B cells in rheumatoid arthritis synovial tissues encode focused antibody repertoires that include antibodies that stimulate macrophage TNF-α production

Clin Immunol. 2020 Mar:212:108360. doi: 10.1016/j.clim.2020.108360. Epub 2020 Feb 5.

Abstract

Rheumatoid arthritis (RA) is characterized by the production of anti-citrullinated protein antibodies (ACPAs). To gain insights into the relationship between ACPA-expressing B cells in peripheral blood (PB) and synovial tissue (ST), we sequenced the B cell repertoire in paired PB and ST samples from five individuals with established, ACPA+ RA. Bioinformatics analysis of paired heavy- and light-chain sequences revealed clonally-related family members shared between PB and ST. ST-derived antibody repertoires exhibited reduced diversity and increased normalized clonal family size compared to PB-derived repertoires. Functional characterization showed that seven recombinant antibodies (rAbs) expressed from subject-derived sequences from both compartments bound citrullinated antigens and immune complexes (ICs) formed using one ST-derived rAb stimulated macrophage TNF-α production. Our findings demonstrate B cell trafficking between PB and ST in subjects with RA and ST repertoires include B cells that encode ACPA capable of forming ICs that stimulate cellular responses implicated in RA pathogenesis.

Keywords: ACPA; Antibody repertoire sequencing; Inflammation; Peripheral blood; Rheumatoid arthritis; Synovial tissue.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anti-Citrullinated Protein Antibodies / immunology*
  • Antibody Diversity / immunology
  • Antigen-Antibody Complex / immunology*
  • Arthritis, Rheumatoid / immunology*
  • B-Lymphocytes / immunology*
  • Computational Biology
  • Humans
  • Macrophage Activation / immunology
  • Macrophages / immunology*
  • Synovial Membrane / cytology
  • Synovial Membrane / immunology*
  • Tumor Necrosis Factor-alpha / immunology*

Substances

  • Anti-Citrullinated Protein Antibodies
  • Antigen-Antibody Complex
  • TNF protein, human
  • Tumor Necrosis Factor-alpha