Affinity Maturation of the Anti-Citrullinated Protein Antibody Paratope Drives Epitope Spreading and Polyreactivity in Rheumatoid Arthritis.

Arthritis & Rheumatology
Sarah KongpachithWilliam H Robinson

Abstract

Anti-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. Plasmablasts 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. Clonally related monoclonal ACPAs and their shared ancestral antibodies each exhibited differential reactivity against citrullinated antigens. Molec...Continue Reading

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Citations

Jun 6, 2020·Arthritis & Rheumatology·Peter SahlströmCaroline Grönwall
Jul 31, 2020·Clinical Reviews in Allergy & Immunology·Carlo Selmi
Mar 30, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Elisa CorsieroMichele Bombardieri
Jun 11, 2021·European Journal of Immunology·Aase Hensvold, Lars Klareskog
Aug 21, 2021·Drug Delivery and Translational Research·Allen B Tu, Jamal S Lewis

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