Structural Analysis of Variable Domain Glycosylation of Anti-Citrullinated Protein Antibodies in Rheumatoid Arthritis Reveals the Presence of Highly Sialylated Glycans

Hafkenscheid, Lise; Bondt, Albert; Scherer, Hans Ulrich; Huizinga, Tom W J; Wuhrer, Manfred; Toes, René E. M.; Rombouts, Yoann

doi:10.1074/mcp.m116.062919

Cited by 90 publications

(105 citation statements)

References 32 publications

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“…In contrast, ACPA-IgM were identical in size compared with their non-citrulline-specific counterparts (figure 1B). ACPA-IgG Fab-glycans are highly sialylated2 and therefore likely to interact with SNA. Consequently, ACPA-IgG could be strongly enriched on SNA purification, while ACPA-IgM remained in the SNA-negative fraction (figure 1C) indicating the absence of such glycan species from ACPA-IgM.…”

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confidence: 99%

The extensive glycosylation of the ACPA variable domain observed for ACPA-IgG is absent from ACPA-IgM

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confidence: 99%

The extensive glycosylation of the ACPA variable domain observed for ACPA-IgG is absent from ACPA-IgM

et al. 2017

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“…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 . Moreover, increased glycosylation could be seen up to 15 years prior to disease manifestation and increased closer to symptom onset .…”

Section: Anti‐citrullinated Protein Antibodiesmentioning

confidence: 99%

“…49 On the protein level, over 90% of ACPA were found to bear V-domain glycans. 50 Moreover, increased glycosylation could be seen up to 15 years prior to disease manifestation and increased closer to symptom onset. 51 Interestingly, ACPA V-domain glycosylation may also have clinical relevance, as ACPA-positive predisease individuals were more prone to develop RA when their ACPA was highly V-domain glycosylated.…”

Section: Anti -Citrullinated Protein Antibod Ie Smentioning

confidence: 99%

Autoantibodies and B Cells: The ABC of rheumatoid arthritis pathophysiology

Volkov

Schie

Woude

2019

Immunological Reviews

117

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Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation. In the last few decades, new insights into RA‐specific autoantibodies and B cells have greatly expanded our understanding of the disease. The best‐known autoantibodies in RA—rheumatoid factor (RF) and anti‐citrullinated protein antibodies (ACPA)—are present long before disease onset, and both responses show signs of maturation around the time of the first manifestation of arthritis. A very intriguing characteristic of ACPA is their remarkably high abundance of variable domain glycans. Since these glycans may convey an important selection advantage of citrulline‐reactive B cells, they may be the key to understanding the evolution of the autoimmune response. Recently discovered autoantibodies targeting other posttranslational modifications, such as anti‐carbamylated and anti‐acetylated protein antibodies, appear to be closely related to ACPA, which makes it possible to unite them under the term of anti‐modified protein antibodies (AMPA). Despite the many insights gained about these autoantibodies, it is unclear whether they are pathogenic or play a causal role in disease development. Autoreactive B cells from which the autoantibodies originate have also received attention as perhaps more likely disease culprits. The development of autoreactive B cells in RA largely depends on the interaction with T cells in which HLA “shared epitope” and HLA DERAA may play an important role. Recent technological advances made it possible to identify and characterize citrulline‐reactive B cells and acquire ACPA monoclonal antibodies, which are providing valuable insights and help to understand the nature of the autoimmune response underlying RA. In this review, we summarize what is currently known about the role of autoantibodies and autoreactive B cells in RA and we discuss the most prominent hypotheses aiming to explain the origins and the evolution of autoimmunity in RA.

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“…Among all Igs, glycosylation within the IgG‐Fc region is relatively well‐studied. Many researchers have investigated IgG‐Fc glycosylation in different diseases, such as rheumatoid arthritis, lupus erythematosus, myasthenia gravis, hemolytic anemia, gastric cancer and inflammatory bowel disease . Some studies have also investigated the glycosylation pattern on the IgG‐Fab region.…”

Section: Introductionmentioning

confidence: 99%

Quantitative determination of human IgA subclasses and their Fc‐glycosylation patterns in plasma by using a peptide analogue internal standard and ultra‐high‐performance liquid chromatography/triple quadrupole mass spectrometry

Chen

Shiao

et al. 2020

Rapid Comm Mass Spectrometry

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Rationale Glycosylation on immunoglobulins is important for the immune function. In this study, we developed and validated a method for the absolute quantification of IgA subclasses and relative quantification of IgA‐Fc glycopeptides by using affinity purification and ultrahigh‐performance liquid chromatography/tandem mass spectrometry (UHPLC/MS/MS). Only micro‐volumes of plasma were required from each sample and we also applied the method to discover IgA and IgA‐glycopeptide profiles in patients with chronic kidney diseases and IgA nephropathy. Methods Peptide M affinity beads were used to purify IgA, and a cost‐effective peptide analogue was added as internal standard. With an efficient on‐bead digestion process, purified samples were analyzed by UHPLC/MS/MS in multiple reaction monitoring mode. Results Correlation coefficients were greater than 0.999 for the IgA1 and IgA2 calibration curves and greater than 0.994 for glycopeptide regression curves. Intraday and interday precisions for IgA1 and IgA2 were <1.6% and <5.1% RSD, respectively. Intraday and interday accuracies ranged from 102.6 to 114.9% and 103.5 to 113.5% for IgA1 and IgA2, respectively. Stabilities of IgA1 and IgA2 at −80°C for 7 to 15 days ranged from 96.0 to 109.4%, respectively. The Pearson's correlation coefficient was 0.916 when comparing the IgA quantification results of the 30 clinical samples by using ELISAs and the developed UHPLC/MS/MS method. Compared with healthy controls, IgA and IgA‐glycopeptides showed different profiles in patients with chronic kidney diseases and IgA nephropathy. Conclusions The developed method showed good validation results, and the absolute quantification results of IgA correlated with those from ELISA. The pilot application study showed that IgA and IgA‐glycopeptides can be potential biomarker candidates for kidney diseases, and more clinical sample applications are worth investigating.

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Structural Analysis of Variable Domain Glycosylation of Anti-Citrullinated Protein Antibodies in Rheumatoid Arthritis Reveals the Presence of Highly Sialylated Glycans

Cited by 90 publications

References 32 publications

The extensive glycosylation of the ACPA variable domain observed for ACPA-IgG is absent from ACPA-IgM

The extensive glycosylation of the ACPA variable domain observed for ACPA-IgG is absent from ACPA-IgM

Autoantibodies and B Cells: The ABC of rheumatoid arthritis pathophysiology

Quantitative determination of human IgA subclasses and their Fc‐glycosylation patterns in plasma by using a peptide analogue internal standard and ultra‐high‐performance liquid chromatography/triple quadrupole mass spectrometry

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