ACR Meeting Abstracts

ACR Meeting Abstracts

  • Home
  • Meetings Archive
    • ACR Convergence 2020
    • 2020 ACR/ARP PRSYM
    • 2019 ACR/ARP Annual Meeting
    • 2018 ACR/ARHP Annual Meeting
    • 2017 ACR/ARHP Annual Meeting
    • 2017 ACR/ARHP PRSYM
    • 2016-2009 Meetings
    • Download Abstracts
  • Keyword Index
  • Advanced Search
  • Your Favorites
    • Favorites
    • Login
    • Register
    • View and print all favorites
    • Clear all your favorites
  • Meeting Resource Center

Abstract Number: 2902

Antibodies to PAD4 Drive Monocyte Activation and Differentiation into Osteoclast-like Cells

Pooja Naik1, Jing Shi2, Felipe Andrade3 and Erika Darrah4, 1Department of Medicine, Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, 2Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, 3Medicine/Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, 4Department of Medicine/Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: Activation triggers, autoantibodies, cytokines, osteoclasts and rheumatoid arthritis (RA)

  • Tweet
  • Email
  • Print
Save to PDF
Session Information

Date: Wednesday, October 24, 2018

Session Title: 6W009 ACR Abstract: RA–Etiology & Pathogenesis II (2898–2903)

Session Type: ACR Concurrent Abstract Session

Session Time: 9:00AM-10:30AM

Background/Purpose: Agonistic antibodies to Peptidylarginine Deiminase 4 (PAD4) are hallmarks of a severe form of rheumatoid arthritis (RA) characterized by the most erosive joint damage and lung disease. PAD4 activation and the production of citrullinated autoantigens targeted in RA is likely a major mechanism by which these antibodies may worsen the disease. However, whether anti-PAD4 antibodies may have other effector functions in RA is unknown. The recent discovery that PAD4 is found on the surface of monocytes drove our interest to define the consequences that anti-PAD4 binding may have on the function of these cells.

Methods: We investigated the consequences of PAD4-activating antibody binding to monocytes using a well-characterized panel of human anti-PAD4 and control monoclonal antibodies (mAbs). Extracellular citrullination of fibrinogen was used to study antibody-mediated PAD4 activation on surface of monocytes. We measured anti-PAD4 antibody surface binding and monocyte activation using flow cytometry, and release of pro-inflammatory cytokines using ELISA at 24 hours. We assessed differentiation of monocytes into osteoclasts using tartrate resistant acid phosphatase (TRAP) staining and quantitative estimation of acid phosphatase (AP) activity in the presence of a sub-optimal dose of RANKL at 14 days.

Results: PAD4 is expressed on the monocyte surface in an enzymatically active state that can be hyperactivated twofold upon binding by PAD4 antibodies. Flow cytometry studies revealed preferentially binding of PAD4 mAbs to PAD4 present on surface of monocytes where 63% monocytes bound with PAD4 mAbs versus 1.9% binding with control mAbs (p= 0.0087). Moreover, PAD4 mAbs but not control mAbs induced monocyte activation with upregulation of surface markers such as CD40, CD11c and PDL-1 after 24 hours. Other activation markers such as CD80, CD86 and HLA-DR remained unchanged. Interestingly, monocytes treated with PAD4 mAbs released 100-fold more RA-associated pro-inflammatory cytokines, including IL-6 (1440 pg/ml) and TNF-alpha (94pg/ml), compare to monocytes incubated with control mAbs (14 pg/ml and 0 pg/ml, respectively). At 14 days, we observed larger osteoclast-like cells that were positively stained for TRAP in the presence of PAD4 mAbs compared to control mAbs. This corresponded to a three-fold increase in the amount of AP released by cells cultured with PAD4 mAbs over control mAbs.

Conclusion: Anti-PAD4 autoantibodies can directly interact with monocytes and influence their pathophysiological functions. The pro-inflammatory activation and differentiation into osteoclast-like cells may contribute to the erosive joint disease observed in this severe RA subset.


Disclosure: P. Naik, None; J. Shi, None; F. Andrade, Medimmune; BMS; Pfizer, 2, 5, 7; E. Darrah, Padlock Therapeutics; Medimmune; Pfizer, 2, 5, 7.

To cite this abstract in AMA style:

Naik P, Shi J, Andrade F, Darrah E. Antibodies to PAD4 Drive Monocyte Activation and Differentiation into Osteoclast-like Cells [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/antibodies-to-pad4-drive-monocyte-activation-and-differentiation-into-osteoclast-like-cells/. Accessed January 27, 2021.
  • Tweet
  • Email
  • Print
Save to PDF

« Back to 2018 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/antibodies-to-pad4-drive-monocyte-activation-and-differentiation-into-osteoclast-like-cells/

Advanced Search

Your Favorites

You can save and print a list of your favorite abstracts by clicking the “Favorite” button at the bottom of any abstract. View your favorites »

ACR Convergence: Where Rheumatology Meets. All Virtual. November 5-9.

ACR Pediatric Rheumatology Symposium 2020

© COPYRIGHT 2021 AMERICAN COLLEGE OF RHEUMATOLOGY

Wiley

  • Home
  • Meetings Archive
  • Advanced Search
  • Meeting Resource Center
  • Online Journal
  • Privacy Policy
  • Permissions Policies
loading Cancel
Post was not sent - check your email addresses!
Email check failed, please try again
Sorry, your blog cannot share posts by email.
This site uses cookies: Find out more.