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Title: Investigation of the linkage between Gaucher disease and B-cell disorders including multiple myeloma
Author: Ayto, Robert Michael
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2011
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Aim. To investigate the association between Gaucher disease (GD) and gammopathy. Introduction. Gaucher disease is a disorder characterised by deficiency in lysosomal glucocerebrosidase, foamy macrophages, cytopenias, bony lesions, organomegaly and a high incidence of monoclonal/polyclonal gammopathy. Abnormalities in the bone marrow microenvironment, including pseudo-Gaucher cells, have been reported in non-GD patients with myeloma. Methods. Gaucher gene analysis, co-culture, drug assays, western blotting, enzymatic assays, flow cytometry, immunofluorescence and cytotoxic assays. Results. GD patients had a high incidence of gammopathy (polyclonal/monoclonal). Serum biomarkers of macrophage burden were predictive of gammopathy and the Zimran severity score was higher in those with monoclonal than polyclonal gammopathy. Enzyme replacement therapy ameliorated polyclonal gammopathy and stabilised paraprotein levels. Gaucher mutations were not prevalent in Jewish patients with paraproteinaemia (8/77 patients). Non-GD patients with paraproteinaemia had normal serum chitotriosidase and monocyte glucocerebrosidase activity. GD monolayers (osteoclasts/macrophages) did not confer a proliferative or survival advantage on co-cultured myeloma cell lines. GD monolayers, compared to control cultures, reduced sensitivity to melphalan and this was contact dependent. Western blotting identified differences in the levels of Bim and Bcl-xL between myeloma cells harvested from control and GD monolayers. When cultured alone, GD monolayers generated more osteoclasts and this was enhanced by plasma cell coculture (contact independent). GD monolayers did not preferentially rescue myeloma cells pre-treated with doxorubicin from cell death. Patients with GD have decreased lymphocyte glucocerebrosidase activity, abnormal lipid trafficking and low peripheral NK (natural-killer), invariant NK and CD4+ve T-cell numbers. Invariant NK cells, GD derived, displayed impaired proliferation to α-galactosylceramide. Cytotoxicity assays, derived from the GD peripheral blood mononuclear cells, displayed inferior killing compared to control assays. NK killing assays were equivalent between controls and GD patients. Conclusion. This thesis presents novel data, which may confer an increased risk of gammopathy in GD.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available