Affinity maturation shapes the function of agonistic antibodies to peptidylarginine deiminase type 4 in rheumatoid arthritis

Jing Shi, Erika Darrah, Gary P. Sims, Tomas Mustelin, Kevon Sampson, Maximilian F. Konig, Clifton Bingham, Antony Rosen, Felipe A Andrade

Research output: Contribution to journalArticle

Abstract

OBJECTIVES: The 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.

METHODS: We 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.

RESULTS: Among 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.

CONCLUSIONS: PAD4-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.

Original languageEnglish (US)
Pages (from-to)141-148
Number of pages8
JournalAnnals of the Rheumatic Diseases
Volume77
Issue number1
DOIs
StatePublished - Jan 1 2018

Keywords

  • ant-ccp
  • autoantibodies
  • autoimmune diseases
  • autoimmunity
  • rheumatoid Arthritis

ASJC Scopus subject areas

  • Rheumatology
  • Immunology and Allergy
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)

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