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Antibodies to IgG4 Hinge Can Be Found in Rheumatoid Arthritis Patients During All Stages of Disease and May Exacerbate Chronic Antibody‐Mediated Inflammation
Author(s) -
Stadt Lotte A.,
Vrieze Henk,
Derksen Ninotska I. L.,
Brouwer Mieke,
Wouters Diana,
Schaardenburg Dirkjan,
Wolbink Gertjan,
Rispens Theo
Publication year - 2014
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.38335
Subject(s) - autoantibody , antibody , medicine , rheumatoid arthritis , immunology , inflammation , arthritis
Objective In rheumatoid arthritis (RA), autoantibodies such as anti–citrullinated protein antibodies (ACPAs) develop in response to neoepitopes that are formed under conditions of chronic inflammation. These autoantibodies may subsequently be fragmented by inflammation‐associated proteases, leading to the formation of F(ab′) 2 fragments. The hinge of F(ab′) 2 fragments can serve as a neoepitope, and so‐called antihinge antibodies (AHAs) can be found in RA patients, which might modulate the function of (fragmented) autoantibodies. We undertook this study to investigate the presence and specificities of AHAs in different stages of RA and to study their function. Methods The presence of AHAs was assessed by radioimmunoassay in healthy controls, blood donors who later developed RA, patients with arthralgia, patients with early RA, and patients with established RA. Specificity of the AHAs was analyzed with inhibition assays, and complement‐activating ability was studied with a C4b deposition assay. Results Antibodies to IgG1 hinge, IgG2 hinge, and IgG4 hinge were detected in patients with established RA, with anti–IgG4 hinge antibodies being most specific (appearing in 1% of healthy controls, 3.8% of blood donors who later developed RA, 13% of arthralgia patients, 19% of early RA patients, and 16% of established RA patients). Anti–IgG4 hinge antibodies were subclass specific and were able to restore C4b deposition by IgG4 F(ab′) 2 fragments. In patients with arthralgia and patients with early RA, anti–IgG4 hinge antibodies were associated with rheumatoid factors and ACPAs. Conclusion Anti–IgG4 hinge antibodies are present in RA patients and have low sensitivity but high specificity for RA. Since a significant proportion of ACPAs can be of the IgG4 subclass, the formation of anti–IgG4 hinge antibodies may represent one mechanism of ACPA‐mediated inflammation.