Rheumatoid Factor as a Potentiator of Anti-Citrullinated Protein Antibody-Mediated Inflammation in Rheumatoid Arthritis

被引:192
作者
Sokolove, Jeremy [1 ,2 ]
Johnson, Dannette S. [3 ,4 ]
Lahey, Lauren J. [1 ,2 ]
Wagner, Catriona A. [1 ,2 ]
Cheng, Danye [1 ,2 ]
Thiele, Geoffrey M. [5 ,6 ]
Michaud, Kaleb [5 ,6 ]
Sayles, Harlan [5 ,6 ]
Reimold, Andreas M. [7 ,8 ]
Caplan, Liron [9 ,10 ]
Cannon, Grant W. [11 ,12 ]
Kerr, Gail [13 ,14 ]
Mikuls, Ted R. [5 ,6 ]
Robinson, William H. [1 ,2 ]
机构
[1] Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USA
[2] Stanford Univ, Sch Med, Stanford, CA 94305 USA
[3] Jackson VA Med Ctr, Jackson, MS USA
[4] Univ Mississippi, Jackson, MS USA
[5] Omaha VA Med Ctr, Omaha, NE USA
[6] Univ Nebraska Med Ctr, Omaha, NE USA
[7] Dallas VA Med Ctr, Dallas, TX USA
[8] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA
[9] Dept Vet Affairs, Denver, CO USA
[10] Univ Colorado, Sch Med, Denver, CO USA
[11] George E Wahlen VA Med Ctr, Salt Lake City, UT USA
[12] Univ Utah, Salt Lake City, UT USA
[13] Washington DC VA Med Ctr, Washington, DC USA
[14] Georgetown Univ, Washington, DC USA
关键词
FC-GAMMA RECEPTOR; DISEASE-ACTIVITY; US VETERANS; IGM; AUTOANTIBODIES; ASSOCIATION; COMPLEXES; PEPTIDE; FIBRINOGEN; INDUCTION;
D O I
10.1002/art.38307
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 (anticyclic citrullinated peptide [anti-CCP]-/RF-), anti-CCP-/RF+, anti-CCP-/RF+, or double-positive (antiCCP+/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 alpha 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 alpha 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.
引用
收藏
页码:813 / 821
页数:9
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