Variable domain N-linked glycosylation and negative surface charge are key features of monoclonal ACPA: implications for B-cell selection
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 decreased 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 also through non-antigen driven mechanisms.
Code (0)
등록된 구현이 없습니다.
Similar Papers 제목 키워드 기반
Ridge Regression Estimated Linear Probability Model Predictions of O-glycosylation in Proteins with Structural and Sequence Data
The likelihood of O-GlcNAc glycosylation in human proteins is predicted using the ridge regression estimated linear probability model (LPM). To achieve this, sequences from three similar post-translational modifications …
Single-molecule stretching shows glycosylation sets tension in the hyaluronan-aggrecan bottlebrush
Large bottlebrush complexes formed from the polysaccharide hyaluronan (HA) and the proteoglycan aggrecan contribute to cartilage compression resistance and are necessary for healthy joint function. A variety of mechanica…
Ridge Regression Estimated Linear Probability Model Predictions of N-glycosylation in Proteins with Structural and Sequence Data
Absent experimental evidence, a robust methodology to predict the likelihood of N-glycosylation in human proteins is essential for guiding experimental work. Based on the distribution of amino acids in the neighborhood o…
regressionTwo different modes of oscillation in a gene transcription regulatory network with interlinked positive and negative feedback loops
We study the oscillatory behaviour of a gene regulatory network with interlinked positive and negative feedback loop. Frequency and amplitude are two important properties of oscillation. Studied network produces two diff…
Computationally Discovered Potentiating Role of Glycans on NMDA Receptors
N-methyl-D-aspartate receptors (NMDARs) are glycoproteins in the brain central to learning and memory. The effects of glycosylation on the structure and dynamics of NMDARs are largely unknown. In this work, we use extens…