This thesis contains several investigations into the contribution of complement proteins, especially C1q, in several human diseases. Additionally, human autoantibodies against C1q (anti-C1q) are... Show moreThis thesis contains several investigations into the contribution of complement proteins, especially C1q, in several human diseases. Additionally, human autoantibodies against C1q (anti-C1q) are studied, cloned and characterized in order to further the understanding of their role in autoimmune disease. Show less
Khidir, S.J.H.; Toes, R.E.M.; Mulligen, E. van; Helm-van Mil, A.H.M. van der 2024
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
Nagy, N.A.; Lozano Vigario, F.; Sparrius, R.; Capel, T.M.M. van; Ree, R. van; Tas, S.W.; ... ; Jong, E.C. de 2023
Autoimmune diseases are heterogeneous pathologies characterized by a breakdown of immunological tolerance to self, resulting in a chronic and aberrant immune response to self-antigens. The scope... Show moreAutoimmune diseases are heterogeneous pathologies characterized by a breakdown of immunological tolerance to self, resulting in a chronic and aberrant immune response to self-antigens. The scope and extent of affected tissues can vary greatly per autoimmune disease and can involve multiple organs and tissue types. The patho-genesis of most autoimmune diseases remains unknown but it is widely accepted that a complex interplay be-tween (autoreactive) B and T cells in the context of breached immunological tolerance drives autoimmune pathology. The importance of B cells in autoimmune disease is exemplified by the successful use of B cell tar-geting therapies in the clinic. For example, Rituximab, a depleting anti-CD20 antibody, has shown favorable results in reducing the signs and symptoms of multiple autoimmune diseases, including Rheumatoid Arthritis, Anti-Neutrophil Cytoplasmic Antibody associated vasculitis and Multiple Sclerosis. However, Rituximab depletes the entire B cell repertoire, leaving patients susceptible to (latent) infections. Therefore, multiple ways to target autoreactive cells in an antigen-specific manner are currently under investigation. In this review, we will lay out the current state of antigen-specific B cell inhibiting or depleting therapies in the context of autoimmune diseases. Show less
The imbalance between pathogenic and protective T cell subsets is a cardinal feature of autoimmune disorders such as multiple sclerosis (MS). Emerging evidence indicates that endogenous and... Show moreThe imbalance between pathogenic and protective T cell subsets is a cardinal feature of autoimmune disorders such as multiple sclerosis (MS). Emerging evidence indicates that endogenous and dietary-induced changes in fatty acid metabolism have a major impact on both T cell fate and autoimmunity. To date, however, the molecular mechanisms that underlie the impact of fatty acid metabolism on T cell physiology and autoimmunity remain poorly understood. Here, we report that stearoyl-CoA desaturase-1 (SCD1), an enzyme essential for the desaturation of fatty acids and highly regulated by dietary factors, acts as an endogenous brake on regulatory T-cell (Treg) differentiation and augments autoimmunity in an animal model of MS in a T cell-dependent manner. Guided by RNA sequencing and lipidomics analysis, we found that the absence of Scd1 in T cells promotes the hydrolysis of triglycerides and phosphatidylcholine through adipose triglyceride lipase (ATGL). ATGL-dependent release of docosahexaenoic acid enhanced Treg differentiation by activating the nuclear receptor peroxisome proliferator-activated receptor gamma. Our findings identify fatty acid desaturation by SCD1 as an essential determinant of Treg differentiation and autoimmunity, with potentially broad implications for the development of novel therapeutic strategies and dietary interventions for autoimmune disorders such as MS. Show less
This thesis describes studies of individuals with systemic lupus erythematosus (SLE) presenting with neuropsychiatric (NP) symptoms at the Leiden NPSLE clinic. A diverse range of studies, including... Show moreThis thesis describes studies of individuals with systemic lupus erythematosus (SLE) presenting with neuropsychiatric (NP) symptoms at the Leiden NPSLE clinic. A diverse range of studies, including laboratory, radiological, clinical and patient´s reported outcomes are presented.The Leiden NPSLE clinic is a tertiary referral center for patients with SLE and neuropsychiatric (NP) symptoms. In the NPSLE clinic, patients are assessed by a multidisciplinary team. Thereafter, clinical, radiological and laboratory measures are weighed in a consensus meeting to correctly attribute the NP symptoms: related to lupus activity (NPSLE) or not. This extensive and standardized assessment of NPSLE, a rare and heterogenous disease lacking a gold standard, is unique and creates the opportunity to explore many aspects of NPSLE in well-defined phenotypes.In the first part of this thesis, we evaluate both classification and treatment of patients withSLE and NP symptoms. The second part of this thesis focuses on a diverse range of clinicaloutcomes of NPSLE, including both morbidity and mortality. The last part of this thesisassesses potential biomarkers for (specific manifestations of) NPSLE. Show less
Introduction: Early diagnosis of systemic sclerosis (SSc) is important to start therapeutic interventions timely. Important risk factors for progression to SSc are the SSc-specific autoantibodies,... Show moreIntroduction: Early diagnosis of systemic sclerosis (SSc) is important to start therapeutic interventions timely. Important risk factors for progression to SSc are the SSc-specific autoantibodies, of whom anti-centromere antibodies (ACA) and anti-topoisomerase I antibodies (ATA) are the most frequent. ATA is associated with a severe disease course. A more detailed characterisation of the ATA-response in SSc might increase insights in preclinical disease stages and improve prognostication. To address this we identified all patients with suspected very early ATA-positive SSc, defined as all patients who are ATA-positive not fulfilling American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) 2013 criteria, in the Leiden Combined Care in Systemic Sclerosis (CCISS)-cohort and found very low numbers. Methods This triggered us to search the literature on the ATA prevalence in patients with suspected very early SSc and contribution of the SSc-specific autoantibodies to progression from suspected very early to definite SSc. To increase insights on the ATA-response in suspected very early SSc, we then evaluated the association between the ATA-response and time between onset of Raynaud's phenomenon (RP) and first non-RP symptom, as a proxy for progressing to definite SSc, in all patients with ATA-positive SSc from the Leiden CCISS-cohort. Results: In short, included studies show that prevalence of ATA is much lower in suspected very early SSc than in populations fulfilling ACR/EULAR 2013 criteria. After 1-15 years of follow-up, only 52% of the patients with suspected very early SSc progress to definite SSc. ATA-IgG levels tend to be higher in patients with ATA-positive SSc with more rapid disease progression. Conclusion: Although a role of ATA in disease progression is suggested, more studies on the ATA response in suspected very early SSc are warranted. Show less
Our immune system is supposed to protect us from infections, but it can also attack our own tissues if not properly controlled. This can lead to autoimmune diseases like rheumatoid arthritis (RA).... Show moreOur immune system is supposed to protect us from infections, but it can also attack our own tissues if not properly controlled. This can lead to autoimmune diseases like rheumatoid arthritis (RA). People with RA have antibodies to the body’s own proteins (self), but it is not known how they arise. The data described in this thesis show that these antibodies cross-react with self-proteins carrying different post-translational modifications, suggesting that multiple proteins may be involved in the initial loss of the immune system’s ability to discriminate between self- and foreign-proteins. As another unique feature, these antibodies carry additional sugars at an unexpected site in the molecule. Our data show that these sugars (variable domain glycans) can prevent binding to potential self-proteins, affect complement activation, and set the threshold for immune B-cell activation. In addition, our data show that the abundance of these sugars increases toward disease onset and predicts the development of chronic, persistent disease or the chance of subsequent remission. Taken together, these sugars may help B cells to escape the tight control mechanism in our body that are in place to prevent the development autoimmunity. This new “sugar mechanism” could be beneficial for diagnosis and future treatment. Show less
Objective: To determine the effect of tetanus toxoid (TT) revaccination on circulating B-, T-and NK-cell com-partments in myasthenia gravis (MG) patients.Methods: Lymphocyte (sub)populations and... Show moreObjective: To determine the effect of tetanus toxoid (TT) revaccination on circulating B-, T-and NK-cell com-partments in myasthenia gravis (MG) patients.Methods: Lymphocyte (sub)populations and differentiation stages were assessed by flow cytometry in 50 TT revaccinated MG patients. TT-specific proliferative responses were explored in PBMC cultures. Results: In patients treated with azathioprine B-and NK cell numbers were strongly decreased. Lymphocyte (sub) populations remained unaffected upon TT revaccination. t All patients showed a significant TT-induced prolif-erative response.Conclusion: TT revaccination is effective in MG patients with stable disease irrespective of their thymectomy status and medication and does not alter the composition of the lymphocyte compartment. Show less
Objectives: To compare the cumulative incidence and disease severity of reported SARS-CoV-2 omicron breakthrough infections between patients with immune-mediated inflammatory diseases (IMID) on... Show moreObjectives: To compare the cumulative incidence and disease severity of reported SARS-CoV-2 omicron breakthrough infections between patients with immune-mediated inflammatory diseases (IMID) on immunosuppressants and controls, and to investigate determinants for breakthrough infections. Methods: Data were used from an ongoing national prospective multicentre cohort study on SARS-CoV-2 vaccination responses in patients with IMID in the Netherlands (Target-to-B! (T2B!) study). Patients wih IMID on immunosuppressants and controls (patients with IMID not on immunosuppressants and healthy controls) who completed primary immunisation were included. The observation period was between 1 January 2022 and 1 April 2022, during which the SARS-CoV-2 omicron (BA.1 and BA.2 subvariant) was dominant. A SARS-CoV-2 breakthrough infection was defined as a reported positive PCR and/or antigen test at least 14 days after primary immunisation. A multivariate logistic regression model was used to investigate determinants. Results: 1593 patients with IMID on immunosuppressants and 579 controls were included. The cumulative incidence of breakthrough infections was 472/1593 (29.6%; 95% CI 27% to 32%) in patients with IMID on immunosuppressants and 181/579 (31.3%; 95% CI 28% to 35%) in controls (p=0.42). Three (0.5%) participants had severe disease. Seroconversion after primary immunisation (relative risk, RR 0.71; 95% CI 0.52 to 0.96), additional vaccinations (RR 0.61; 95% CI 0.49 to 0.76) and a prior SARS-CoV-2 infection (RR 0.60; 95% CI 0.48 to 0.75) were associated with decreased risk of breakthrough infection. Conclusions: The cumulative incidence of reported SARS-CoV-2 omicron breakthrough infections was high, but similar between patients with IMID on immunosuppressants and controls, and disease severity was mostly mild. Additional vaccinations and prior SARS-CoV-2 infections may reduce the incidence of breakthrough infections. Show less
Muscle-specific kinase (MuSK) plays a critical role in establishing and maintaining neuromuscular synapses. Antibodies derived from immunizing animals with MuSK were important tools to help detect... Show moreMuscle-specific kinase (MuSK) plays a critical role in establishing and maintaining neuromuscular synapses. Antibodies derived from immunizing animals with MuSK were important tools to help detect MuSK and its activity. The role of antibodies in MuSK-related research got an extra dimension when autoantibodies to MuSK were found to cause myasthenia gravis (MG) in 2001. Active immunization with MuSK or passive transfer of polyclonal purified IgG(4) fractions from patients reproduced myasthenic muscle weakness in a range of animal models. Polyclonal patient-purified autoantibodies were furthermore found to block agrin-Lrp4-MuSK signaling, explaining the synaptic disassembly, failure of neuromuscular transmission and ultimately muscle fatigue observed in vivo. MuSK autoantibodies are predominantly of the IgG4 subclass. Low levels of other subclass MuSK antibodies coexist, but their role in the pathogenesis is unclear. Patient-derived monoclonal antibodies revealed that MuSK antibody subclass and valency alters their functional effects and possibly their pathogenicity. Interestingly, recombinant functional bivalent MuSK antibodies might even have therapeutic potential for a variety of neuromuscular disorders, due to their agonistic nature on the MuSK signaling cascade. Thus, MuSK antibodies have proven to be helpful tools to study neuromuscular junction physiology, contributed to our understanding of the pathophysiology of MuSK MG and might be used to treat neuromuscular disorders. The source of MuSK antibodies and consequently their (mixed) polyclonal or monoclonal nature were important confounding factors in these experiments. Here we review the variety of MuSK antibodies described thus far, the insights they have given us and their potential for the future. Show less
Najm, A.; Alunno, A.; Sivera, F.; Ramiro, S.; Haines, C.; Working Grp Training Rheumatology 2020
Objectives To gain insight into current methods and practices for the assessment of competences during rheumatology training, and to explore the underlying priorities and rationales for competence... Show moreObjectives To gain insight into current methods and practices for the assessment of competences during rheumatology training, and to explore the underlying priorities and rationales for competence assessment.Methods We used a qualitative approach through online focus groups (FGs) of rheumatology trainers and trainees, separately. The study included five countries-Denmark, the Netherlands, Slovenia, Spain and the United Kingdom. A summary of current practices of assessment of competences was developed, modified and validated by the FGs based on an independent response to a questionnaire. A prioritising method (9 Diamond technique) was then used to identify and justify key assessment priorities.Results Overall, 26 participants (12 trainers, 14 trainees) participated in nine online FGs (2 per country, Slovenia 1 joint), totalling 12 hours of online discussion. Strong nationally (the Netherlands, UK) or institutionally (Spain, Slovenia, Denmark) standardised approaches were described. Most groups identified providing frequent formative feedback to trainees for developmental purposes as the highest priority. Most discussions identified a need for improvement, particularly in developing streamlined approaches to portfolios that remain close to clinical practice, protecting time for quality observation and feedback, and adopting systematic approaches to incorporating teamwork and professionalism into assessment systems.Conclusion This paper presents a clearer picture of the current practice on the assessment of competences in rheumatology in five European countries and the underlying rationale of trainers' and trainees' priorities. This work will inform EULAR Points-to-Consider for the assessment of competences in rheumatology training across Europe. Show less
Complement is a key component of the innate immune defence and in addition forms a bridge to the adaptive immune responses. As such complement is of vital importance for efficient protection... Show moreComplement is a key component of the innate immune defence and in addition forms a bridge to the adaptive immune responses. As such complement is of vital importance for efficient protection against infections. However, the activity of the complement system can also aberrantly be directed against the tissues of the body itself and contribute to organ damage in a variety of diseases. In several rheumatic diseases complement activation is suggested to play a pronounced role. This review will highlight the role of both complement activation and complement regulation in rheumatic disease.A contribution of complement to the disease process is often suggested based on the presence of complement activation fragments in the target tissues or the presence of complement activation fragments in the circulation. The role that complement plays in different rheumatic diseases is often unknown but is thought to contribute to tissue damage as a consequence of autoantibody mediated immune complex formation and deposition. In addition reduced complement inhibition mediated by endogenous complement regulators can also enhance complement activity and tissue damage. In observational studies, it is difficult to distinguish whether complement activation is a result of enhanced activation or decreased regulation. Until recently, strong conclusions on the relative importance of complement activation to the pathology were largely restricted to animal experiments. Usage of complement targeting therapeutics in humans will hopefully give us the opportunity to study the actual contribution of complement activation towards disease progression and tissue damage in rheumatic disease into more detail. Show less
Type 1 diabetes (T1D) results from the immune-mediated destruction of the insulin-producing beta cells. Genetic predisposition, impaired immune regulation, and beta cell (dys)function all... Show moreType 1 diabetes (T1D) results from the immune-mediated destruction of the insulin-producing beta cells. Genetic predisposition, impaired immune regulation, and beta cell (dys)function all contribute to disease initiation and progression. A critical gap in our knowledge is what causes the break in peripheral tolerance that eventually leads to beta cell destruction. We propose that neoepitopes generated by dysfunctional beta cells activate immune surveillance, causing beta cell autoimmunity. ER stress imposed both by intrinsic beta cell physiology and by external secondary triggers seems to be a crucial component in this process. Understanding the molecular mechanisms underlying beta cell dysfunction and neoantigen generation is critical to identify clinically relevant neoepitopes. This subsequently provides more insight in the disease dynamics as well as contribute to translational research in the development of biomarker assays and development of therapeutic strategies targeting autoreactive T-cells and beta cell function. Our task will be to restore the balance between immune reactivity and beta cell function, in order to prevent, treat, or cure type 1 diabetes. Show less
In this thesis we have analyzed an important number of laboratory, radiological, clinical and patient´s reported outcomes in systemic lupus erythematosus (SLE) patients presenting with... Show moreIn this thesis we have analyzed an important number of laboratory, radiological, clinical and patient´s reported outcomes in systemic lupus erythematosus (SLE) patients presenting with neuropsychiatric (NP) manifestations. Our studies are among the most robust to date in this field due to the large number of patients included, the prospective character and the standard assessment followed by a multidisciplinary expert consensus.Furthermore our studies include the novelty of a phenotypic characterization of all NP manifestations according to the suspected underlying pathophysiological mechanism (inflammation or immune-mediated vs. ischemic or thrombotic). These studies give more light to the understanding of the underlying pathophysiological mechanisms of nervous involvement in SLE. Show less
Kallweit, U.; Bassetti, C.L.A.; Oberholzer, M.; Fronczek, R.; Beguin, M.; Strub, M.; Lammers, G.J. 2018
Identification of the cellular mechanisms involved in the occurrence and persistence of autoreactive lymphocytes is key for understanding T1D etiology. Comparing autoreactive T lymphocytes from... Show moreIdentification of the cellular mechanisms involved in the occurrence and persistence of autoreactive lymphocytes is key for understanding T1D etiology. Comparing autoreactive T lymphocytes from healthy individuals and T1D patients can provide clues as to what the driving force is for the destruction of β-cells and might designate potential targets for (immune) intervention. Elucidating in what way T1D associated gene variants actually contribute to disease development, i.e. understanding the functional aspects of genetic risk, and how genetic control of autoantigens influences autoimmunity may provide crucial clues to the clarification of the enigma of T1D. This thesis aims to answer several of these issues by investigating the role of transcriptional and post-transcriptional gene control in T1D. Show less
