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Title: The role of toll-like receptor 9 on B-cell activating factor expression and function in normal human B-cells
Author: Abu-rish, Eman Yousuf Ali
ISNI:       0000 0004 2739 365X
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2013
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B-cell autoreactivity is a characteristic abnormality in several autoimmune diseases. In systemic lupus erythematosus (SLE), inappropriate activation of TLR7 and TLR9, accompanied by high serum levels of BAFF, are implicated in disease pathogenesis. In murine B-cells, TLR9 activation resulted in up-regulating BAFF expression, while such a direct effect has not yet been established in normal human B-cells (nhB-cells). Therefore, the effect of CpG-2006, a synthetic TLR9 ligand, on the expression and function of BAFF and its receptors (BAFF-R, TACI and BCMA) in nhB-cells was studied. BAFF expression, in response to CpG-2006, was significantly upregulated at the level of mRNA, intracellular and membrane-bound protein in nhB-cell. In contrast, enhancement of BAFF secretion in culture supernatants of CpG-2006-stimulated nhB-cells was not detected. CpG-2006 treatment of nhB-cells significantly enhanced the expression of TACI and BCMA, but did not affect BAFF-R expression. CpG-2006-stimulated B-cells, in co-cultures with freshly isolated nhB-cells, co-stimulated B-cell receptor-induced cellular proliferation of the freshly isolated nhB-cells. This effect was completely blocked by a BAFF-specific monoclonal antibody. CpG-2006 treatment of nhB-cells sensitised them to proliferate in response to exogenous BAFF, whereas exogenous BAFF per se had no effect on the proliferation of untreated nhB-cells. This effect was inhibited by an anti-BAFF-R blocking antibody, but was not inhibited by anti-TACI or anti-BCMA antibodies. CpG-2006 mediated BAFF expression through NF-κB and ERK1/2 pathways, and partially through p38MAPK. Simultaneous treatment of nhB-cells with CpG-2006 and either of the inhibitory ODNs (ODN-TTAGGG or ODN-2088), at 1:5 ratio (CpG-2006: INH-ODN), inhibited CpG-2006-induced BAFF expression in nhB-cells. Finally, BJAB, RPMI and RAMOS B-cell tumour lines failed to represent nhB-cell’s responses to CpG-2006 treatment. Taken together, these novel findings demonstrate a functional cross-talk between TLR9 and BAFF in nhB-cells, and have possible implications for the roles of TLR9 and BAFF in the pathogenesis of SLE.
Supervisor: Browning, Michael Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available