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

Affinity maturation shapes the function of agonistic antibodies to peptidylarginine deiminase type 4 in rheumatoid arthritis.
Published: 
Jan 2018
Publisher: 
BMJ Journals
Author: 
Tomas Mustelin, MD, D. Med. Sci.

Shi J1, Darrah E1, Sims GP2, Mustelin T2, Sampson K1, Konig MF1, Bingham CO 3rd1, Rosen A1, Andrade F1.

Author information

1  Division of Rheumatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
2  Respiratory, Inflammation, and Autoimmunity, MedImmune LLC, Gaithersburg, Maryland, USA.

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.

PMID: 29070531
PMCID: PMC5935255 [Available on 2019-01-01]
DOI:    10.1136/annrheumdis-2017-211489