Rheumatoid factor as a potentiator of anti-citrullinated protein antibody-mediated inflammation in rheumatoid arthritis

Jeremy Sokolove, Dannette S. Johnson, Lauren J. Lahey, Catriona A. Wagner, Danye Cheng, Geoffrey M. Thiele, Kaleb Michaud, Harlan Sayles, Andreas M. Reimold, Liron Caplan, Grant W. Cannon, Gail Kerr, Ted R. Mikuls, William H. Robinson

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Abstract

Objective The co-occurrence of rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) positivity in rheumatoid arthritis (RA) is well described. However, the mechanisms underlying the potential interaction between these 2 distinct autoantibodies have not been well defined. The aim of this study was to evaluate the epidemiologic and molecular interaction of ACPAs and RF and its association with both disease activity and measures of RA-associated inflammation. Methods In a cohort of 1,488 US veterans with RA, measures of disease activity and serum levels of cytokines and multiplex ACPAs were compared between the following groups of patients: double-negative (anti-cyclic citrullinated peptide [anti-CCP]-/RF-), anti-CCP+/RF-, anti-CCP-/RF+, or double-positive (anti-CCP+/RF+). Additional studies were performed using an in vitro immune complex (IC) stimulation assay in which macrophages were incubated with ACPA ICs in the presence or absence of monoclonal IgM-RF, and tumor necrosis factor α production measured as a readout of macrophage activation. Results Compared with the double-negative subgroup (as well as each single-positive subgroup), the double-positive subgroup exhibited higher disease activity as well as higher levels of C-reactive protein and inflammatory cytokines (all P < 0.001). In vitro stimulation of macrophages by ACPA ICs increased cytokine production, and the addition of monoclonal IgM-RF significantly increased macrophage tumor necrosis factor α production (P = 0.003 versus ACPA ICs alone). Conclusion The combined presence of ACPAs and IgM-RF mediates increased proinflammatory cytokine production in vitro and is associated with increased systemic inflammation and disease activity in RA. Our data suggest that IgM-RF enhances the capacity of ACPA ICs to stimulate macrophage cytokine production, thereby providing a mechanistic link by which RF enhances the pathogenicity of ACPA ICs in RA.

Original languageEnglish (US)
Pages (from-to)813-821
Number of pages9
JournalArthritis and Rheumatology
Volume66
Issue number4
DOIs
StatePublished - 2014

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Rheumatoid Factor
Rheumatoid Arthritis
Inflammation
Antibodies
Proteins
Immunoglobulin M
Cytokines
Macrophages
Tumor Necrosis Factor-alpha
Macrophage Activation
Veterans
Antigen-Antibody Complex
C-Reactive Protein
Autoantibodies
Virulence

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology

Cite this

Sokolove, J., Johnson, D. S., Lahey, L. J., Wagner, C. A., Cheng, D., Thiele, G. M., ... Robinson, W. H. (2014). Rheumatoid factor as a potentiator of anti-citrullinated protein antibody-mediated inflammation in rheumatoid arthritis. Arthritis and Rheumatology, 66(4), 813-821. https://doi.org/10.1002/art.38307

Rheumatoid factor as a potentiator of anti-citrullinated protein antibody-mediated inflammation in rheumatoid arthritis. / Sokolove, Jeremy; Johnson, Dannette S.; Lahey, Lauren J.; Wagner, Catriona A.; Cheng, Danye; Thiele, Geoffrey M.; Michaud, Kaleb; Sayles, Harlan; Reimold, Andreas M.; Caplan, Liron; Cannon, Grant W.; Kerr, Gail; Mikuls, Ted R.; Robinson, William H.

In: Arthritis and Rheumatology, Vol. 66, No. 4, 2014, p. 813-821.

Research output: Contribution to journalArticle

Sokolove, J, Johnson, DS, Lahey, LJ, Wagner, CA, Cheng, D, Thiele, GM, Michaud, K, Sayles, H, Reimold, AM, Caplan, L, Cannon, GW, Kerr, G, Mikuls, TR & Robinson, WH 2014, 'Rheumatoid factor as a potentiator of anti-citrullinated protein antibody-mediated inflammation in rheumatoid arthritis', Arthritis and Rheumatology, vol. 66, no. 4, pp. 813-821. https://doi.org/10.1002/art.38307
Sokolove, Jeremy ; Johnson, Dannette S. ; Lahey, Lauren J. ; Wagner, Catriona A. ; Cheng, Danye ; Thiele, Geoffrey M. ; Michaud, Kaleb ; Sayles, Harlan ; Reimold, Andreas M. ; Caplan, Liron ; Cannon, Grant W. ; Kerr, Gail ; Mikuls, Ted R. ; Robinson, William H. / Rheumatoid factor as a potentiator of anti-citrullinated protein antibody-mediated inflammation in rheumatoid arthritis. In: Arthritis and Rheumatology. 2014 ; Vol. 66, No. 4. pp. 813-821.
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title = "Rheumatoid factor as a potentiator of anti-citrullinated protein antibody-mediated inflammation in rheumatoid arthritis",
abstract = "Objective The co-occurrence of rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) positivity in rheumatoid arthritis (RA) is well described. However, the mechanisms underlying the potential interaction between these 2 distinct autoantibodies have not been well defined. The aim of this study was to evaluate the epidemiologic and molecular interaction of ACPAs and RF and its association with both disease activity and measures of RA-associated inflammation. Methods In a cohort of 1,488 US veterans with RA, measures of disease activity and serum levels of cytokines and multiplex ACPAs were compared between the following groups of patients: double-negative (anti-cyclic citrullinated peptide [anti-CCP]-/RF-), anti-CCP+/RF-, anti-CCP-/RF+, or double-positive (anti-CCP+/RF+). Additional studies were performed using an in vitro immune complex (IC) stimulation assay in which macrophages were incubated with ACPA ICs in the presence or absence of monoclonal IgM-RF, and tumor necrosis factor α production measured as a readout of macrophage activation. Results Compared with the double-negative subgroup (as well as each single-positive subgroup), the double-positive subgroup exhibited higher disease activity as well as higher levels of C-reactive protein and inflammatory cytokines (all P < 0.001). In vitro stimulation of macrophages by ACPA ICs increased cytokine production, and the addition of monoclonal IgM-RF significantly increased macrophage tumor necrosis factor α production (P = 0.003 versus ACPA ICs alone). Conclusion The combined presence of ACPAs and IgM-RF mediates increased proinflammatory cytokine production in vitro and is associated with increased systemic inflammation and disease activity in RA. Our data suggest that IgM-RF enhances the capacity of ACPA ICs to stimulate macrophage cytokine production, thereby providing a mechanistic link by which RF enhances the pathogenicity of ACPA ICs in RA.",
author = "Jeremy Sokolove and Johnson, {Dannette S.} and Lahey, {Lauren J.} and Wagner, {Catriona A.} and Danye Cheng and Thiele, {Geoffrey M.} and Kaleb Michaud and Harlan Sayles and Reimold, {Andreas M.} and Liron Caplan and Cannon, {Grant W.} and Gail Kerr and Mikuls, {Ted R.} and Robinson, {William H.}",
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T1 - Rheumatoid factor as a potentiator of anti-citrullinated protein antibody-mediated inflammation in rheumatoid arthritis

AU - Sokolove, Jeremy

AU - Johnson, Dannette S.

AU - Lahey, Lauren J.

AU - Wagner, Catriona A.

AU - Cheng, Danye

AU - Thiele, Geoffrey M.

AU - Michaud, Kaleb

AU - Sayles, Harlan

AU - Reimold, Andreas M.

AU - Caplan, Liron

AU - Cannon, Grant W.

AU - Kerr, Gail

AU - Mikuls, Ted R.

AU - Robinson, William H.

PY - 2014

Y1 - 2014

N2 - Objective The co-occurrence of rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) positivity in rheumatoid arthritis (RA) is well described. However, the mechanisms underlying the potential interaction between these 2 distinct autoantibodies have not been well defined. The aim of this study was to evaluate the epidemiologic and molecular interaction of ACPAs and RF and its association with both disease activity and measures of RA-associated inflammation. Methods In a cohort of 1,488 US veterans with RA, measures of disease activity and serum levels of cytokines and multiplex ACPAs were compared between the following groups of patients: double-negative (anti-cyclic citrullinated peptide [anti-CCP]-/RF-), anti-CCP+/RF-, anti-CCP-/RF+, or double-positive (anti-CCP+/RF+). Additional studies were performed using an in vitro immune complex (IC) stimulation assay in which macrophages were incubated with ACPA ICs in the presence or absence of monoclonal IgM-RF, and tumor necrosis factor α production measured as a readout of macrophage activation. Results Compared with the double-negative subgroup (as well as each single-positive subgroup), the double-positive subgroup exhibited higher disease activity as well as higher levels of C-reactive protein and inflammatory cytokines (all P < 0.001). In vitro stimulation of macrophages by ACPA ICs increased cytokine production, and the addition of monoclonal IgM-RF significantly increased macrophage tumor necrosis factor α production (P = 0.003 versus ACPA ICs alone). Conclusion The combined presence of ACPAs and IgM-RF mediates increased proinflammatory cytokine production in vitro and is associated with increased systemic inflammation and disease activity in RA. Our data suggest that IgM-RF enhances the capacity of ACPA ICs to stimulate macrophage cytokine production, thereby providing a mechanistic link by which RF enhances the pathogenicity of ACPA ICs in RA.

AB - Objective The co-occurrence of rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) positivity in rheumatoid arthritis (RA) is well described. However, the mechanisms underlying the potential interaction between these 2 distinct autoantibodies have not been well defined. The aim of this study was to evaluate the epidemiologic and molecular interaction of ACPAs and RF and its association with both disease activity and measures of RA-associated inflammation. Methods In a cohort of 1,488 US veterans with RA, measures of disease activity and serum levels of cytokines and multiplex ACPAs were compared between the following groups of patients: double-negative (anti-cyclic citrullinated peptide [anti-CCP]-/RF-), anti-CCP+/RF-, anti-CCP-/RF+, or double-positive (anti-CCP+/RF+). Additional studies were performed using an in vitro immune complex (IC) stimulation assay in which macrophages were incubated with ACPA ICs in the presence or absence of monoclonal IgM-RF, and tumor necrosis factor α production measured as a readout of macrophage activation. Results Compared with the double-negative subgroup (as well as each single-positive subgroup), the double-positive subgroup exhibited higher disease activity as well as higher levels of C-reactive protein and inflammatory cytokines (all P < 0.001). In vitro stimulation of macrophages by ACPA ICs increased cytokine production, and the addition of monoclonal IgM-RF significantly increased macrophage tumor necrosis factor α production (P = 0.003 versus ACPA ICs alone). Conclusion The combined presence of ACPAs and IgM-RF mediates increased proinflammatory cytokine production in vitro and is associated with increased systemic inflammation and disease activity in RA. Our data suggest that IgM-RF enhances the capacity of ACPA ICs to stimulate macrophage cytokine production, thereby providing a mechanistic link by which RF enhances the pathogenicity of ACPA ICs in RA.

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