Genomic and Molecular Aspects of Mature Human B Cells
Sammanfattning: This thesis covers aspects of the mature human B cell and its different guises on its way to become a fully differentiated antibody forming plasma cell (AFC), the key player in the humoral immune system. The understanding of the complex molecular mechanisms taking place in the B cell, as it first encounters antigen, enters the germinal center (GC) reaction, giving rise to memory cells and plasma cells, is not only of importance for the curious scientist, but will also benefit the understanding of B cells in disease. For instance, what is the cause of B cell lymphomas and what role does B cells play in the etiology of autoimmunity? These questions and many more will be greatly facilitated by gaining knowledge of the molecular events influencing healthy B cells. This thesis is based on four original papers (I-IV) which deals with several different aspects of the mature human B cell. In paper I we looked into the properties of CD44 signaling and its role in B cell activation. Naive B cells isolated from human tonsils and sorted by FACS, were cultured in vitro for 3 days, stimulated with anti-BCR, and anti-CD40 stimuli in condition one and with an additional anti-CD44 stimuli in condition two. B cells, sampled at 6, 24 and 72 hours from each condition were analyzed by high-density oligonucleotide microarray analysis. The results demonstrated a role for CD44 in immunomodulation and inflammation, since transcripts for molecules such as IL-6 and IL-1alpha were specifically up-regulated by CD44. In paper II, by using high-density oligonucleotide microarrays, we analyzed mantel cell lymphomas (MCL) in relation to normal mature B cell subsets comprising naive, pre-activated, germinal center and memory cell subsets. From this analysis we could conclude that the malignant transformation event of MCLs appears to be an event occurring during the transition from a primary B cell follicle to a germinal center. In paper III we looked closer into what differs between human GC centroblasts and centrocytes isolated by FACS. By using high-density oligonucleotide microarray analysis and flow cytometry we concluded that the current phenotypic description of the different GC B cell subsets is misleading and that the centrocyte population represents a heterogeneous subset of cells comprising centroblasts, centrocytes and plasmablasts. In paper IV we extended our analysis of the mature tonsillar B cell subsets from paper II and III to also include plasmacells, GC founder cells, sub-epithelial cells and GC B cells described by other means. The microarray analysis grouped cells into three main categories: proliferating, non-proliferating and plasma cells. Cell type specific transcription programs were characterized.
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