ArticleArthritis & rheumatology (Hoboken, N.J.)2019
Affinity Maturation of the Anti-Citrullinated Protein Antibody Paratope Drives Epitope Spreading and Polyreactivity in Rheumatoid Arthritis.
Article in Arthritis & rheumatology (Hoboken, N.J.), 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 102 citations in OpenAlex.
- Senescent-like activated naive B cells contribute to progression to clinical rheumatoid arthritis.Nature aging · 2026Article
- Protective and Pathogenic Antibodies to Citrullinated Antigens.Immunological reviews · 2026Review
- Neutrophil Extracellular Trap Formation-Derived Peptidylarginine Deiminases in the Citrullination of Oral Bacteria to Promote Inflammation in Rheumatoid Arthritis.The Journal of rheumatology · 2026Article
- Pharmacological insights into gut microbiota modulation in systemic lupus erythematosus: Mechanisms, treatment strategies, and clinical implications.The Journal of pharmacology and experimental therapeutics · 2025Review
- A 3D Surface Plot for the Effective Visualization of Specific Serum Antibody Binding Properties.Antibodies (Basel, Switzerland) · 2025Article
- Fibroblasts in immune responses, inflammatory diseases and therapeutic implications.Nature reviews. Rheumatology · 2025Review
- Citrullinated peptides as drug candidates for rheumatoid arthritis.Frontiers in immunology · 2025Review
- Lymph nodes as gatekeepers of autoimmune diseases.RMD open · 2024Review
- Article
- Distinct mucosal endotypes as initiators and drivers of rheumatoid arthritis.Nature reviews. Rheumatology · 2024Review
- Galangin: A Promising Flavonoid for the Treatment of Rheumatoid Arthritis-Mechanisms, Evidence, and Therapeutic Potential.Pharmaceuticals (Basel, Switzerland) · 2024Review
- The peculiar features, diversity and impact of citrulline-reactive autoantibodies.Nature reviews. Rheumatology · 2024Review
- The monocyte cell surface is a unique site of autoantigen generation in rheumatoid arthritis.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Antigen-specific Fab profiling achieves molecular-resolution analysis of human autoantibody repertoires in rheumatoid arthritis.Nature communications · 2024Article
- Seven-chain adaptive immune receptor repertoire analysis in rheumatoid arthritis reveals novel features associated with disease and clinically relevant phenotypes.Genome biology · 2024Article
- B-Cell Receptor Repertoire: Recent Advances in Autoimmune Diseases.Clinical reviews in allergy & immunology · 2024Review
- Aberrant Activation of Immune and Non-Immune Cells Contributes to Joint Inflammation and Bone Degradation in Rheumatoid Arthritis.International journal of molecular sciences · 2023Review
- Significance of Type II Collagen Posttranslational Modifications: From Autoantigenesis to Improved Diagnosis and Treatment of Rheumatoid Arthritis.International journal of molecular sciences · 2023Review
- Oral mucosal breaks trigger anti-citrullinated bacterial and human protein antibody responses in rheumatoid arthritis.Science translational medicine · 2023Article
- Making inroads to precision medicine for the treatment of autoimmune diseases: Harnessing genomic studies to better diagnose and treat complex disorders.Cambridge prisms. Precision medicine · 2023Review
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
objectiveAnti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis (RA). While epitope spreading of the serum ACPA response is believed to contribute to RA pathogenesis, little is understood regarding how this phenomenon occurs. This study was undertaken to analyze the antibody repertoires of individuals with RA to gain insight into the mechanisms leading to epitope spreading of the serum ACPA response in RA.
methodsPlasmablasts from the blood of 6 RA patients were stained with citrullinated peptide tetramers to identify ACPA-producing B cells by flow cytometry. Plasmablasts were single-cell sorted and sequenced to obtain antibody repertoires. Sixty-nine antibodies were recombinantly expressed, and their anticitrulline reactivities were characterized using a cyclic citrullinated peptide enzyme-linked immuosorbent assay and synovial antigen arrays. Thirty-six mutated antibodies designed either to represent ancestral antibodies or to test paratope residues critical for binding, as determined from molecular modeling studies, were also tested for anticitrulline reactivities.
resultsClonally related monoclonal ACPAs and their shared ancestral antibodies each exhibited differential reactivity against citrullinated antigens. Molecular modeling identified residues within the complementarity-determining region loops and framework regions predicted to be important for citrullinated antigen binding. Affinity maturation resulted in mutations of these key residues, which conferred binding to different citrullinated epitopes and/or increased polyreactivity to citrullinated epitopes.
conclusionThese results demonstrate that the different somatic hypermutations accumulated by clonally related B cells during affinity maturation alter the antibody paratope to mediate epitope spreading and polyreactivity of the ACPA response in RA, suggesting that these may be key properties that likely contribute to the pathogenicity of ACPAs.
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