TY - JOUR
T1 - Rheumatoid factor autoantibody repertoire profiling reveals distinct binding epitopes in health and autoimmunity
AU - Oskam, Nienke
AU - Ooijevaar-de Heer, Pleuni
AU - Kos, Dorien
AU - Jeremiasse, Jorn
AU - van Boheemen, Laurette
AU - Verstappen, Gwenny M.
AU - Kroese, Frans G. M.
AU - van Schaardenburg, Dirkjan
AU - Wolbink, Gertjan
AU - Rispens, Theo
N1 - Funding Information: This work was supported by the Dutch Arthritis Foundation (grant 17-2-404). Publisher Copyright: © 2023 BMJ Publishing Group. All rights reserved.
PY - 2023/7/1
Y1 - 2023/7/1
N2 - 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.
AB - 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.
KW - Sjogren's syndrome
KW - arthritis, rheumatoid
KW - autoantibodies
KW - autoimmunity
KW - rheumatoid factor
UR - http://www.scopus.com/inward/record.url?scp=85160242212&partnerID=8YFLogxK
U2 - https://doi.org/10.1136/ard-2023-223901
DO - https://doi.org/10.1136/ard-2023-223901
M3 - Article
C2 - 37055152
SN - 0003-4967
VL - 82
SP - 945
EP - 956
JO - Annals of the rheumatic diseases
JF - Annals of the rheumatic diseases
IS - 7
M1 - 223901
ER -