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Reijm, S. 2024

On the origin and evolution of the autoreactive B cell response in rheumatoid arthritis

Doctoral Thesis

open access

The aim of the studies described in this thesis is to come to better understanding of the anti-modified protein antibody (AMPA) response in rheumatoid arthritis (RA) and to investigate the origin... Show moreThe aim of the studies described in this thesis is to come to better understanding of the anti-modified protein antibody (AMPA) response in rheumatoid arthritis (RA) and to investigate the origin of this response at both the antibody and B cell level. This is relevant as such studies could give insights on how B cell tolerance in RA is breached and gives rise to autoreactive B cells and the production of autoantibodies. This knowledge is important for preventing the disease or defining potential targets to treat the disease. Show less

Krijbolder, D.I. 2023

Emerging opportunities in clinically suspect arthalgia: crossing the frontiers of rheumatoid arthritis

Doctoral Thesis

open access

Dit proefschrift richt zich op het symptomatische voorstadium van reumatoïde artritis, clinically suspect arthalgia, met de volgende doelstellingen: beter begrijpen van de symptomen en de hieraan... Show moreDit proefschrift richt zich op het symptomatische voorstadium van reumatoïde artritis, clinically suspect arthalgia, met de volgende doelstellingen: beter begrijpen van de symptomen en de hieraan onderliggende mechanismen (deel I), met MRI in de CSA-fase meerleren over het ontstaan van RA en identificeren van mensen met een verhoogd risico op RA (deel II), onderzoeken of medicamenteuze behandeling in de CSA-fase zin heeft en hoe deze behandeling eruit zou moeten zien (deel III). Show less

Leeuwen, T. van 2023

Bioorthogonal chemistry to unveil antigen processing events

Doctoral Thesis

some documents under embargo until 2025-05-23

The research described in this thesis focused on the use of bioorthogonal antigens to investigate immunological processes in antigen presenting cells. Bioorthogonal antigens are antigenic proteins... Show moreThe research described in this thesis focused on the use of bioorthogonal antigens to investigate immunological processes in antigen presenting cells. Bioorthogonal antigens are antigenic proteins produced through recombinant expression in a methionine auxotrophic E. coli strain. This allows for the replacement of methionine residues with the bioorthogonal non-canonical amino acid, azidohomoalanine (Aha), that resembles methionine. Aha contains an azide group that enables the selective and rapid visualization or enrichment of the antigen after a biological experiment using alkyne-modified fluorophores or alkyne-containing resins, respectively, via copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). The research involved studying the effects of post-translational modifications (PTMs), antigen complexation and glycosylation of antibodies in immune complexes on the uptake, proteolysis, and T cell activation by dendritic cells (DCs) of Aha-containing antigens. Additionally, a new method was developed to enrich low abundant bioorthogonal antigenic fragments from complex mixtures. This method can be used in future studies to identify processed Aha-containing fragments from immune cells that are preserved for T cell presentation. Show less

Kristyanto, H. 2023

Autoreactive B cells in rheumatoid arthritis

Doctoral Thesis

some documents under embargo until 2025-10-19

Rheumatoid arthritis (RA) is an autoimmune disease affecting joints which is hallmarked by the presence of autoantibodies against citrrulianted protein (ACPA). This thesis describes the phenotypic... Show moreRheumatoid arthritis (RA) is an autoimmune disease affecting joints which is hallmarked by the presence of autoantibodies against citrrulianted protein (ACPA). This thesis describes the phenotypic and functional characteristics of ACPA-expressing autoreactive B cells which suggest potential pathologic roles of these B cells in RA pathogenesis. The thesis also describes strategies to specifically deplete ACPA-expressing B cells to improve current RA therapeutic options. Show less

Yang, W. 2023

Lipid signaling and inflammation: metabolomics for better diagnosis and treatment strategy

Doctoral Thesis

some documents under embargo until 2024-11-24

Lipid signaling is an essential biological event/process in a plethora of pathophysiological conditions. The underlying idea of this thesis is that many of the roles and the complex interplay of... Show moreLipid signaling is an essential biological event/process in a plethora of pathophysiological conditions. The underlying idea of this thesis is that many of the roles and the complex interplay of the individual signaling lipids in inflammatory processes and related conditions in health and disease is not well known, and therefore has to be studied integrally as a complex network. In order to study this complex interplay, an improved broad analytical method is necessary to analyze a wide range of different signaling lipid classes such as oxylipins, (nitro) free fatty acids, endocannabinoids, bile acids and different subclasses of lysophospholipids. Therefore, the aim of this thesis is to develop a better method to study signaling lipids, and to apply it to study the role of these molecules in several relevant biological questions for a better understanding of inflammation related pathophysiology including autoimmune diseases, neurodegeneration and regulatory effect of exercise training. Show less

Wouters, F. 2023

Clinically suspect arthralgia: unraveling the development of rheumatoid arthritis

Doctoral Thesis

open access

In this thesis two main aims were addressed. It has long been established that early treatment of rheumatoid arthritis (RA) improves disease outcomes. In Part I of this thesis we therefore further... Show moreIn this thesis two main aims were addressed. It has long been established that early treatment of rheumatoid arthritis (RA) improves disease outcomes. In Part I of this thesis we therefore further investigated the early detection of at-risk individuals by studying a large cohort of patients with clinically suspect arthralgia (CSA). We explored the value of two easy clinical tests, their potential to detect underlying inflammatory processes and to predict disease progression. In addition we investigated the presence of subclinical synovitis on imaging as starting point for treatment with disease modifying anti-rheumatic drugs (DMARDs) and the value of magnetic resonance imaging (MRI) detected erosions as new predictor for RA-development. In Part II of this thesis we aimed to determine which disease processes are involved in the different phases of RA-development. Knowledge on disease pathogenesis and timing of influencing factors can help to better target treatment during RA-development. We therefore evaluated whether autoantibody-response maturation occurred during the phase of CSA, and investigated the timing of genetic risk factor human leukocyte antigen-shared epitope (HLA-SE) and environmental risk factor smoking during the development of autoantibody-positive disease. Show less

Verstappen, M. 2023

Conceptualization of disease resolution in rheumatoid arthritis

Doctoral Thesis

open access

Sustained DMARD-free remission (SDFR) is the best possible outcome in RA. It is characterized by sustained absence of clinical arthritis, which is accompanied by resolution of symptoms and... Show moreSustained DMARD-free remission (SDFR) is the best possible outcome in RA. It is characterized by sustained absence of clinical arthritis, which is accompanied by resolution of symptoms and restoration of normal physical functioning. Therefore it’s the best proxy for cure in RA. The mechanisms underlying SDFR-development are yet unidentified. Hypothetically, there are two possible scenarios. The first hypothesis is based on the concept of regaining immune-tolerance, which implies that RA-patients are similar at diagnosis and that disease-processes during the disease-course shift into a favorable direction, resulting in regaining a state in which arthritis is persistently absent. This could imply that SDFR is theoretically achievable for all RA-patients. The alternative hypothesis is that RA-patients who achieve SDFR are intrinsically different from those who cannot. This would imply that DMARD-cessation could be restricted to a subgroup of RA-patients. Since the 1990s, DMARD-discontinuation and SDFR have been increasingly studied as long-term-outcome in RA. In auto-antibody-negative RA, SDFR is presumably restricted to a subgroup of patients with high serological-markers of inflammation at diagnosis and a rapid and sustained decrease in inflammation after treatment-start. Identifying these RA-patients could be helpful in realizing personalized-medicine. In auto-antibody-positive RA, only few patients achieve SDFR and no definite conclusions can be drawn, but data could suggest that SDFR-patients might be a subgroup with relatively low inflammation from disease-presentation onwards. Show less

Brouwers, H. 2022

Pro-resolving fatty acids and oxylipids in osteoarthritis and rheumatoid arthritis

Doctoral Thesis

open access

The studies described in this thesis provides the field with valuable data on the potential therapeutic effects of fatty acids and specialized pro-resolving lipid mediators in rheumatoid arthritis... Show moreThe studies described in this thesis provides the field with valuable data on the potential therapeutic effects of fatty acids and specialized pro-resolving lipid mediators in rheumatoid arthritis and osteoarthritis. The omega-6 fatty acid AdA shows potent pro-resolving effects on the production of pro-inflammatory chemoattractantLTB4 with great promise to limit RA disease progression. In contrast to the promising potential therapeutic effects of AdA in RA, the evidence for pro-resolving effects in OA is still scarce. The results of the studies from this thesis show that neither LXA4, LXB4, RvE2 or Mar-1 were able to reduce OA disease activity in the experimental set-up we used. Finally, the studies described in this thesis show the utmost critical importance of the right sample preparation and storage for the intended subsequent analysis. Show less

Vergroesen, R.D. 2022

Putting the pieces together: B-cell receptor sequencing of autoreactive B cells in rheumatoid arthritis

Doctoral Thesis

open access

Anti-citrullinated protein antibodies (ACPA) are highly specific biomarkers for rheumatoid arthritis (RA). ACPA are predominantly of the immunoglobulin (Ig)G isotype and 90% of ACPA-IgG contains N... Show moreAnti-citrullinated protein antibodies (ACPA) are highly specific biomarkers for rheumatoid arthritis (RA). ACPA are predominantly of the immunoglobulin (Ig)G isotype and 90% of ACPA-IgG contains N-glycans in the variable domain. With the research in this thesis, we showed that this remarkably high frequency of N-glycans on secreted ACPA-IgG corresponds to a high frequency of N-glycosylation sites in full-length variable region B-cell receptor (BCR) transcripts of ACPA-expressing B cells. We looked at clonotypes and mutational analysis of the BCR sequences and studied the frequency, position and introduction of N-glycosylation sites that distinguish ACPA-expressing B cells in RA from other (antigen-specific) B-cells. Show less

Eektimmerman, F. 2022

Personalized medicine in rheumatoid arthritis

Doctoral Thesis

open access

Rheumatoid arthritis (RA) is a chronic, symmetrical, autoimmune disease characterized by inflammation of the joints, as well as damage to a variety of body systems, including the skin, eyes, lungs,... Show moreRheumatoid arthritis (RA) is a chronic, symmetrical, autoimmune disease characterized by inflammation of the joints, as well as damage to a variety of body systems, including the skin, eyes, lungs, heart and blood vessels. Therefore, to prevent (potential) damage with a more favorable course of the disease, it is important to intervene both early and agressively with medication in the treatment of RA. Typically, methotrexate is used as the first treatment, possibly in conjuction with other disease-modifying antirheumatic drugs, or with prednisolone to reduce inflammation rapidly. While the treatment of RA has improved considerably in recent decades, drug treatment does not work for everyone due to toxicity or lack of responsiveness. Therefore, it is suspected that genetics plays a major role in the both efficacy and toxicity of current RA medication. The goal of this thesis is to identify the genetic factors that influence the effectiveness or toxicity of the drugs used in RA. Show less

Pieper Pournara, L. 2021

Bioorthogonal antigens as tool for investigation of antigen processing and presentation

Doctoral Thesis

open access

In order to be able to develop effective medicine and treatments to prevent or cure autoimmune diseases or cancer we need to understand the mechanisms how they arise and what drives their course... Show moreIn order to be able to develop effective medicine and treatments to prevent or cure autoimmune diseases or cancer we need to understand the mechanisms how they arise and what drives their course.Unravelling the fundamental molecular mechanisms influencing the onset and course of diseases such as allergies, rheumatoid arthritis or cancer can be tackled using bioorthogonal antigens – chemically functionalized proteins.To tackle this challenge this thesis uses an inter-disciplinary approach. Combining standard immunological experimental methods with special, highly selective bioorthogonal chemical reactions. These reactions are bioorthogonal because, unlike normal organic chemistry, they are compatible with the physiological environment of a cell. This approach allows for following for example the location of the protein over time within a cell or alterations in the immune response due to disease related changes to the protein without disturbing the processes themself.This is a significant advantage because without changing the method used, new information can be retrieved from the same set of experiments, at any point in time during the process and a plethora of new readout options yielding additional data sets.This promises new insights into the causal relation of time, localisation and factors influencing effective anti-cancer vaccine-design and cancer immunotherapy or new biological drugs to prevent or delay onset and progression of autoimmune diseases. Show less

Dakkak, Y.J. 2020

The forefoot in early rheumatoid arthritis: Anatomy, imaging and clinical aspects

Doctoral Thesis

open access

Rheumatoid arthritis (RA) is a disease of the synovium that involves the small joints of hands and feet. The focus in RA-research, however, has primarily been on involvement of the hands. In this... Show moreRheumatoid arthritis (RA) is a disease of the synovium that involves the small joints of hands and feet. The focus in RA-research, however, has primarily been on involvement of the hands. In this thesis we studied involvement of the forefoot. Throughout this thesis we found that synovitis in the rheumatoid foot affects more than just the joints. In an anatomic study we revealed that the tendon-sheaths in the forefoot also possess a synovial layer. Inflammation of this, detected by MRI that is referred to as tenosynovitis, was an important aspect of RA involvement in the forefoot. In addition, intermetatarsal bursae also detected by MRI are also often inflamed due to disease-involvement. These extra-articular involvements of the synovium that are found in RA importantly contribute to joint swelling and walking disability, and are therefore clinically relevant. Therefore we believe that it is essential for the clinician to pay attention to the forefeet of patients with RA to have a complete idea of disease activity Show less

Dávila Fajardo, C.L. 2020

Genetic variants contribute to differences in response and toxicity to drugs used in autoimmune diseases: Rheumatoid arthritis and systemic lupus erythematosus

Doctoral Thesis

open access

The primary objective of this thesis is to investigate the role of pharmacogenetics in predicting drug response in treatments for the autoimmune diseases: RA and SLE. For this reason, this thesis... Show moreThe primary objective of this thesis is to investigate the role of pharmacogenetics in predicting drug response in treatments for the autoimmune diseases: RA and SLE. For this reason, this thesis is divided in two parts: pharmacogenetics related with drugs used in RA and pharmacogenetics of rituximab used in SLE and other autoimmune diseases. Part 1: Pharmacogenetics of drugs used in RA MTX is the most common DMARD used in RA. However, its use is hampered by frequent adverse drug events among which gastrointestinal toxicity is most frequent. Hepatotoxicity is a relatively rare but serious adverse event related to the use of MTX and is largely unpredictable. In chapter 2 an overview is presented of the previously performed studies concerning pharmacogenetic predictive biomarkers for MTX-induced hepatotoxicity. Treatment with anti-TNF agents results in a reduction of disease activity in most RA patients. However, a substantial part of patients does not respond to this therapy for unknown reasons. It would be highly beneficial to be able to predict whether or not an individual patient responds to treatment. Chapters 4 and 5 describe the investigations on the role of different candidate SNPs related to the efficacy of the treatment with different anti-TNFs in RA. In addition, in chapter 3 a replication study is presented based on 4 polymorphisms that were found associated with anti-TNF response in RA in a previously published genomewide association study. Part 2: Pharmacogenetics of rituximab used in SLE and other autoimmune diseases In chapters 6–8 the role of different genetic variants related to the pharmacodynamics of the drug or of the diseases are evaluated to study the contribution to differences in the response to rituximab in patients with SLE and other systemic autoimmune diseases. In chapter 6, the possible involvement of the -174 IL-6 polymorphism in the clinical response to rituximab in different systemic autoimmune diseases is assessed. In chapter 7, the aim is to investigate the possible involvement of the FCGR3A-158F/V polymorphism in the clinical response to rituximab in Spanish patients with different systemic autoimmune diseases. In chapter 8, the role of G/T polymorphism at the IL2–IL21 region in the rituximab response in a cohort of SLE patient and different autoimmune disorders is analyzed. Chapter 9 provides a summary of this thesis, chapter 10 the Dutch summary (Nederlandse samenvatting), and chapter 11 the general discussion and future perspective of this thesis. Show less

Boeters, D.M. 2020

Early identification and resolution of rheumatoid arthritis

Doctoral Thesis

open access

overzicht van verschillende voorspellers voor het ontwikkelen van RA binnen patiënten met artralgie

rol van nieuwe autoantistoffen en MRI in vroege diagnostiek RA

onderzoek naar behalen van DMARD...

overzicht van verschillende voorspellers voor het ontwikkelen van RA binnen patiënten met artralgie

rol van nieuwe autoantistoffen en MRI in vroege diagnostiek RA

onderzoek naar behalen van DMARD-vrije remissie: voorkomen van immunologische remissie en identificatie van subgroep van RA-patiënten met verhoogde kans op remissie

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Hafkenscheid, L. 2020

Anti Citrullinated Protein Antibodies-IgG variable domain glycosylation in rheumatoid arthritis

Doctoral Thesis

open access

Rheumatoid arthritis (RA) is an auto-inflammatory disease, affecting ~1% of the world population. RA is hallmarked by the presence of autoantibodies, one of the well-known autoantibodies in RA are... Show moreRheumatoid arthritis (RA) is an auto-inflammatory disease, affecting ~1% of the world population. RA is hallmarked by the presence of autoantibodies, one of the well-known autoantibodies in RA are the anti-citrullinated protein antibodies (ACPA). ACPA is highly specific for RA and about 70-80% of the RA patients are positive for ACPA. Previously, we discovered that ACPA-IgG are extensively glycosylated in the variable (V) region. In this thesis, we determined that over 90% of the ACPA-IgG carries glycans in the v-domain were as only 17% of the conventional IgG carries additional glycans. Additionally, the glycans were highly sialylated. Intriguingly, we also showed that the glycans are introduced via somatic hyper mutations in the germinal center reaction. Furthermore, we discovered that ACPA-IgG v-domain glycosylation is a predictive marker for the development of ACPA positive RA. Lastly, we found that the binding strength is not influenced by the glycans but it influences the amount of available binding sites. Nevertheless, the ACPA-BCR still overcome negative selection which might suggest that the glycans can trigger an alternative way for positive selection in the germinal center. This will be subject for further studies regarding the role of ACPA-IgG v-domain glycosylation. Show less

Kempers, A.C. 2020

The Anti-Citrullinated Protein Antibody immune response and its effector functions in Rheumatoid Arthritis

Doctoral Thesis

some documents under embargo

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic and persistent inflammation of the joints. Around 50-80% of the RA patients harbour either one or multiple types... Show moreRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic and persistent inflammation of the joints. Around 50-80% of the RA patients harbour either one or multiple types of autoantibodies, under which also Anti-Citrullinated Protein Antibodies (ACPA). ACPA are highly specific for RA and are strongly associated with the severity of arthritis. The studies described in this thesis aim to explore the structure and biological function of ACPA and the B cells producing these ACPA.The studies highlight the importance of the synovial environment for the survival of ACPA B cells. Moreover, we demonstrate that the variable region of ACPA-IgG differs from that of ACPA-IgM by the introduction of glycans, and that glycans in the constant part of antibodies can be modulated by influences from the micro-environment. This may affect the biological functions of the antibodies. Furthermore, we show that ACPA can bind to so-called Fc gamma receptor I on immune cells which could be a potential effector mechanisms of ACPA. These findings demonstrate that the structure and environment of ACPA play an important role in the ACPA immune response and provide multiple arguments for the active contribution of ACPA in the chronic inflammation of RA. Show less

Delft, M.A.M. van 2020

The characterization of anti-carbamylated protein antibodies in rheumatic diseases : isotype usage, avidity and molecular composition

Doctoral Thesis

open access

The scope of this thesis is to describe the immunological characteristics and molecular composition of anti-CarP antibodies in rheumatoid arthritis, as well as the presence of anti-CarP antibodies... Show moreThe scope of this thesis is to describe the immunological characteristics and molecular composition of anti-CarP antibodies in rheumatoid arthritis, as well as the presence of anti-CarP antibodies in relation to bone erosions on diseases other than RA. This thesis is subdivided in three parts.Part 1: Characterisation of the anti-CarP antibody response in rheumatoid arthritisBoth ACPA and anti-CarP antibodies are present in RA.We describe the examination of the anti-CarP antibody response in RA by means of isotype and IgG-subclass usage in baseline serum samples of RA-patients as well as by means of the avidity of anti-CarP antibodies. Moreover, the anti-CarP IgG V-domain glycosylation was studied.Part 2: Possibilities for a mucosal origin of autoantibodies in rheumatoid arthritisSeveral lines of evidence obtained in the recent years indicate a role for mucosal surfaces in the development of auto-immune responses associated with RA. Therefore, we studied the molecular composition of RA associated IgA autoantibodies.Part 3: anti-CarP antibodies in other rheumatic diseases that can be characterized by bone erosionsBecause anti-CarP antibodies and ACPAs are also present in other clinical conditions than RA, we investigated their presence and association with bone erosions in Systemic Lupus Erythematosus and hand osteorthritis. Show less

Aizenberg, E. 2019

Computer-aided techniques for assessment of MRI-detected inflammation for early identification of inflammatory arthritis

Doctoral Thesis

open access

Inflammatory arthritis comprises a group of diseases in which the immune system attacks the body’s own tissues. Two prevalent types of inflammatory arthritis are rheumatoid arthritis (RA) and... Show moreInflammatory arthritis comprises a group of diseases in which the immune system attacks the body’s own tissues. Two prevalent types of inflammatory arthritis are rheumatoid arthritis (RA) and spondyloarthritis (SpA). Clinical research points to the importance of early diagnosis, as treatment in early disease stages increases chances of better outcome and improved quality of life for patients. To this end, the diagnostic potential of imaging modalities sensitive to local inflammation, such as magnetic resonance imaging (MRI), is of great interest. The goal of this thesis was to develop computer-aided methods for assessment of MRI-detected inflammation with the aim of aiding early diagnosis of inflammatory arthritis. In particular, we focused on the tasks of comparative visualization, automatic quantification, and feature selection. The presented studies showcase the potential of comparative visualization and automatic quantification to overcome the limitations of visual scoring and lay out a fertile ground for future improvements. Additionally, the understanding of the diagnostic role of individual inflammatory features in prediction of RA development is further advanced. Collectively, these findings can help facilitate the use of MRI for early diagnosis of inflammatory arthritis and potentially increase chances of better outcome and quality of life for patients. Show less

Verheul, M.K. 2019

Unravelling the anti-carbamylated protein antibody response in rheumatoid arthritis

Doctoral Thesis

open access

Although quite some data is available on anti-CarP antibodies, several questions remain unanswered, including the reproducibility of the clinical data on anti-CarP antibodies, such as their... Show moreAlthough quite some data is available on anti-CarP antibodies, several questions remain unanswered, including the reproducibility of the clinical data on anti-CarP antibodies, such as their presence before disease onset and association with joint damage. It is also unknown whether these findings can be expanded to non-caucasian populations. Furthermore, it is unclear how anti-CarP antibodies are induced, what proteins they recognize, whether they are able to recognize multiple carbamylated proteins and what the characteristics of these autoantibodies are. Here, some of these questions will be answered. In this thesis, I will first discuss the clinical implications of the presence of anti-CarP antibodies compared to RA-specific autoantibodies in both RA patients other relevant conditions (chapters 2 till 7). This is followed by more detailed investigations into the characteristics of anti-CarP antibodies and their antigens (chapters 8 till 12). Show less

Bergstra, S.A. 2018

Worldwide treatment opportunities of rheumatoid arthritis

Doctoral Thesis

open access

In this thesis we aimed to investigate ways to optimize treatment strategies and the choice of treatment for individual patients, to be implemented in a worldwide context. Although major advances... Show moreIn this thesis we aimed to investigate ways to optimize treatment strategies and the choice of treatment for individual patients, to be implemented in a worldwide context. Although major advances have been made in the treatment of RA, it is still uncertain which treatment is the best choice for each individual patient. This can result in both overtreatment and undertreatment, increasing the burden of RA for patients as well as for society. In clinical trials and daily practice there appears to be a development towards earlier treatment, with higher dosages of medication and more stringent treatment targets. In part 1 of this thesis, some of these developments were investigated and challenged. In countries across the world, patients do not benefit similarly from recent advances in the treatment of RA. In part 2 of this thesis, we aimed to identify contributing factors to inequalities in access to treatment and care and clinical outcomes across countries, as a first step towards improvement. Show less

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