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Differential ACPA B...
Differential ACPA Binding to Nuclear Antigens Reveals a PAD-Independent Pathway and a Distinct Subset of Acetylation Cross-Reactive Autoantibodies in Rheumatoid Arthritis
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- Lloyd, Katy A. (author)
- Karolinska Univ Hosp, Karolinska Inst, Div Rheumatol, Ctr Mol Med,Dept Med, Stockholm, Sweden
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- Wigerblad, Gustaf (author)
- Karolinska Univ Hosp, Karolinska Inst, Div Rheumatol, Ctr Mol Med,Dept Med, Stockholm, Sweden;NIAMSD, Syst Autoimmun Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA
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- Sahlstrom, Peter (author)
- Karolinska Institutet,Karolinska Univ Hosp, Karolinska Inst, Div Rheumatol, Ctr Mol Med,Dept Med, Stockholm, Sweden;Charite, Dept Med, Berlin, Germany
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- Garimella, Manasa G. (author)
- Karolinska Institutet,Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden
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- Chemin, Karine (author)
- Karolinska Institutet,Karolinska Univ Hosp, Karolinska Inst, Div Rheumatol, Ctr Mol Med,Dept Med, Stockholm, Sweden
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- Steen, Johanna (author)
- Karolinska Univ Hosp, Karolinska Inst, Div Rheumatol, Ctr Mol Med,Dept Med, Stockholm, Sweden
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- Titcombe, Philip J. (author)
- Karolinska Univ Hosp, Karolinska Inst, Div Rheumatol, Ctr Mol Med,Dept Med, Stockholm, Sweden;Univ Minnesota, Sch Med, Ctr Immunol, Minneapolis, MN 55455 USA
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- Marklein, Bianka (author)
- NIAMSD, Syst Autoimmun Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA
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- Zhou, Diana (author)
- Karolinska Univ Hosp, Karolinska Inst, Div Rheumatol, Ctr Mol Med,Dept Med, Stockholm, Sweden
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- Stalesen, Ragnhild (author)
- Karolinska Institutet,Karolinska Univ Hosp, Karolinska Inst, Div Rheumatol, Ctr Mol Med,Dept Med, Stockholm, Sweden
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- Ossipova, Elena (author)
- Karolinska Univ Hosp, Karolinska Inst, Div Rheumatol, Ctr Mol Med,Dept Med, Stockholm, Sweden
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- Lundqvist, Christina, 1988 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning,Institute of Medicine, Department of Rheumatology and Inflammation Research
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- Ekwall, Olov, 1968 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för pediatrik,Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning,Institute of Clinical Sciences, Department of Pediatrics,Institute of Medicine, Department of Rheumatology and Inflammation Research
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- Rönnelid, Johan (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi
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- Mueller, Daniel L. (author)
- Univ Minnesota, Sch Med, Ctr Immunol, Minneapolis, MN 55455 USA
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- Karlsson, Mikael C. I. (author)
- Karolinska Institutet,Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden
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- Kaplan, Mariana J. (author)
- NIAMSD, Syst Autoimmun Branch, Intramural Res Program, NIH, Bethesda, MD 20892 USA
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- Skriner, Karl (author)
- Charite, Dept Med, Berlin, Germany
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- Klareskog, Lars (author)
- Karolinska Institutet,Karolinska Univ Hosp, Karolinska Inst, Div Rheumatol, Ctr Mol Med,Dept Med, Stockholm, Sweden
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- Wermeling, Fredrik (author)
- Karolinska Institutet,Karolinska Univ Hosp, Karolinska Inst, Div Rheumatol, Ctr Mol Med,Dept Med, Stockholm, Sweden
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- Malmstrom, Vivianne (author)
- Karolinska Institutet,Karolinska Univ Hosp, Karolinska Inst, Div Rheumatol, Ctr Mol Med,Dept Med, Stockholm, Sweden
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- Gronwall, Caroline (author)
- Karolinska Institutet,Karolinska Univ Hosp, Karolinska Inst, Div Rheumatol, Ctr Mol Med,Dept Med, Stockholm, Sweden
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(creator_code:org_t)
- 2019-01-04
- 2019
- English.
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In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 9, s. 1-22
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Abstract
Subject headings
Close
- Rheumatoid arthritis (RA) associated anti-citrullinated protein autoantibodies (ACPA) target a wide range of modified proteins. Citrullination occurs during physiological processes such as apoptosis, yet little is known about the interaction of ACPA with nuclear antigens or apoptotic cells. Since uncleared apoptotic cells and neutrophil extracellular trap (NET) products have been postulated to be central sources of autoantigen and immunostimulation in autoimmune disease, we sought to characterize the anti-nuclear and anti-neutrophil reactivities of ACFA. Serology showed that a subset of anti-CCP2 seropositive RA patients had high reactivity to full-length citrullinated histones. In contrast, seronegative RA patients displayed elevated IgG reactivity to native histone compared to controls, but no citrulline-specific reactivity. Screening of 10 single B-cell derived monoclonal AGFA from RA patients revealed that four ACPA exhibited strong binding to apoptotic cells and three of these had anti-nuclear (ANA) autoantibody reactivity. Modified histones were confirmed to be the primary targets of this anti-nuclear ACPA subset following immunoprecipitation from apoptotic cell lysates. Monoclonal ACPA were also screened for reactivities against stimulated murine and human neutrophils, and all the nuclear-reactive monoclonal ACPA bound to NETs. Intriguingly, one ACPA mAb displayed a contrasting cytoplasmic perinuclear neutrophil binding and may represent a different NET-reactive ACPA subset. Notably, studies of CRISPR-Cas9 PAD4 KO cells and cells from PAD KO mice showed that the cytoplasmic NET-binding was fully dependent on PAD4, whilst nuclear- and histone-mediated NEI reactivity was largely PAD-independent. Our further analysis revealed that the nuclear binding could be explained by consensus-motif driven ACPA cross-reactivity to acetylated histones. Specific acetylated histone peptides targeted by the monoclonal antibodies were identified and the anti-modified protein autoantibody (AMPA) profile of the ACPA was found to correlate with the functional activity of the antibodies. In conclusion, when investigating monoclonal ACPA, we could group ACPA into distinct subsets based on their nuclear binding-patterns and acetylation-mediated binding to apoptotic cells, neutrophils, and NETs. Differential anti-modified protein reactivities of RA-autoantibody subsets could have an important functional impact and provide insights in RA pathogenesis.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Reumatologi och inflammation (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Rheumatology and Autoimmunity (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
Keyword
- anti-citrullinated protein autoantibodies
- acetylation
- rheumatoid arthritis
- anti-CCP
- PAD4
- apoptosis
- neutrophil extracellular traps (NETs)
- ANA
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Lloyd, Katy A.
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Wigerblad, Gusta ...
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Sahlstrom, Peter
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Garimella, Manas ...
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Chemin, Karine
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Steen, Johanna
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Titcombe, Philip ...
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Marklein, Bianka
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Zhou, Diana
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Stalesen, Ragnhi ...
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Ossipova, Elena
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Lundqvist, Chris ...
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Ekwall, Olov, 19 ...
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Rönnelid, Johan
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Mueller, Daniel ...
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Karlsson, Mikael ...
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Kaplan, Mariana ...
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Skriner, Karl
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Klareskog, Lars
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Wermeling, Fredr ...
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Malmstrom, Vivia ...
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Gronwall, Caroli ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Rheumatology and ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Immunology in th ...
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Frontiers in Imm ...
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Uppsala University
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Karolinska Institutet
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University of Gothenburg