B. burgdorferi has a wide variety of strategies to hide from the host immune system. Complement regulatory binding proteins have been described for almost all complement resistant B. burgdorferi sl... Show moreB. burgdorferi has a wide variety of strategies to hide from the host immune system. Complement regulatory binding proteins have been described for almost all complement resistant B. burgdorferi sl, except for the complement resistant B. bavariensis, one of the species that is known to frequently cause Lyme neuroborreliosis. In chapter 2 it is attempted to identify CRASP-1 proteins in B. bavariensis, formerly known as B. garinii OspA serotype 4. Potential CRASP-1 proteins will be cloned and studied for their ability to interact with host derived fluid phase regulators of complement. The specific role of complement resistance in early effective infection and dissemination of B. burgdorferi sl has not been well investigated. Can complement resistance lead to a better and more effective infection and dissemination? In chapter 3 an in vivo experiment in which the infectivity and dissemination patterns of complement sensitive and complement resistant B. burgdorferi sl in a C3 deficient mouse model is described. After effective transmission from the tick to the host the next challenge in B. burgdorferi infection is rapid and accurate detection of the pathogen. Diagnostics of Lyme disease is often compromised due to specific pathogen properties combined with technical shortcomings of bacterial serology. Two indirect detection methods which can aid in diagnosing patients suffering from Lyme neuroborreliosis were studied. In chapter 4 the performance of the C6-peptide ELISA for detecting antibodies in CSF in Lyme neuroborreliosis patients is studied. While in chapter 5 levels of CXCL13 in several patient populations as a potential biomarker for the diagnosis of Lyme neuroborreliosis is studied. For both indirect markers of presence of B. burgdorferi the specificity in clinically resembling and neuroinfectious diseases is of key importance. Several other infectious and inflammatory diseases that have a clinical presentation that can resemble Lyme disease are included in the analysis. Diagnosing Lyme disease can be difficult in some populations, first because Lyme disease is a relatively rare infection, resembling a large spectrum of other autoimmune and inflammatory diseases. Clinicians could often consider testing for Lyme disease. It is also important to do this in specific preselected populations, because the positive predictive value of a test, but specifically indirect tests such as serology, in a random population, is low.In chapter 6 all patients that present with complaints of arthritis at the early arthritis clinic are tested for Lyme arthritis. The prevalence of B. burgdorferi seropositivity in this population is studied. Another aim is to identify clinical factors which should urge the doctor to test, or explicitely not test, for Lyme disease in a patient presenting with arthritis in Europe. In chapter 7 a case of an HIV positive patient presenting with a meningoencephalitis caused by B. burgdorferi is described. The literature on HIV and Lyme neuroborreliosis co-infections is also reviewed. Show less
This thesis describes the clinical significance of thebiomarker C4d, a split product of the complement system, in several manifestations of systemic autoimmunediseases such as SLE and... Show moreThis thesis describes the clinical significance of thebiomarker C4d, a split product of the complement system, in several manifestations of systemic autoimmunediseases such as SLE and antiphospholipid syndrome. The findings in this thesis suggest that this biomarker might be of use in unraveling disease mechanisms where complement activation is involved, as well as serving as a diagnostic tool to detect patients at risk of antibody mediated tissue injury Show less
Pol, P. van der; Schlagwein, N.; Gijlswijk, D.J. van; Berger, S.P.; Roos, A.; Bajema, I.M.; ... ; Kooten, C. van 2012
Ischemia/reperfusion injury (IRI) remains a major problem in renal transplantation. Clinical studies have identified that high serum levels of Mannan-binding lectin (MBL), the initiator of the... Show moreIschemia/reperfusion injury (IRI) remains a major problem in renal transplantation. Clinical studies have identified that high serum levels of Mannan-binding lectin (MBL), the initiator of the lectin pathway of complement activation, are associated with inferior renal allograft survival. Using a rat model, we identified an entirely novel role for MBL in mediating renal IRI. Therapeutic inhibition of MBL was protective against kidney dysfunction, tubular damage, neutrophil and macrophage accumulation, and expression of proinflammatory cytokines and chemokines. Following reperfusion, exposure of tubular epithelial cells to circulation-derived MBL resulted in internalization of MBL followed by the rapid induction of tubular epithelial cell death. Interestingly, this MBL-mediated tubular injury was completely independent of complement activation since attenuation of complement activation was not protective against renal IRI. Our identification that MBL-mediated cell death precedes complement activation strongly suggests that exposure of epithelial cells to MBL immediately following reperfusion is the primary culprit of tubular injury. In addition, also human tubular epithelial cells in vitro were shown to be susceptible to the cytotoxic effect of human MBL. Taken together, these data reveal a crucial role for MBL in the early pathophysiology of renal IRI and identify MBL as a novel therapeutic target in kidney transplantation. Show less
Hoek, B. van; Rooij, B.J. de; Verspaget, H.W. 2012
De activatie van zowel witte bloedcellen als complement systeem (betrokken bij het immuunsysteem) zijn geassocieerd met atherosclerose (slagaderverkalking). Het proefschrift bestaat uit drie delen;... Show moreDe activatie van zowel witte bloedcellen als complement systeem (betrokken bij het immuunsysteem) zijn geassocieerd met atherosclerose (slagaderverkalking). Het proefschrift bestaat uit drie delen; In deel I laten wij in 3 hoofdstukken zien dat vetten belangrijker zijn dan glucose voor de activatie van de witte bloedcellen en dus meer in staat zijn om een ontstekingsfenomeen op gang te brengen die leidt tot slagaderverkalking. Verder laten wij zien dat pati_nten met familiair verhoogd cholesterol (FH) en familiair verhoogd cholesterol en verhoogde voedingsvetten (triglyceriden) (FGH) na glucose-belasting een blijvende witte bloedcelactivatie hebben in tegenstelling tot gezonde vrijwilligers. Tenslotte werd aangetoond dat het structurele eiwit van de partikels waarin voedingsvetten vanuit de darmen worden vervoerd (apoB48) geassocieerd is met intima media dikte (een marker voor slagaderverkalking) In deel II associ_ren wij in 3 hoofstukken witte bloedcelactivatie met slagaderverkalking. Zo werd bijvoorbeeld aangetoond dat er in de kransslagaders met slagaderverkalking een hogere witte bloedcelactivatiestatus is dan in andere kransslagaders en bloedvaten zonder slagaderverkalking. Verder is de activatie van monocyten (een subgroep van witte bloedcellen) een voorspeller voor toekomstige hart- en vaatziekten. In deel III zijn ook 3 hoofdstukken beschreven met daarin de rol van mannose bindend lectine (MBL) die een van de routes is van complementactivatie (betrokken bij immuniteit; opruimen van lichaamsvreemde stoffen zoals bacteri_n). In hoofdstuk 1 werd beschreven dat mensen die lage MBL-waarden hebben, een minder effici_ntere vetstofwisseling hebben dan mensen met voldoende MBL-waarden. Echter, als we puur naar slagaderverkalking kijken, zien we dat MBL geen invloed heeft op de progressie van krasslagaderverkalking bij mensen met pre-existent krasslagaderverkalking. Show less
Major advancements in the understanding of the immune system have provided us with the opportunity for rational design of therapeutic immunological interventions. The notion that dendritic cells ... Show moreMajor advancements in the understanding of the immune system have provided us with the opportunity for rational design of therapeutic immunological interventions. The notion that dendritic cells (DC) play a crucial role in the activation of T lymphocytes has made DC biology of central importance for vaccine development. Accordingly, efficient delivery of antigen to DCs is one of main objectives in vaccine development. In this thesis, antibody-mediated antigen targeting is evaluated as a potential antigen delivery strategy for therapeutic vaccination. Complexes of protein antigen and antigen-specific antibodies are natural formulations that bind to Fc__ receptors. Fc__R ligation on DCs leads to efficient uptake, DC maturation and presentation of the antigen to T lymphocytes. Interaction of Ag-Ab complexes with Fc__Rs on DCs provides a link between the humoral and cellular arms of the immune response. This thesis contains an extensive evaluation of Fc__R-mediated antigen delivery to dendritic cells in the context of T lymphocyte-mediated immunotherapy. In addition, it contains a detailed analysis of Fc__R function on DCs and addresses the kinetics of cross-presentation of antigen after Fc__R-mediated uptake. Show less
The Guillain-Barr_ syndrome (GBS) is an acute, post-infectious neuropathy. Several clinical presentations are known, but general symptoms are symmetric muscle weakness and loss of tendon reflexes.... Show moreThe Guillain-Barr_ syndrome (GBS) is an acute, post-infectious neuropathy. Several clinical presentations are known, but general symptoms are symmetric muscle weakness and loss of tendon reflexes. In more than half of the GBS patients, antibodies against gangliosides can be detected in their serum. Gangliosides are glycosphingolipids, which are located in the outer layer of cell membranes, and play a role in cell-cell recognition and communication. Because gangliosides are highly enriched in the presynaptic nerve membranes, a role in synaptic transmission and the process of neurotransmitter release is assumed. We explored the physiological role of these gangliosides in transmitter release in neuromuscular synapses of mice using electrophysiological techniques. Furthermore, these synapses were also studied for the pathophysiological effects caused by antibodies against the gangliosides. The results show that gangliosides appear not to be fundamental for neuromuscular function, but rather have a modulating role. In addition, blocking of the complement system, using complement-component C5-inhibitors, is an effective method to protect the nerve membrane against the damaging effects of the activated complement system as a result of anti-ganglioside antibody binding. These and other experimental findings of this thesis are discussed in view of the current literature and the pathogenesis and therapeutical aspects of GBS. Show less
The innate immune system plays an important role in solid organ transplantation. This thesis focuses on the role of the lectin pathway of complement activation in kidney and simultaneous pancreas... Show moreThe innate immune system plays an important role in solid organ transplantation. This thesis focuses on the role of the lectin pathway of complement activation in kidney and simultaneous pancreas-kidney transplantation (SPKT) and describes the role of properdin in tubular complement activation and clearance of apoptotic cells. Mannose-binding lectin (MBL) is the initiating molecule of the lectin pathway of complement activation and its levels are largely determined by frequently occurring polymorphisms of the MBL gene. Our studies show that high MBL levels in the transplant recipient are associated with poorer graft survival and in the case of SPKT also with poorer survival of the recipient. While low MBL levels are associated with better survival we also show that low MBL does increase the risk for infectious complications after SPKT. Properdin is classically described as a stabilizer of the alternative pathway of complement activation. This thesis points towards a new role for properdin by describing a direct interaction with apoptotic cells and with the tubular epithelium of the kidney. By directly binding to these cellular surfaces properdin may contribute to the clearance of apoptotic cells and participate in complement activation and renal damage in proteinuric states. Show less
Activation of the complement system provides an important mechanism of defense of an organism against invading pathogens. In the healthy individual this defense is finely regulated to prevent... Show moreActivation of the complement system provides an important mechanism of defense of an organism against invading pathogens. In the healthy individual this defense is finely regulated to prevent attack of the complement system against cells and tissues of the host, however in abnormal situations this regulation can be out of balance. In the present thesis we look at a mouse model where the classical pathway of complement, in conjunction with anti-C1q autoantibodies, is shown to be involved in the development of renal disease (Chapter 2). In Chapter 3, a novel mouse model of complement-mediated glomerulonephritis is described. This model seems to be dependent on the alternative pathway of complement activation as well as on Fc receptors, and provides a novel tool to dissect the contribution of different effector systems in renal inflammation.Then the natural complement-inhibitory properties of the defensin Human Neutrophil Peptide-1 and the extracellular matrix molecules decorin and biglycan are investigated, which are presented to play a role in the regulation of complement in vitro, which hopefully can be extended to in vivo situations of health and disease in the near future (Chapter 4 & 5). The thesis is concluded with a general discussion in Chapter 6. Show less
The aim of this thesis was to gain more insight in the involvement of inflammatory processes in vessel wall remodeling seen after PTA or bypass surgery and put these processes in the perspective of... Show moreThe aim of this thesis was to gain more insight in the involvement of inflammatory processes in vessel wall remodeling seen after PTA or bypass surgery and put these processes in the perspective of restenosis, vein graft failure and potential therapeutic preventive strategies. Therefore, we firstly focused on inflammation in general, using the anti-inflammatory agent Dexamethasone, assessing the effects of such a broad approach on restenosis and vein graft remodeling. Then, we further focused on some specific parts of the immune system, namely Interleukin 10 (IL10), chemokines and the complement cascade. Il10 was chosen because it is one of the most studied anti-inflammatory cytokines and this property makes it a potential candidate for ant-restenosis therapy. Furthermore, it was hypothesized that chemokines are involved in vascular remodeling, since they are generally known for their regulatory properties regarding influx of inflammatory cells to tissues and this is one of the first phenomena seen in vascular remodeling. The complement cascade was studied in this context since it contains pro-inflammatory activity and some end-products of the cascade, like chemokines, are potent chemotactic agents. Show less
