The exposure of autoantigens by microparticles underlies the formation of potent inflammatory components: the microparticle-associated immune complexes

Authors

  • Nathalie Cloutier,

    1. Faculté de Médecine de l'Université Laval, Centre de Recherche en Rhumatologie et Immunologie, Centre de Recherche du Centre Hospitalier Universitaire de Québec, Québec, Québec, Canada
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  • Sisareuth Tan,

    1. Molecular Imaging and NanoBioTechnology, IECB, UMR-CBMN University Bordeaux-1, Pessac, France
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  • Luc H. Boudreau,

    1. Faculté de Médecine de l'Université Laval, Centre de Recherche en Rhumatologie et Immunologie, Centre de Recherche du Centre Hospitalier Universitaire de Québec, Québec, Québec, Canada
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  • Catriona Cramb,

    1. Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
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  • Roopashree Subbaiah,

    1. Department of Orthopaedics, Case Western Reserve University, School of Medicine, Cleveland, OH, USA
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  • Lauren Lahey,

    1. Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
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  • Alexandra Albert,

    1. Faculté de Médecine de l'Université Laval, Centre de Recherche en Rhumatologie et Immunologie, Centre de Recherche du Centre Hospitalier Universitaire de Québec, Québec, Québec, Canada
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  • Ruslan Shnayder,

    1. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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  • Reuben Gobezie,

    1. The Cleveland Shoulder Institute, University Hospitals of Cleveland, Cleveland, OH, USA
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  • Peter A. Nigrovic,

    1. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
    2. Division of Immunology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
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  • Richard W. Farndale,

    1. Department of Biochemistry, University of Cambridge, Downing Site, Cambridge, UK
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  • William H. Robinson,

    1. Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
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  • Alain Brisson,

    1. Molecular Imaging and NanoBioTechnology, IECB, UMR-CBMN University Bordeaux-1, Pessac, France
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  • David M. Lee,

    1. Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
    2. Novartis Institutes for Biomedical Research, Basel, Switzerland
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  • Eric Boilard

    Corresponding author
    1. Faculté de Médecine de l'Université Laval, Centre de Recherche en Rhumatologie et Immunologie, Centre de Recherche du Centre Hospitalier Universitaire de Québec, Québec, Québec, Canada
    • Tel: +1 418 656 4141 46175; Fax: +1 418 654 2765

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Abstract

Immunoglobulins, antigens and complement can assemble to form immune complexes (IC). ICs can be detrimental as they propagate inflammation in autoimmune diseases. Like ICs, submicron extracellular vesicles termed microparticles (MP) are present in the synovial fluid from patients affected with autoimmune arthritis. We examined MPs in rheumatoid arthritis (RA) using high sensitivity flow cytometry and electron microscopy. We find that the MPs in RA synovial fluid are highly heterogeneous in size. The observed larger MPs were in fact MP-containing ICs (mpICs) and account for the majority of the detectable ICs. These mpICs frequently express the integrin CD41, consistent with platelet origin. Despite expression of the Fc receptor FcγRIIa by platelet-derived MPs, we find that the mpICs form independently of this receptor. Rather, mpICs display autoantigens vimentin and fibrinogen, and recognition of these targets by anti-citrullinated peptide antibodies contributes to the production of mpICs. Functionally, platelet mpICs are highly pro-inflammatory, eliciting leukotriene production by neutrophils. Taken together, our data suggest a unique role for platelet MPs as autoantigen-expressing elements capable of perpetuating formation of inflammatory ICs.

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