The major targets in Systemic lupus erythematosus (SLE, a systemic autoimmune disease) are nuclear components (DNA, histones, ribonucleoproteins), which are mainly derived from dying cells ... Show moreThe major targets in Systemic lupus erythematosus (SLE, a systemic autoimmune disease) are nuclear components (DNA, histones, ribonucleoproteins), which are mainly derived from dying cells (apoptotic and necrotic cells). Defective clearance of dying cells by phagocytes may lead to the breakdown of peripheral tolerance and initiation of autoimmune SLE. I have investigated the role of the innate immune system in the processing of dying cells and its immunological consequences. I found that a subset of macrophages driven by M-CSF have intrinsic anti-inflammatory properties and are potent phagocytes that have the unique capacity to preferentially bind and ingest early apoptotic cells in a silent manner. I also identified that human peritoneal macrophages freshly isolated from patients on peritoneal dialysis resemble functionally the in vitro-generated M-CSF-driven macrophages. I further showed that the anti-inflammatory and pro-inflammatory macrophages co-exist but can re-differentiate towards opposing phenotype depending on the local cytokine environment. Next to the phagocyte system, I investigated the role of components of the innate immune system in the processing of dying cells. I found that one of the complement regulators called properdin, binds predominantly to late apoptotic and necrotic cells independently of C3b, resulting alternative pathway complement activation. Show less
Primary IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis world wide and leads to end stage renal disease in 30-50% of patients. The hallmark of IgAN is the deposition... Show morePrimary IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis world wide and leads to end stage renal disease in 30-50% of patients. The hallmark of IgAN is the deposition of IgA1 in the mesangial area of the kidney. Since the inflammatory response which leads to progressive renal disease, is triggered and sustained by the deposition of IgA in the renal mesangium, it is important to determine by which mechanisms binding to mesangial cells (MC) occurs. Most likely both the intrinsic renal features, as well as circulating factors, such as structural alterations in serum IgA molecules are thought to be involved in the pathogenesis of IgAN. In this thesis we concentrated on two aspects. First identify and further characterize the IgA binding receptors potentially playing a role in IgA nephropathy, including FcRI/CD89, Fc/µR. Furthermore, we characterized the different molecular forms of IgA with special attention to the specific glycosylation patterns. Finally, we found a clear deposition of SIgA in the glomeruli of IgA nephropathy patients. Altogether, the data presented in this thesis support a role for SIgA in the pathogenesis of a subpopulation of IgAN patients. Show less
The scope of the current thesis is to obtain insight in immunological aspects of transplantation and diabetes. This thesis underscores the current concept of collaboration between the innate and... Show moreThe scope of the current thesis is to obtain insight in immunological aspects of transplantation and diabetes. This thesis underscores the current concept of collaboration between the innate and adaptive immune system by showing close interactions between both immune systems. Mannose binding lectin as a major recognition molecule of the lectin pathway and as a key protein of the immune system was studied in relation to its functional characteristics. Appreciating the Jekyll-and-Hyde character of MBL and the fact that MBL serum levels and functionality are under strict genetic control, MBL was studied under distinct pathological conditions. Chapter 2 describes molecular and biological aspects of mannose binding lectin and the interaction of MBL with the adaptive immune system. Chapter 3 focuses on the involvement of MBL in autoimmunity, by studying juvenile type 1 diabetic patients at disease onset. Chapter 4 addresses the role of the liver in production of serum MBL and evaluates the effect of MBL variant alleles on the susceptibility to infection after liver transplantation. Chapter 5 focuses on the effect of the adaptive immune system on islet transplantation, a novel treatment of type 1 diabetes. Show less
