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Abstract
Background Rheumatoid factors (RF) are one of the hallmark autoantibodies characteristic of rheumatoid arthritis (RA), and are frequently observed in other diseases and in healthy individuals. RFs comprise multiple subtypes with different specificities towards the constant region of human IgG. Studies indicate that these patterns differ between naturally occurring RFs and RFs associated with disease. However, individual specificities characteristic of either have not been clearly defined.
Methods In this study, we developed an extended set of engineered IgG-fragment crystallisable (Fc) targets with preferential RF binding to specific (conformational) epitopes, which was subsequently used for profiling of RF binding patterns in a compiled exploration cohort, consisting of sera from healthy donors with measurable RF and patients with RA, primary Sjögren’s syndrome (pSS) and seropositive arthralgia.
Results We identified an epitope that is strongly associated with RA, which was targeted by both IgM-RF and IgA-RF. We also identified an epitope that is preferentially targeted by healthy donor (IgM) RFs. IgM-RFs derived from healthy donors and patients with RA and pSS all target distinct regions on the IgG-Fc, whereas overall, the IgA-RF repertoire is largely restricted to pathology-associated specificities. Using monoclonal RFs with different specificities, we furthermore demonstrate that the capacity to activate complement or even inhibit IgG-mediated complement activation varies according to the epitopes to which RFs bind.
Conclusions Our results demonstrate both the need and feasibility to redefine ‘RF’ into pathological and physiological autoantibody subtypes.
- Sjogren's syndrome
- rheumatoid factor
- autoimmunity
- autoantibodies
- arthritis, rheumatoid
Data availability statement
Data are available on reasonable request.
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Data availability statement
Data are available on reasonable request.
Footnotes
Handling editor Josef S Smolen
Contributors Designing research studies: NO, TR. Conducting experiments: NO, PO-DH, DK, JJ. Acquiring and analysing data: NO, GMV, FGMK, DvS, GJW. Writing the manuscript: NO, TR. Guarantor: TR.
Funding This work was supported by the Dutch Arthritis Foundation (grant 17-2-404).
Disclaimer The funders had no role in study design, data analyses or writing of the report.
Competing interests DvS, GJW and TR are inventors on a patent application based on the use of bioengineered IgG targets for the characterisation of rheumatoid factor reactivity patterns. The other authors declare no conflict of interest.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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