Thesis (doctoral)--Lund University, 1994. / Added t.p. with thesis statement inserted.

Thesis (M. Sc.)--University of Canterbury, 2006. / Typescript (photocopy). "April 2006." Includes bibliographical references (leaves 101-122). Also available via the World Wide Web.

La parodontite est une pathologie immunoinflammatoire, entrainant une destruction du parodonte, suite à l’interaction entre un biofilm dysbiotique et une réponse immunitaire dérégulée. Parodontite et polyarthrite rhumatoïde présentent des mécanismes immunopathogéniques communs. Ainsi, les lymphocytes B (LB) ont un rôle majeur dans l’étiopathogénie de ces deux affections. Nous avons mené deux études cliniques observationnelles sur des cohortes de patients atteints de parodontite et traités pour leur polyarthrite rhumatoïde par deux immunothérapies touchant les LB : un anti-IL-6R(Tolicizumab) et un anti-CD20 (Rituximab). L’utilisation d’un anti-IL-6R a montré une diminution du TNF-α dans le fluide gingival après 6 mois de traitement, sans modification clinique de la parodontite. Par contre, l’anti-CD20, responsable d’une déplétion en LB, a permis une amélioration des paramètres cliniques parodontaux. Ensuite, nous avons étudié le phénotype des LB dans le sang et la gencive de patients atteints de parodontites sévères. Nos résultats montrent une augmentation des LB effecteurs "mémoires switchés" et une diminution des LB1 CD11b+ régulateurs. Notre travail a permis de mieux comprendre la distribution et le rôle des LB dans la réponse immunitaire dans les parodontites, aussi bien au niveau local que systémique et la discussion ouvre de nombreuses pistes de recherche et de nouvelles stratégies thérapeutiques. / Periodontitis is an immunoinflammatory pathologie, leading to periodontal destruction, following the interaction between a dysbiotic biofilm and a deregulated immune response. Periodontitis and rheumatoid arthritis exhibit common immunopathogenic mechanisms. Thus, B cells have a major role in the etiopathogenesis of these two diseases. We conducted two observational clinical studies in cohorts of patients with periodontitis and treated for rheumatoid arthritis with two immunotherapies for B cells: an anti-IL-6R (Tolicizumab) and an anti-CD20 (Rituximab). The use of anti-IL-6R showed a decrease in TNF-α in gingival crevicular fluid after 6 months of treatment, without clinical change in the periodontitis.On the other hand, the anti-CD20, responsible for a depletion in B cells, allowed an improvement of the periodontal clinical parameters. Then we studied the B cells phenotype in the blood and gingiva of patients with severe periodontitis. Our results show an increase in effector "switched memory" B cells and a decrease in regulator CD11b+ B1 cells.Our work has provided a better understanding of the distribution and role of B cells in the immune response in periodontitis, both locally and systemically, and the discussion opens many research approaches and new therapeutic strategies.

The overall goal of the work, described in this thesis was to investigate the molecular mechanisms that regulate normal pre-B cell proliferation and how these may be altered in transformed pre-B cells. Monoclonal antibodies and molecular biological techniques have allowed a number of stages of pre-B cell differentiation to be defined but little is known about mechanisms controlling their proliferation. Studies of pre-B cell production in animal models and in long-term cultures that support pre-B cell proliferation have suggested that stromal cells play a key role in this regard. As a first step to investigate the mechanisms involved, a number of pre-B cell supportive murine stromal cell lines were isolated and characterized. A number of pre-B cell lines were also isolated, cloned and characterized. From these, spontaneous and Abelson murine leukemia virus transformants were derived. These cell lines were then used in co-culture experiments to demonstrate that stromal cells constitutively secrete a pre-B stimulating factor. Characterization of the pre-B cell stimulating activity produced by one stromal cell line (M2-10B4) showed it to be a 10 Kd molecule sensitive to freezing and different from any cloned hemopoietic growth factor described to date. The possibility that extracellular matrix components might be involved in stromal cell-mediated control of pre-B cell growth was also investigated. It was found that pre-B cells attach specifically to fibronectin and that although fibronectin by itself cannot support pre-B cell proliferation, it contributes to stromal cell stimulation of pre-B cell growth. Both of these mechanisms were found to be affected in malignantly transformed pre-B cell populations irrespective of the mode of transformation. Transformed pre-B cells were found to have acquired the ability to secrete a novel 3 Kd autocrine factor that is also capable of stimulating normal pre-B cells. In addition transformed pre-B cells showed a greatly decreased ability to adhere to fibronectin and had become insensitive to the synergistic stimulating effect of fibronectin. It will be of interest to determine in the future whether these findings have a counterpart in human malignant pre-B cell populations. / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate

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Barbora Hadámková Determination the mechanism of entry F. tularensis into B lymphocytes Diploma thesis Charles University, Faculty Of Pharmacy in Hradec Králové Study program: Pharmacy Background: Besides processing the research with basics knowledge of the problem, the main aim of the study was the analysis of mechanism of entrance of intracellular bacteria Francisella tularensis into B cells. Methods: The B cells, which we obtained through peritoneal lavage from mice Balb/c, we blocked using antibodies individual complement receptors, B cell receptor and Fcƴ receptor. The population of the cells was infected by bacteria F. tularensis LVS/GFP opsonized by complement and/or by antibodies. Using flow cytometry we measured the percentage of infection of individual subpopulations of B cell B1a, B1b and B2 and we evaluated the influence of blocking and opsonization on the infection. Results: From the measured data, we can say that the percentage of infected B cells after infection by F. tularensis opsonized by complement is increased. This increase was more distinct in subtype of B cells B1b and B2. On the other hand, the opsonization F. tularensis by antibodies did not affect the infection. We also found out, that blocking of Fcƴ receptor has decrease the infection, if we used for infection of B cells...

Hepatitis C virus (HCV) infection is characterized by a strong propensity toward chronicity, autoimmune phenomena and lymphomagenesis, supporting a role for lymphocyte dysregulation during persistent viral infection. We have shown that HCV core protein inhibits T-cell functions through interaction with a complement receptor, gC1qR. Here, we further report that B cells also express gC1qR that can be bound by HCV core protein. Importantly, using flow cytometry, we demonstrated differential regulation of B and T lymphocytes by the HCV core-gC1qR interaction, with down-regulation of CD69 activation in T cells but up-regulation of CD69 activation and cell proliferation in B cells. HCV core treatment led to decreased interferon-γ production in CD8+ T cells but to increased immunoglobulin M and immunoglobulin G production as well as cell surface expression of costimulatory and chemokine receptors, including CD86 (B7-2), CD154 (CD40L) and CD195 (CCR5), in CD20+ B cells. Finally, we showed down-regulation of suppressor of cytokine signalling-1 (SOCS-1) using real-time reverse transcription-polymerase chain reaction, accompanied by up-regulation of signal transducer and activator of transcription-1 (STAT1) phosphorylation in B cells in response to HCV core protein, with the opposite pattern observed in HCV core-treated T cells. This study demonstrates differential regulation of B and T lymphocytes by HCV core and supports a mechanism by which lymphocyte dysregulation occurs in the course of persistent HCV infection.

The ABF-1 gene encodes for a protein that belongs to the basic helix-loop-helix family of transcription factors. ABF-1 mRNA molecules have been detected in the lymphoid tissues, which include the bone marrow, lymph nodes, and appendix, as well as transformed B cells lines infected with Epstein-Barr virus. This study investigates the role of ABF-1 in regulating downstream target genes in the human mature B cell line RAJI, as well as the plasma cell line, ARH-77. Quantitative real-time polymerase chain reaction and DNA microarray technology was used to investigate target genes that are subjected to transcriptional regulation by ABF-1. Using ABF-1 inducible cell lines or B cell lines that overexpress ABF -1 by transient transfection experiments, we discovered many cellular genes that change in their transcriptional profiles in response to ABF -1 expression. Based upon the analysis of genes being affected following ABF-1 induction, our results support the hypothesis that ABF-1 primarily functions as a transcriptional repressor in vivo. Many genes that regulate the cellular processes of apoptosis, as well as the cell cycle, were repressed following ABF-1 expression. Because EBV has been reported to control ABF-1 gene expression, the identification of downstream target genes regulated by ABF-1 may provide insight into the molecular events that follow after EBV infection.

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No description available.