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Recently, we described the presence of highly sialylated N-linked glycans in the antigen-binding fragment (Fab) of almost all anti-citrullinated protein antibody (ACPA) IgG molecules.1 2 These glycans could not be found on several other autoantibody systems analysed. Given the low affinity of ACPA,3 this observation raises the intriguing possibility that citrullinated antigen-specific B cells could be selected based on the presence of glycans in the variable domain, rather than on affinity for their cognate antigen. N-glycosylation requires the presence of specific consensus sequences in the amino acid backbone of proteins.4 However, only few human germline Ig variable region genes encode for such sequences.5 So far, we could identify several N-glycosylation sites in ACPA-IgG Fab-domains using mass spectrometry, but none of these were encoded in the germline sequence.1 This suggests that the extensive presence of N-glycans in ACPA-IgG Fab-domains results from somatic mutations. Moreover, it indicates that the ACPA response matures under the influence of T-cell help, presumably in germinal centres, and makes it conceivable that the introduction of N-glycosylation sites …
Contributors AK contributed to the design of the study, the acquisition, interpretation and analysis of data and wrote the manuscript. LH participated in the analysis and interpretation of data. AD and EM participated in the acquisition, analysis and interpretation of data. FvdB and TR provided SNA samples and participated in the interpretation of data. MvO provided synovial fluid samples. LT and TH contributed to the conception and design of the study and the interpretation of data. RT and HUS contributed to the conception and design of the study, interpretation of data and wrote and revised the manuscript. All authors read, revised and approved the final manuscript.
Funding This work was supported by The Netherlands Organization for Scientific Research (NWO) (project 435000033) and the IMI funded project BeTheCure (contract 1151422). LH was supported by the Dutch Arthritis Foundation (NR 12-2-403). HUS is the recipient of an NWO-ZonMW clinical fellowship (project 90714509), a ZonMW VENI grant (project 91617107), a ZonMW Technology Hotel grant (project 435002030) and of a grant from the Dutch Arthritis Foundation (NR 15-2-402).
Competing interests None declared.
Patient consent Parental/Guardian consent obtained.
Ethics approval Sample acquisition for the study was approved by the LUMC ethical review board. Patients gave written informed consent for participation.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Data presented as “data not shown” or additional data for which only representative examples are provided in this manuscript are available from the authors upon request.
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