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
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
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
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
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
Type 1 Diabetes is caused by destruction of insulin producing beta-cells by autoimmune T-cells. Replacement of beta-cells through transplantation can supply new beta-cells, however these are at... Show moreType 1 Diabetes is caused by destruction of insulin producing beta-cells by autoimmune T-cells. Replacement of beta-cells through transplantation can supply new beta-cells, however these are at renewed peril of destruction through auto- and alloreactive immune responses. In this thesis, immune challenges, intervention strategies and biomarkers to guide treatment are investigated. Patient heterogeneity was identified as contributing factor to variations in efficacy of immune intervention therapies for type 1 diabetes. Immune infiltrations that matched with immune monitoring results were seen around islets transplanted to the liver of a patient. Cytokine and autoantibody immune markers were described that correlated with outcome of islet transplantation and combined kidney and pancreas transplantation. Immune consequences of tapering immune suppression after islet transplantation to minimize side effects were explicated. The immunological challenges that await beta-cells of alternative sources after transplantation, such as beta-cell lines and embryonic stem cells, were explored and pointed to need for immune protection and immune monitoring in early transplantation trials. These results support further investigation of immune intervention with disease specific immune modulation and beta-cell encapsulation strategies to achieve the desired drastic improvement in efficacy-risk balance for type 1 diabetes therapies. Show less
