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

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.

• Authors: Jing Shi, Erika Darrah, Gary P Sims, Tomas Mustelin, Kevon Sampson, Maximilian F Konig, Clifton O Bingham 3rd, Antony Rosen, Felipe Andrade
• Journal: Annals of the rheumatic diseases (Ann Rheum Dis) Vol. 77 Issue 1 Pg. 141-148 (Jan 2018) ISSN: 1468-2060 [Electronic] England
• PMID: 29070531 (Publication Type: Journal Article)
• Copyright: © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Chemical References

• Autoantibodies
• PADI3 protein, human
• PADI4 protein, human
• Protein-Arginine Deiminase Type 3
• Protein-Arginine Deiminase Type 4
• Protein-Arginine Deiminases

Topics

• Antibody Affinity
• Arthritis, Rheumatoid (blood, immunology)
• Autoantibodies (blood, immunology)
• B-Lymphocytes (immunology)
• Cross Reactions
• Disease Progression
• Humans
• Protein-Arginine Deiminase Type 3
• Protein-Arginine Deiminase Type 4
• Protein-Arginine Deiminases (blood, immunology)