Plasma levels of the soluble form of the FcγRIIa receptor vary with receptor polymorphisms and are elevated in rheumatoid arthritis

Abstract

Soluble forms of the low-affinity immunoglobulin receptor FcγRIIa (sFcγRIIa) lacking the cytoplasmic tail have been reported in plasma however the mechanism and functional consequences are unknown. This study aimed to evaluate mechanisms of FcγRIIa release compared to GPVI release from platelets, and examine whether genetic polymorphisms at positions 27 and 131 within FcγRIIa correlate with platelet FcγRIIa stability and function. Enzyme-linked immunosorbent assays (ELISAs) were used to measure plasma sFcγRIIa and sGPVI levels. FcγRIIa genotype at positions 27 and 131 was evaluated. sFcγRIIa levels were not significantly different between non-131HH and 131HH but were significantly lower in 27W than non-27W. Treatment of platelets with aggregated immunoglobulin (Ig) G induced release of FcγRIIa and GPVI, but only sGPVI release was statistically significant, required functional FcγRIIa, and was blocked by inhibitors of signaling pathways and metalloproteinases. This indicated that sFcγRIIa was not released from platelets by metalloproteolysis. sFcγRIIa levels were not correlated with sGPVI levels in healthy individuals however levels of sFcγRIIa and sGPVI in plasma from patients with rheumatoid arthritis (RA) were significantly elevated above levels found in healthy individuals. Elevated level of sFcγRIIa in RA patients may reflect active immune-based arthritis and be predictive of active inflammation.

Keywords:

• FcγRIIa
• GPVI
• platelet
• polymorphism
• rheumatoid arthritis

Author Contributions

JQ performed research and interpreted data; ED and BW developed key reagents and interpreted data; DK, GMM, PMH and KX provided key patient samples and reagents; RKA and EEG designed the research and interpreted the data; all authors co-wrote the manuscript.

Conflicts of Interest

All authors have no conflict of interest to declare.

Additional information

Funding

This research was supported by the National Health and Medical Research Council of Australia, National Natural Science Foundation of China [grant no. 81400082]; the Natural Science Foundation of Jiangsu Province [BK20140219]; the funding for the Distinguished Professorship Program of Jiangsu Province, the Six Talent Peaks Project of Jiangsu Province (WSN-133), the Shuangchuang Project of Jiangsu Province, the 333 projects of Jiangsu Province [BRA2017542]; the Science and Technology Foundation for the Selected Overseas Chinese Scholars, State Ministry of Human Resources and Social Security.