1,721,395 research outputs found
Anti-citrullinated peptide antibodies in rheumatoid arthritis and undifferentiated arthritis
Get PDFThe thesis concerns studies on several aspects of the ACPA response in UA and RA patients. One objective was to investigate the effect ACPA on the development of RA and how ACPA and other risk factors could collectively contribute to the development of RA. The second aim was to increase knowledge on the development of the ACPA response itself Chapter 2 is a review on the percentage of patients with UA who develop RA Chapter 3 describes differences and similarities between ACPA-positive and ACPA-negative RA at first presentation to the rheumatologist and after follow-up. The strongest genetic risk factors, SE-alleles, were described to predispose only for ACPA-positive RA. In Chapter 4, it was investigated whether SE is a risk factor for ACPA-positive RA or for the development of ACPA. The contribution of HLA__DRB1 to the development of ACPA-negative RA was investigated in Chapter 5. In Chapter 6, it was determined whether SE-alleles interact with tobaccoexposure in the risk to develop ACPA-positive or ACPA-negative RA and whether different subtypes of SE interact differently with smoking. Chapter 7 evaluates whether tobaccoexposure also influences the isotype of ACPA. Chapters 8 and 9, describe different isotypes and the fine-specificity of the ACPA response. Finally, the results are summarized and discussed.ABBOTT B.V., Bristol-Myers Squibb, het Reumafonds, Roche Nederland B.V., Schering- Plough B.V., Teva Pharma NL en Wyeth Pharmaceuticals B.V.UBL - phd migration 201
Towards a molecular basis for the association of HLA, rheumatoid arthritis and autoantibodies
Get PDFRheumtaoid Arthritis (RA) is an autoimmune disease characterized by extensive inflammation of synovial joints. RA patients can be subdivided in two distinct disease subsets based on the presence of anti-citrullinated protein antibodies (ACPA). The HLA locus is the most important risk factor for ACPA-positive RA. In this thesis we investigate the association between HLA, Rheumatoid Arthritis and ACPA and provide a molecular basis for this assocation.UBL - phd migration 201
Harnessing immune regulation for treatment of human diseases : CD4+CD25+ regulatory T cells & antibody glycosylation
Get PDFThis thesis consists of two parts, focusing on CD4+CD25+ regulatory T cells (Tregs) (Part I) and IgG glycosylations (Part II), respectively. Part I (Chapter 2-5) is mainly dedicated to a better identification/characterization and generation of functional human Tregs in vitro. In Chapter 2, we investigated the dynamics of endogenous FOXP3 expression and its relation to the suppressive function in activated human CD4+ T cells. In Chapter 3, we discovered an inverse correlation between membrane-bound TNF-alpha expression and cell suppressive abilities within human CD4+CD25++ T-cell compartment. In Chapter 4 & 5, we developed efficient approaches to consistently convert effector T cells into Tregs both in mice and humans. The underlying mechanisms responsible for the inconsistency in Treg conversion were unraveled as well. Part II (Chapter 6-7) aims to analyze the glycosylation pattern of antigen-specific antibodies and to obtain more insights on how glycosylation is regulated during an active immune response. Chapter 6 describes a method for the microscale purification and Fc-glycosylation analysis of auto-antibodies in patients with rheumatoid arthritis. In Chapter 7, we identified, by using an in vitro culture system, some factors that can influence the gylcan pattern of secreted IgG1 during the activation and differentiation of B cells.The work described in this thesis was financially supported by an NWO VIDI grant and Dutch Arthritis Association (Grant 0801021).UBL - phd migration 201
Anti-citrullinated protein antibodies (ACPA) in rheumatoid arthritis : linking genetic predisposition to clinical outcome
Get PDFRheumatoid arthritis (RA) is a disease characterized by arthritis of mainly the small joints of the hands and feet, which is thought to be the result of an autoimmune response. It is the most common inflammatory arthritis with a prevalence of 0.5-1.0% in European and North-American populations 1. There is substantial geographic variation in the occurrence of RA with very high prevalences reported in native American-Indian populations 2, and very low prevalences in populations from South-East Asia 3. The disease is approximately three times more frequent in women than in men, and the prevalence increases with age. Besides the potentially destructive arthritis, patients can be affected by various extraarticular features such as secondary Sj_gren__s syndrome, interstitial lung disease, pericarditis and pleuritis. Fortunately, the advent of tumor necrosis factor (TNF) inhibitors and other biological agents have led to a therapeutic revolution for patients with rheumatoid arthritis 4. Instead of having to resign to an inevitably progressive and debilitating disease course, modern-day treatment aims at achieving the lowest possible disease activity and ultimately remission. Nonetheless, rheumatoid arthritis continues to be a major cause of (partial) disability and of loss of productivity, and is associated with substantial economic costs 5. Classification criteria for the disease were first phrased in 1956 6 after Sir Alfred Garrod had introduced the term rheumatoid arthritis in 1876 in an attempt to counteract the unsatisfactory use of designations such as __chronic rheumatism__ and __rheumatic gout__ 7. The purpose of the classification criteria was to facilitate both clinical diagnosis and scientific research. For many years since, the 1987 American College of Rheumatology (ACR) classification criteria have been used to this end, despite the fact that the incorporation of items such as erosive radiographic changes led to limited diagnostic value of these criteria for patients with early arthritis 8. In order to facilitate the study of persons with earlier stages of disease, the ACR and the European League Against Rheumatism (EULAR) have recently developed the 2010 classification criteria for RA as shown in Table 1 9. It is worthwhile to note that these criteria are based on patient characteristics which were associated with the decision by the physician to start treatment with methotrexate. These criteria are a reflection of the shift towards increasingly earlier diagnosis and treatment of rheumatoid arthritis.The research described in this thesis was supported by ZonMW (AGIKO grant). The printing of this thesis was financially supported by Abbott BV, Euro-Diagnostica, Janssen Biologics BV, the J.E. Jurriaanse foundation, Merck Sharp & Dohme BV, Pfizer BV, Phadia BV, the Dutch Arthritis Association (het Reumafonds), Roche Nederland BV, Teva Pharma BV en UCB Pharma BV.UBL - phd migration 201
Dentritic cells and the battle against arthritis
Get PDFIn a murine model for rheumatoid arthritis, we wished to investigated whether it was possible to skew the immune response with a cellular vaccin to protect the mice against the induction and/or progeression of arthritis. the model that was used for this purpose was Collagen-Induced Arthritis (CIA). As dendritic cells (DCs) are the main antigen-presenting cells and key players in setting immune responses and connecting innate witth adaptive immunity, it is favorable to use these cells to manipulate the immune system to circumvent autoimmunity, in this case CIA. Because CIA is still implicated as a Th1-mediated disease, the aim was to skew the immune system towards a more Th2-like phenotype or to induce a T cell with a regulatory capacity. Therefore, several ways to stimulate DCs and subsequently the evolving T cell response were selected, to analyze whether Th2 cells or regulatory T cells were activated, resulting in the inhibition of arthritis.LEI Universiteit LeidenReumafonds (Dutch Arthritis Association)
J.E. Jurriaanse StichtingKlinische evaluatie en behandeling van reumatische ziekte
From undifferentiated arthritis to rheumatoid arthritis : epidemiology, immunology and early intervention
Get PDFIn this thesis clinical and immunological studies in patients with undifferentiated (UA) and rheumatoid arthritis (RA) are described. Depending on the study population 6-55% of the patients who presented with UA actually fulfilled the criteria for RA as defined by the ACR in 1987 over time. In the first four years, radiographic joint damage, disease activity and HAQ were comparable in patients with RA presenting with UA and patients presenting with RA. Treatment of UA patients with methotrexate resulted in postponing progression to RA and retarding radiographic joint damage. In UA patients who had low/intermediate pretreatment ACPA-levels and were treated with methotrexate, the incidence of RA was lower than in patients with high levels. The disease activity score that was used in RA patients was validated in patients with UA. To identify which patient with UA will progress to RA, a prediction rule was developed. In patients with RA, treatment with TNF-alpha resulted in recovery of regulatory T cells. The importance of these regulatory T cells was emphasized in the strength of the anti-inflammatory response to the human cartilage glycoprotein 39 in healthy individuals: it even suppressed other pro-inflammatory responses, whereas patients with RA reacted with a pro-inflammatory responseSubsidie tbv onderzoek: ZonMw, Reumafonds Financiele ondersteuning voor de druk van het proefschrift: Abbott bv, AstraZeneca, JE Jurriaanse Stichting, Het Reumafonds, Merck Sharp & Dohme bv, Roche, Schering-Plough, Sectra DXR-online, TEVA Pharma en UCB PharmaUBL - phd migration 201
CD8+ T-cell tolerance and immunity
Get PDFLUMCDe rol van de T cel immuun respons, gericht tegen tumorantigenen van virale of cellulaire origine, bij bestrijding van tumore
Immune regulation by mast cells
Get PDFThe objective of this PhD thesis is to understand mast cell (and basophil) functions and their role in autoimmune disease by focusing on three main aims: 1. To characterize the interaction between innate and Fc receptor triggers on mast cell and basophil function 2. To analyze the interaction between mast cells and CD4+ T cells 3. To understand the function of mast cells in chronic inflammation In this thesis I showed that mast cells can significantly contribute to chronic inflammation through their activation by Fc receptors and TLRs, as well as their interaction with CD4+ T cells, thereby increasing our understanding of their role in allergy and autoimmunity and providing several therapeutic targets to prevent mast cell-mediated immune responses.The work described in this thesis was funded by the Dutch Arthritis Foundation, whom we thank for their support. Additional financial support was obtained from the Dutch Organization for Scientific Research (Vici grant), the Research Foundation Sole Mio, the Leiden Research Foundation (STROL), the Centre for Medical Systems Biology (CMSB) within the framework of the Netherlands Genomics Initiative (NGI), the IMI JU funded project BeTheCure, contract no 115142-2, and European Union (Seventh Framework Programme integrated project Masterswitch; grant Number: 223404). Printing of this thesis was financially supported by the Leiden University Medical Center, Leiden University, and BD Biosciences.UBL - phd migration 201
Candidate gene studies in rheumatoid arthritis
Get PDFRheumatoid arthritis is a chronic auto-immune disorder, of which persistent synovitis, bone erosions and auto-antibody formation are characteristic features. Although the etiology of the disease remains largely unknown, it is established that genetic risk factors play a pivotal role in disease pathology. Both family and twin studies have shown that the genetic contribution to the disease can be estimated around 50%. In the current thesis the genetic contribution of non-HLA genes to RA susceptibility was further investigated and the functional relevance of these loci was explored. The studies described were able to establish several previously identified risk factors in a statistical robust manner. Also novel genetic risk factors that are associated with RA susceptibility could be identified, as well as risk factors that are conferred to specific subgroups of the disease.UBL - phd migration 201
- …
