Analysen zur differentiellen Plasmazellhomöostase beim Menschen - Kontrolle des humoralen Immungedächtnisses

Humoral memory becomes apparent by the persistence of specific serum antibody titres and is provided by antibody-seceting plasma cells in the bone marrow. The homeostasis of plasma cells and the regulation of humoral memory, especially in man, are poorly understood. Plasma cells are generated within immune responses from activated B cells via an intermediate cell differentiation stage, the plasmablasts. During their translocation from secondary lymphoid tissues to the bone marrow, they become detectable in the peripheral blood. Using a flow cytometric approach to detect antigen specific plasmablasts induced by a tetanus booster vaccination, the simultaneous presence of newly generated HLA-DR plasmablasts and functionally distinct HLA-DR mature plasma in the blood was described in detail in the current thesis. Migratory and dividing plasmablasts and non-migratory, non-dividing plasma cells were always detected at comparable ratio in the peripheral blood, reflecting their stoichiometric relationship. Based on this observation, the mobilization of mature plasma cells from the bone marrow by newly generated plasmablasts induced in a systemic immune response was hypothesized. Thus, the fate of plasma cells does not generally end in the bone marrow, as assumed hitherto. The mobilization of mature plasma cells by plasmablasts represents an adaption mechanism of the humoral memory, that is described in the present work for the first time. This mechanism would allow the humoral memory to accomodate a new antigen specificity while maintaining the stability of pre-exisiting specificities. Different from plasmablasts induced by a systemic vaccination, plasmablasts generated in the immunological steady-state show features of mucosal immune reactions and respective cell migration properties, in that they express IgA, 4 7 integrin and a functional mucosal cell chemotaxis receptor, CCR10. Consistently, they most likely immigrate into mucosal plasma cell depots, such as the lamina propria, and do not interfere with plasma cells of the bone marrow. Consequently, the stability of humoral memory is preserved in steady-state and adaption of the humoral memory occurs exclusively during systemic immune reactions. The production of mucosal plasmablasts during steady-state is independent of concurrent systemic immune reactions and is not impaired in splenectomized individuals, showing the independency of systemic (parenteral) and mucosal immune reactions at the level of circulating plasmablasts. The chronic production of circulating mucosal plasmablasts is also continued during the comprehensive (therapeutic) depletion of B cells with the anti-CD20 antibody rituximab in patients with rheumatoid arthritis. This reflects autonomous execution of a mucosal antibody response in vivo through the generation of mucosal plasmablasts. These plasmablasts derive most likely from mucosal precursor B cells that do not (re-)circulate, are not (entirely) depleted by rituximab and show molecular features of memory B cells. A reliable relation between the persistent generation of mucosal plasmablasts and the disease activity in patients with rheumatoid arthritis or clinical responsiveness to rituxmab was not observed. The present work addresses plasma cell homeostasis in man to understand the regulation of humoral memory, with a focus on differential behaviour of plasmablasts induced in systemic vs. mucosal immune responses and functional distinction between recently generated plasmablasts and mature plasma cells. Based on experimental results, a model explaining the stability and adaptibility of humoral memory was established.