On the presence of HLA-SE alleles and ACPA-IgG variable domain glycosylation in the phase preceding the development of rheumatoid arthritis

Kissel, Theresa; Schie, Karin A van; Hafkenscheid, Lise; Lundquist, Anders; Kokkonen, Heidi; Wuhrer, Manfred; Huizinga, Tom W J; Scherer, Hans Ulrich; Toes, René E. M.; Rantapää-Dahlqvist, Solbritt

doi:10.1136/annrheumdis-2019-215698

Cited by 46 publications

(44 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As we mentioned before, the occurrence of the HLA-DRB1 SE allele may trigger the formation of N-glycosylation sites in ACPA-IgG [30]. The presence of N-Linked Glycans in ACPA-IgG is already considered a promising biomarker of pre-clinical RA, as they could be detected up to 15 years before the first symptoms.…”

Section: The Bumpy Road To Diagnostic Utility Of Hla-drb1mentioning

confidence: 87%

“…Interestingly, a clear association between HLA-DRB1 SE and ACPA-positivity is that healthy individuals have not been found [44]. A recent study shows that this phenomenon can be at least partially explained by the impact of SE on ACPA-IgG V-domain glycosylation, not ACPA-positivity itself [30].…”

Section: Shared Epitope Hypothesismentioning

confidence: 99%

“…The formation of N-glycosylation sites is likely to be a cause of the pathogenicity of ACPA, or it may affect their persistence. Long-term observations of RA patients indicate that the ACPA glycosylation process can be detected already more than 15 years before the RA onset and intensifies as the first symptoms of the disease approach [30,31]. The incorporation of N-glycosylation sites is thought to be a result of CD4+ T cell dependent somatic hypermutation of ACPA [32].…”

Section: The Pathogenic Link Between Acpa and Hla In Rheumatoid Arthrmentioning

confidence: 99%

“…According to the results of recent studies, the occurrence of HLA-DRB1 risk alleles predispose the formation of N-glycosylation sites in ACPA-IgG, but the precise mechanism of this predisposition is not known [30]. Nevertheless, due to the fact that HLA-DR (encoded by HLA-DRB1 gene) molecules are necessary for the activation of CD4+ T cell, we assume that it is likely that HLA-DRB1 risk alleles induce somatic hypermutation of ACPA, leading to their pathogenicity.…”

Section: The Pathogenic Link Between Acpa and Hla In Rheumatoid Arthrmentioning

confidence: 99%

See 3 more Smart Citations

Current Understanding of an Emerging Role of HLA-DRB1 Gene in Rheumatoid Arthritis–From Research to Clinical Practice

Wysocki

Olesińska

Paradowska‐Gorycka

2020

Cells

View full text Add to dashboard Cite

Rheumatoid arthritis (RA) is an autoimmune disease with an unclear pathogenic mechanism. However, it has been proven that the key underlying risk factor is a genetic predisposition. Association studies of the HLA-DRB1 gene clearly indicate its importance in RA morbidity. This review presents the current state of knowledge on the impact of HLA-DRB1 gene, functioning both as a component of the patient’s genome and as an environmental risk factor. The impact of known HLA-DRB1 risk variants on the specific structure of the polymorphic HLA-DR molecule, and epitope binding affinity, is presented. The issues of the potential influence of HLA-DRB1 on the occurrence of non-articular disease manifestations and response to treatment are also discussed. A deeper understanding of the role of the HLA-DRB1 gene is essential to explore the complex nature of RA, which is a result of multiple contributing factors, including genetic, epigenetic and environmental factors. It also creates new opportunities to develop modern and personalized forms of therapy.

show abstract

Section: The Bumpy Road To Diagnostic Utility Of Hla-drb1mentioning

confidence: 87%

Section: Shared Epitope Hypothesismentioning

confidence: 99%

Section: The Pathogenic Link Between Acpa and Hla In Rheumatoid Arthrmentioning

confidence: 99%

Section: The Pathogenic Link Between Acpa and Hla In Rheumatoid Arthrmentioning

confidence: 99%

See 2 more Smart Citations

Current Understanding of an Emerging Role of HLA-DRB1 Gene in Rheumatoid Arthritis–From Research to Clinical Practice

Wysocki

Olesińska

Paradowska‐Gorycka

2020

Cells

View full text Add to dashboard Cite

show abstract

“…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 . 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 Antibodiesmentioning

confidence: 99%

Autoantibodies and B Cells: The ABC of rheumatoid arthritis pathophysiology

Volkov

Schie

Woude

2019

Immunological Reviews

117

View full text Add to dashboard Cite

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.

show abstract

Association of a Serum Protein Signature With Rheumatoid Arthritis Development

O’Neil

Spicer

Smolik

et al. 2020

Arthritis & Rheumatology

View full text Add to dashboard Cite

Objective. The pathophysiologic events that precede the onset of rheumatoid arthritis (RA) remain incompletely understood. This study was undertaken to identify changes in the serum proteome that precede the onset of RA, with the aim of providing new insights into the pathogenic mechanisms that lead to its development. Methods. In a cohort of first-degree relatives of Indigenous North American RA patients, the SomaScan proteomics platform was used to determine the levels of 1,307 proteins in multiple longitudinal serum samples from 17 individuals who were followed up prospectively to the time of disease onset. Proteomic signatures from this group of individuals (designated the progressor group) were compared to those in a group of individuals who were considered at risk of developing RA, stratified as either positive (n = 63) or negative (n = 47) for anti-citrullinated protein antibodies (ACPAs) (designated the at-risk group). Machine learning was used to identify a protein signature that could accurately classify those individuals at highest risk of future RA development. Results. A preclinical proteomic signature that differentiated RA progressors from at-risk individuals, irrespective of ACPA status, was identified (area under the curve 0.913, accuracy 91.2%). Importantly, the predictive preclinical proteomic signature was present not only in serum samples obtained close to the onset of RA, but also in serum samples obtained a median of 30.9 months prior to onset. Network analysis implicated the activation of Toll-like receptor 2 and production of tumor necrosis factor and interleukin-1 as key events that precede RA progression. Conclusion. Alterations in the serum proteome in the preclinical phase of RA can emerge years prior to the onset of disease. Our findings suggest that the serum proteome provides a rich source of proteins serving both to classify at-risk individuals and to identify molecular pathways involved in the development of clinically detectable RA.

show abstract

On the presence of HLA-SE alleles and ACPA-IgG variable domain glycosylation in the phase preceding the development of rheumatoid arthritis

Cited by 46 publications

References 16 publications

Current Understanding of an Emerging Role of HLA-DRB1 Gene in Rheumatoid Arthritis–From Research to Clinical Practice

Current Understanding of an Emerging Role of HLA-DRB1 Gene in Rheumatoid Arthritis–From Research to Clinical Practice

Autoantibodies and B Cells: The ABC of rheumatoid arthritis pathophysiology

Association of a Serum Protein Signature With Rheumatoid Arthritis Development

Contact Info

Product

Resources

About