ArticleAnnals of the rheumatic diseases2018
Affinity maturation shapes the function of agonistic antibodies to peptidylarginine deiminase type 4 in rheumatoid arthritis.
Article in Annals of the rheumatic diseases, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 22 citations in OpenAlex.
- The miR-3164/PAD4 axis regulates NETosis to prevent airway inflammation and remodeling through the TLR2/NF-κB signaling pathway.European journal of medical research · 2025Article
- Anti-Peptidylarginine Deiminase 4 Autoantibodies Derived From Patients With Rheumatoid Arthritis Exert Pathogenic Effects by Activating Monocytes and Exacerbating Inflammatory Arthritis.Arthritis & rheumatology (Hoboken, N.J.) · 2025Article
- Evidence of membranolytic targeting and intracellular citrullination in neutrophils isolated from patients with rheumatoid arthritis.Scientific reports · 2024Article
- Antibody discovery identifies regulatory mechanisms of protein arginine deiminase 4.Nature chemical biology · 2024Article
- Neutrophil-derived PAD4 induces citrullination of CKMT1 exacerbates mucosal inflammation in inflammatory bowel disease.Cellular & molecular immunology · 2024Article
- Citrulline Not a Major Determinant in the Recognition of Peptidylarginine Deiminase 2 and 4 by Autoantibodies in Rheumatoid Arthritis.Arthritis & rheumatology (Hoboken, N.J.) · 2020Article
- PAD enzymes in rheumatoid arthritis: pathogenic effectors and autoimmune targets.Nature reviews. Rheumatology · 2020Review
- Insights into the study and origin of the citrullinome in rheumatoid arthritis.Immunological reviews · 2020Review
- Implantable and Injectable Biomaterial Scaffolds for Cancer Immunotherapy.Frontiers in bioengineering and biotechnology · 2020Review
- Impaired B-cell tolerance checkpoints promote the development of autoimmune diseases and pathogenic autoantibodies.Immunological reviews · 2019Review
- [Rheumatoid arthritis].Zeitschrift fur Rheumatologie · 2018Review
- Smoking is not linked to the development of anti-peptidylarginine deiminase 4 autoantibodies in rheumatoid arthritis.Arthritis research & therapy · 2018Article
- Perspective on Protein Arginine Deiminase Activity-Bicarbonate Is a pH-Independent Regulator of Citrullination.Frontiers in immunology · 2018Article
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Authors and funding
9 authors at 1 institution in 1 country.
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Abstract
objectivesThe citrullinating enzyme peptidylarginine deiminase type 4 (PAD4) is the target of a polyclonal group of autoantibodies in patients with rheumatoid arthritis (RA). A subgroup of such antibodies, initially identified by cross-reactivity with peptidylarginine deiminase type 3 (PAD3), is strongly associated with progression of radiographic joint damage and interstitial lung disease and has the unique ability to activate PAD4. The features of these antibodies in terms of their T cell-dependent origin, genetic characteristics and effect of individual antibody specificities on PAD4 function remain to be defined.
methodsWe used PAD4 tagged with the monomeric fluorescent protein mWasabi to isolate PAD4-specific memory B cells from anti-PAD4 positive patients with RA and applied single cell cloning technologies to obtain monoclonal antibodies.
resultsAmong 44 single B cells, we cloned five antibodies with PAD4-activating properties. Sequence analysis, germline reversion experiments and antigen specificity assays suggested that autoantibodies to PAD4 are not polyreactive and arise from PAD4-reactive precursors. Somatic mutations increase the agonistic activity of these antibodies at low calcium concentrations by facilitating their interaction with structural epitopes that modulate calcium-binding site 5 in PAD4.
conclusionsPAD4-activating antibodies directly amplify a key process in disease pathogenesis, making them unique among other autoantibodies in RA. Understanding the molecular basis for their functionality may inform the design of future PAD4 inhibitors.
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