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The majority of patients with rheumatoid arthritis (RA) harbours IgG antibodies targeting citrullinated protein antigens (ACPA). Recently, we showed that >90% of ACPA-IgG in serum are glycosylated in the variable domain.1 N-linked glycosylation requires a consensus sequence in the protein backbone (N-X-S/T (asparagine-X-serine/threonine), where X is any amino acid except proline), which is scarce in germline-encoded Ig variable region genes.2 3 Accordingly, hyperglycosylation of ACPA-IgG requires either clonal expansion of B cells expressing B-cell receptors (BCR) containing germline-encoded N-glycosylation sites or generation of de novo sites through somatic hypermutation (SHM).4
Here, we analysed the BCR repertoire of ACPA-expressing B cells to understand the molecular basis of this remarkable glycosylation. ACPA-expressing B cells were sorted as pools (10 cells per pool) from peripheral blood mononuclear cells of eight patients with ACPA-positive RA.5 Anchoring reverse transcription of immunoglobulin sequences and amplification by nested (ARTISAN) PCR-based BCR sequencing6 followed by full-length variable region IgG transcript analysis revealed high nucleotide mutation rates in 97 unique ACPA-IgG heavy chains (HC; mean ±SD: 52.86±16.73; figure 1A). 81% of these contained one or more N-glycosylation sites.
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