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Fc gamma receptor binding profile of anti-citrullinated protein antibodies in immune complexes suggests a role for FcγRI in the pathogenesis of synovial inflammation
A.C. Kempers1, M.R. Nejadnik2, Y. Rombouts3, A. Ioan-Facsinay4, M. Van Oosterhout5, W. Jiskoot6, T.W. Huizinga7, R.E. Toes8, H.U. Scherer9
- Department of Rheumatology, Leiden University Medical Center, The Netherlands.
- Division of Drug Delivery Technology, Cluster BioTherapeutics, Leiden Academic Center for Drug Research, Leiden University, The Netherlands.
- Department of Rheumatology, Leiden University Medical Center; Center for Proteomics and Metabolomics, Leiden University Medical Center; and Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, France.
- Department of Rheumatology, Leiden University Medical Center, The Netherlands.
- Department of Rheumatology, Groene Hart Ziekenhuis, Gouda, The Netherlands.
- Division of Drug Delivery Technology, Cluster BioTherapeutics, Leiden Academic Center for Drug Research, Leiden University, The Netherlands.
- Department of Rheumatology, Leiden University Medical Center, The Netherlands.
- Department of Rheumatology, Leiden University Medical Center, The Netherlands.
- Department of Rheumatology, Leiden University Medical Center, The Netherlands. h.u.scherer@lumc.nl
CER10508
2018 Vol.36, N°2
PI 0284, PF 0293
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PMID: 29352854 [PubMed]
Received: 13/04/2017
Accepted : 01/08/2017
In Press: 15/01/2018
Published: 18/04/2018
Abstract
OBJECTIVES:
Anti-citrullinated protein antibodies (ACPA) are highly specific for rheumatoid arthritis (RA). Here, we studied binding of ACPA-IgG immune complexes (IC) to individual Fc gamma receptors (FcγR) to identify potential effector mechanisms by which ACPA could contribute to RA pathogenesis.
METHODS:
ACPA-IgG1 and control IgG1(IgG1 depleted of ACPA-IgG1) were isolated from plasma and synovial fluid (SF) of RA patients by affinity chromatography using CCP2 peptides. Subsequently, IC were generated using fluorescently labelled F(ab’)2 fragments against the F(ab’)2 region of IgG, or by using citrullinated fibrinogen. IC were incubated with FcγR-transfected CHO cell lines or neutrophils from healthy donors. FcγR binding of IC was analysed by flow cytometry in the presence or absence of specific blocking antibodies.
RESULTS:
ACPA-IgG1 IC predominantly bound to FcγRI and FcγRIIIA on FcγR-transfected CHO cell lines, while much lower binding was observed to FcγRIIA and FcγRIIB. ACPA-IgG1 IC showed reduced binding to FcγRIIIA compared to control IgG1 IC, in line with enhanced ACPA-IgG1 Fc core-fucosylation. Neutrophils activated in vitro to induce de novo expression of FcγRI showed binding of ACPA-IgG IC, and blocking studies revealed that almost 30% of ACPA-IgG IC binding to activated neutrophils was mediated by FcγRI.
CONCLUSIONS:
Our studies show that ACPA-IgG1 IC bind predominately to activating FcγRI and FcγRIIIA, and highlight FcγRI expressed by activated neutrophils as relevant receptor for these IC. As neutrophils isolated from SF exhibit an activated state and express FcγRI in the synovial compartment, this IC-binding could contribute to driving disease pathogenesis in RA.
