B-cell receptor sequencing of anti-citrullinated protein antibody (ACPA) IgG-expressing B cells indicates a selective advantage for the introduction of N -glycosylation sites during somatic hypermutation

Acquiring new N-glycosylation sites in variable regions of immunoglobulin genes by somatic hypermutation is a common feature of autoimmune diseases

“…Importantly, in pSS the IgG encoding transcripts exhibited no evidence for signs of antigen selection in the complementarity determining regions. Furthermore, most (60%) of the ac-Nglycs were seen in the framework (FR) 3 region, which is similar to the findings in ACPA-expressing B cells 1. Together, these findings indicate that alternative selection mechanism may result in survival of aberrantly selected B cells in autoimmune diseases, like pSS and RA.…”

“…With great interest, we read the contribution of Vergroesen et al that was published recently in Annals of the Rheumatic Diseases 1. In this manuscript, the authors describe the observation that immunoglobulin variable (V) region heavy and light chain transcripts from anti-citrullinated protein antibody (ACPA) IgG-expressing B cells in patients with rheumatic arthritis (RA) contain N-glycosylation sites (Nglycs) acquired by somatic hypermutation, whereas these acquired Nglycs (ac-Nglycs) were absent in tetanus toxoid (TT) specific B cells of healthy individuals.…”

Autoantibodies and B Cells: The ABC of rheumatoid arthritis pathophysiology

“…Recent studies have suggested that—in case of ACPA—clone selection during SHM may in fact be driven by the introduction of V‐domain N‐ glycosylation sites . Intriguingly, these preliminary results indicate that V‐domain N‐ glycosylation sites seem to be selectively introduced during SHM without unambiguously increasing affinity toward citrullinated antigens.…”

“…For total IgG, V‐domain glycosylation has been estimated to be around 14% . For citrulline‐reactive B cells, however, over 80% of the sequences were found to contain V‐domain glycosylation sites . On the protein level, over 90% of ACPA were found to bear V‐domain glycans .…”

Response to: ‘Acquiring new N-glycosylation sites in variable regions of immunoglobulin genes by somatic hypermutation is a common feature of autoimmune diseases’ by Visser et al

“…We thank Visser et al 1 for their interesting correspondence to our recently published letter entitled ‘B-cell receptor sequencing of anticitrullinated protein antibody (ACPA) IgG-expressing B cells indicates a selective advantage for the introduction of N -glycosylation sites during somatic hypermutation’ 2. Visser et al performed a meta-analysis on publicly available datasets to analyse acquired N -glycosylation sites in the variable region of B cell receptors (BCRs) derived from patients with different autoimmune diseases.…”