Genetics
Session Type: Abstract Submissions (ACR)
Background/Purpose
Circulating monocytes are progrenitor of extra-cellular matrix producing cells involved in fibrosis and show highest expression of angiotensin II (ATR) and endothelin receptors (ETR) compared to other peripheral blood mononuclear cell (PBMC) subsets(1, 2). Stimulating autoantibodies (aab) against AT1R and ETAR are elevated in patients with Systemic Sclerosis (SSc) and associated with mortality and the development of disease complications such as PAH, lung fibrosis and digital ulcers(3). SSc-IgG positive for Anti-AT1R and Anti-ETAR-aabs induces through the respective receptors the production of the profibrotic chemokine CCL18 in PBMCs(2).
We analysed whether effects of autoantibodies (aab) against angiotensinII receptor type 1 (AT1R) and endothelin receptor type A (ETAR) in patients with Systemic Sclerosis (SSc) might be influenced by expression of respective receptors and their functional counterparts AT2R and ETBR.
(1) Rasini E, et al. Regulatory peptides. 2006 May 15;134(2-3):69-74. PubMed PMID: 16530863.
(2) Gunther J, et al. Arthritis research & therapy. 2014 Mar 11;16(2):R65. PubMed PMID: 24612997.
(3) Riemekasten G, et al. Annals of the rheumatic diseases. 2011 Mar;70(3):530-6. PubMed PMID: 21081526.
Methods
AT1R, AT2R, ETAR and ETBR expression was measured on CD14+ monocytes of 29 SSc patients and 18 healthy donors by flow cytometry. PBMCs of 11 healthy donors were analyzed for receptor expression as well and in vitro stimulated with affinity purified IgG of SSc patients and normal controls. Afterwards, CCL18 concentration was measured in the supernatants by ELISA.
Results
Monocytes of SSc-patients presented higher expression of all 4 receptors compared to NC and an increased AT1R/AT2R ratio. ETAR/ETBR ratio was significantly reduced in patients with lung fibrosis and correlated negatively with the modified Rodnan Skin Score (Spearman rank correlation’s coefficient r=-0.49, p<0.01).
PBMCs stimulated with SSc-IgG showed higher CCL18 concentration in supernatants than PBMCs stimulated with NC-IgG (p<0.0001). CCL18 induction by NC-IgG and SSc-IgG correlated with AT1/AT2 ratio (SSc-IgG: r=0.72, p=0.03, NC-IgG: r=0.98; p<0.0001) and negatively with ETA/ETB ratio (SSc-IgG: r=-0.82, p=0.03, NC-IgG: r=-0.93; p=0.007) of receptor positive monocytes.
Conclusion
Receptor expression might reflect systemic activation of the angiotensin and endothelin system in SSc. Since patients with lung fibrosis and high mRSS showed a reduced ETAR/ETBR ratio, imbalance of ATR and ETR may influence effects of aab in SSc and could serve as a marker for disease complications. High AT1R/AT2R but low ETAR/ETBR ratios on monocytes correspond to higher secretion of CCL18 suggesting a link between receptor expression and monocytic function.
Disclosure:
J. Rademacher,
None;
J. Guenther,
None;
A. Kill,
Actelion Pharmaceuticals US,
2;
E. Siegert,
None;
G. Riemekasten,
Actelion Pharmaceuticals US,
2,
CellTrend,
5.
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