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Title

Variable domain N-linked glycosylation and negative surface charge are key features of monoclonal ACPA: Implications for B-cell selection

Authors
Lloyd, Katy A
Steen, Johanna
Amara, Khaled
Titcombe, Philip J
Israelsson, Lena
Lundström, Susanna L
Zhou, Diana
Zubarev, Roman A
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Published in European Journal of Immunology. 2018, vol. 48, no. 6, p. 1030-1045
Abstract Autoreactive B cells have a central role in the pathogenesis of rheumatoid arthritis (RA), and recent findings have proposed that anti-citrullinated protein autoantibodies (ACPA) may be directly pathogenic. Herein, we demonstrate the frequency of variable-region glycosylation in single-cell cloned mAbs. A total of 14 ACPA mAbs were evaluated for predicted N-linked glycosylation motifs in silico, and compared to 452 highly-mutated mAbs from RA patients and controls. Variable region N-linked motifs (N-X-S/T) were strikingly prevalent within ACPA (100%) compared to somatically hypermutated (SHM) RA bone marrow plasma cells (21%), and synovial plasma cells from seropositive (39%) and seronegative RA (7%). When normalized for SHM, ACPA still had significantly higher frequency of N-linked motifs compared to all studied mAbs including highly mutated HIV broadly-neutralizing and malaria-associated mAbs. The Fab glycans of ACPA-mAbs were highly sialylated, contributed to altered charge, but did not influence antigen binding. The analysis revealed evidence of unusual B-cell selection pressure and SHM-mediated decrease in surface charge and isoelectric point in ACPA. It is still unknown how these distinct features of anti-citrulline immunity may have an impact on pathogenesis. However, it is evident that they offer selective advantages for ACPA+ B cells, possibly through non-antigen driven mechanisms.
Identifiers
PMID: 29512823
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Article (Published version) (3 MB) - document accessible for UNIGE members only Limited access to UNIGE
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Research group Mécanisme de l'inflammation articulaire (44)
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LLOYD, Katy A et al. Variable domain N-linked glycosylation and negative surface charge are key features of monoclonal ACPA: Implications for B-cell selection. In: European Journal of Immunology, 2018, vol. 48, n° 6, p. 1030-1045. doi: 10.1002/eji.201747446 https://archive-ouverte.unige.ch/unige:110670

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Deposited on : 2018-11-12

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