2,263 research outputs found
AMD. Studies on pathogenesis, treatment and prevention of age-related macular degeneration
No full textContains fulltext :
120582.pdf (Publisher’s version ) (Open Access)Radboud Universiteit Nijmegen, 20 december 2013Promotores : Hoyng, C.B., Daha, M.R. Co-promotores : Hollander, A.I. den, Klevering, B.J
Preferential binding of unusually long peptides to MHC class I and its influence on the selection of target peptides for T cell recognition
No full textA classic feature of antigen presentation for CD8 T cell recognition is that MHC class I molecules generally present peptides of 8-10 amino acids in length. However, recent studies have demonstrated that peptides of >10 residues play a significant role in immune surveillance by T cells restricted by some HLA class I alleles. In the present study, we describe several examples of unusually long viral peptides of 11 or 12 residues, recognized by CTLs in the context of HLA-B35. Interestingly, all these immunogenic peptides completely encompass shorter canonical length sequences that conform to the HLA-B35 binding motif, but which fail to stimulate detectable T cell responses. The mechanism for this phenomenon appears to involve the preferential binding to HLA-B35 of the atypically long CD8 T cell target peptides over the overlapping canonical length sequences. These data suggest that the peptide length specificity of some HLA class I alleles is broad, allowing peptides of >10 residues to sometimes dominate over canonical length class I ligands as targets for T cell recognition
Role of IgM and C-reactive protein in ischemia reperfusion injury
No full textIschemia-reperfusion injury (IRI) is a pathophysiological event that occurs in many clinical conditions, ranging from surgery, acute artery occlusion to transplantation. Complement activation is thought to be a crucial step in IRI, because complement inhibition and complement deficiency considerably attenuate irreversible injury. However, the specific complement pathway remains unclear. All three complement pathways: the classical, the alternative, and the mannose-binding lectin dependent pathway may be involved in the development of IRI, depending on the model, the tissue, and the time course of inflammation. Ischemia leads to the exposition of neoantigens on the jeopardized tissues, which could be recognized by C-reactive protein (CRP) and natural IgM antibodies. The binding of CRP and IgM to these neoepitopes is followed by complement activation. In this thesis, we demonstrated that both proteins bind to jeopardized tissues and activate the complement system, in particular intestines from rats subjected to IRI. Furthermore, it was shown that IgM levels against altered phospholipids correlated with the levels of inflammatory mediators in patients subjected to tissue damage suggesting that IgM participates in amplification of inflammation. The development of strategies to prevent binding of CRP and/or IgM is an attractive approach for a therapy for reducing IRI.UBL - phd migration 201
Esperienza ed evento della verità. Pratica filosofica e astrazione scientifica nel pensiero di A.N. Whitehead
No full textThis article analyzes the relationship between philosophy, experience and event in A.N. Whitehead’s thought. From the critics of the concept of object, the author retraces and describes the peculiar “abstract-concrete dialectic”, at the center of the researches concerning the perceptual experience.
Furthermore, according to Whitehead’s later works, she demonstrates how the philosophical practice is different from all other kinds of science, although it requires science itself because of the co-implication of object and event, abstraction and recognition
Complement and disease : activation and control
No full textActivation 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.UBL - phd migration 201
Modulated rat dendritic cells in renal transplantation models : immune regulation and graft outcome
No full textFollowing allograft transplantation, the immune system is triggered to induce an immunogenic response against the non-self organ. To prevent the induction of this immunogenic response, recipients are treated with immunosuppressive medication. The majority of these medications target T cells, which play a key role in the rejection process, and thereby prevent acute rejection in most of the recipients. Non-specific targeting of these T cells not only prevents acute rejection, it also prevents responses against pathogens or tumor growth. In addition, long-term use of immunosuppressive agents may cause organ failure due to toxic effects on the organ [1]. Therefore, the ultimate goal is to develop a therapy, which targets alloreactive T cells, allowing a normal response against pathogens and tumors, in the absence of chronic use of immunosuppressive agents. Various strategies have been employed to induce such a donor-specific tolerance, amongst which treatment with immature DC [2]. These immature DC have, in contrast to mature DC, the capacity to induce tolerogenic responses and are therefore an attractive candidate for cellular therapy. The studies presented in this thesis demonstrate that in fully mismatched kidney transplantation models, administration of modulated donor-derived DC to recipient__s results in regulation of recipient__s immune response. Both the donor-specific hyporesponsiveness of recipient T cells and the reduced influx of CD8+ T cells into the graft of LPS-DexDC treated recipients indicate a positive effect of this treatment. However, optimization of this treatment is necessary, since no prolonged allograft survival was induced. Several mechanisms, which are not regulated by LPS-DexDC, may be responsible for the observed rejection, amongst which the preformed alloantibodies, increased levels of C3 in the graft and the increased influx of NK cells. Additional studies are required to explore the modulating effects of antibodies which block co-stimulation and/or short courses of immunosuppressive drugs as a co-treatment in these settings.This work was supported by the EU grants QLRT-2001-01215 LSHB-CT-2004-512090 (RISET)UBL - phd migration 201
Il "Guerrin Meschino" di Gesualdo Bufalino : un'"opra" in versi
No full textGesualdo Bufalino first published Il Guerrin Meschino in 1991 in a non-commercial edition. In 1993, after a deep revision, he re-published his work with publisher Bompiani: the novel has a modified plot, and the author decided to insert three new poems in addition to the opening and closing poems, formerly present in 1991’s edition. This paper, in its entirety supported by handwritten material preserved at Fondazione Gesualdo Bufalino (Comiso), is divided in two parts: the first part illustrates the differences between the first and the second edition, the second part provides a critical edition of the five poems
Pathogenic role of (S)IgA in IgA nephropathy
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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 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.LEI Universiteit LeidenDutch kidney foundation, Jurriaansestichting, 3A-out foundationniet-projectgebonden outpu
Apoptotic cell clearance by macrophages and dendritic cells : immunoregulation in the context of innate immunity
No full textThe 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.LEI Universiteit LeidenThe Dutch Kidney Foundation (C02.2015)Nier en pancreas transplantati
Immune regulation in IgA nephropathy
No full textIgA nephropathy (IgAN) is the most common form of glomerulonephritis worldwide. The hallmark of the disease is depositions of polymeric IgA1 in the mesangium of the glomeuli. These depositions will lead to inflammation in the kidneys and eventually to deterioration of renal function. The pathogenesis of IgAN is not clear, but it is generally accepted that disturbances in the immune system of IgAN patients are responsible for this disease. In the current thesis we have investigated the immune response of IgAN patients in comparison with control persons. We have shown that IgAN patients have a hampered primary IgA immune response upon mucosal vaccination with a neoantigen, whereas a systemic vaccination with a neoantigen resulted in a similar immune response in both groups. We hypothesized that dendritic cells (DC), as professional antigen presenting cells could have an impaired function , or that less DC are present in the nasal mucosa. We were able to show that the number of DC present in the nasal mucosa of IgAN patients was not reduced as compared with controls. Using an in vitro model we studied the function of DC in the primary immune response and showed that DC of IgAN patients induced less IgA production in na_ve B cells than DC of control persons. Furthermore we studied the size distribution of the antigen specific IgA molecules in IgAN patients. In summary we showed that patients with IgAN have an impaired IgA production upon mucosal vaccination with a neoantigen and that at least part of this IgA hypo response is due to an impaired capacity of DC to induce IgA production, whereas the number of mucosal DC in IgAN patients is not reduced.Groene Hart Ziekenhuis, Gouda Fresenius Medical Care, Baxter Renal Division, Amgen B.V., Novartis Pharma B.V., Shire NederlandUBL - phd migration 201
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