Medical Biology - Theses
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ItemThe Transcription Factor T-bet in the Control of Germinal Centre Dynamics in Malaria( 2019)With reductions in the global malaria burden stalled, this preventable and curable infectious disease caused by the Plasmodium parasites, remains a public health challenge that affects the world’s most vulnerable populations. Naturally acquired immunity plays an important role in protection from disease; however, there is long-standing evidence that it requires years of repeated infections to develop. The reasons for this are largely elusive, but immuno-epidemiological studies support that protective antibodies and memory B cells are short-lived and inefficiently generated to infection. Moreover, recurrent infections are associated with an expansion of atypical memory B cells that may have impaired function. Histological analyses revealed significant disorganisation of the spleen in severe malaria patients, which led to the concept that acute infection may undermine the acquisition of B cell memory. T helper 1 pro-inflammatory responses induced by blood-stage infection were subsequently shown to compromise the induction of humoral immunity by inhibiting effective T follicular helper (Tfh) cell differentiation and germinal centre (GC) reactions. The relative contribution of the T helper 1 lineage-defining transcription factor, T-bet, in CD4+ T cells and B cells to GC development in malaria, was investigated using the P. berghei ANKA blood-stage infection model. T-bet expression in CD4+ T cells limited the differentiation of Tfh cells that supported GC development in the spleen. This led to an impaired generation of antibody-secreting cells and memory B cells following infection. In addition to its impact on CD4+ T cells, T-bet was highly up-regulated in GC B cells elicited by infection, and limited the magnitude of the GC response in a B cell-intrinsic manner. Strikingly, T-bet expression in the B cell compartment modulated the transcriptional landscape of GC B cells to promote the GC dark zone program but constrained light zone development. In particular, T-bet suppressed expression of the regulator of G-protein signaling 13, which down-regulates the responsiveness of B cells to migrate towards the chemokine CXCL12, for effective dark and light zone transition within the GC. T-bet-driven dark zone skewing of the GC reaction following malaria infection associated with enhanced somatic hypermutation of GC B cells, and improved the avidity of antibodies against the parasite. Therefore, this thesis supports a model in which malaria-elicited inflammation mediated by T-bet, exquisitely modulates the dynamics of the GC reaction, promoting GC B cell dark zone polarization that promotes the generation of B cells with increased affinity for antigen, consequently enhancing affinity maturation. This provides novel insight into the cellular mechanisms that underlie the development of humoral immune responses in malaria, and has implications for other chronic infections and autoimmune disease that are characterised by a similarly potent inflammatory milieu.
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ItemResolving causes and consequences in a model of autoimmune disease( 2010)Antibody is an essential component of immunity that triggers a series of mechanisms to neutralise and clear pathogens. In a situation where the targets of antibody cannot be cleared, for instance when they are a normal part of the host, self-directed antibody activates these same mechanisms to drive continued destruction of host tissues. The production of antibody is therefore a critical point of regulation in the prevention of autoimmune disease. A sequence of control points exists that prevents B cells expressing self-reactive antibody from differentiating to form plasma cells. Once this differentiation step has occurred, a plasma cell can persist for years unimpeded. No current therapies target plasma cells and their capacity for persistence precludes any potential benefit of B cell depletion strategies. The factors required for plasma cell maintenance are inadequately characterised, and even less is known of the means by which plasma cell homeostasis is regulated. In systemic lupus erythematosus (SLE), an antibody-mediated autoimmune disease, plasma cells can accumulate and secrete excess antibody into the serum. When this antibody reacts against self-components it may trigger autoimmune disease. With time, the recruitment of auxiliary cell types into the disease process can compound disease development and promote the maturation of self-reactive plasma cells into high-affinity, isotype switched antibody-producing cells whose capacity for inflicting tissue damage is considerably amplified. This cyclic pattern of disease development confounds the study of underlying cell-intrinsic defects, obscuring causes of disease from those aspects of the phenotype that are a consequence of inflammatory processes occurring as part of disease progression. Using the Lyn-deficient mouse model of SLE, this thesis demonstrates that certain aspects of this antibody-mediated disease require the participation of T cells to establish destructive IgG-driven inflammatory processes. When the contribution of T cells is diminished, an IgA-mediated pathology is revealed that is entirely reliant on the presence of IL-6. Pharmacological inhibitors of IL-6 and concurrent blockade of T cell help may therefore be an effective strategy for preventing the production of pathogenic IgG and IgA autoantibodies in SLE patients. Occurring in parallel and independently of these factors is an accumulation of unswitched plasma cells in peripheral lymphoid organs of Lyn-deficient mice. These plasma cells appear to accumulate by virtue of their enhanced capacity for survival, which is a direct result of the loss of Lyn in these cells. Lyn normally limits STAT3 signalling following IL-6 stimulation of plasma cells and in its absence loss of negative regulation of STAT3 signalling may reduce the threshold for plasma cell survival by STAT3-dependent factors such as IL-6. This could allow plasma cells to accrue beyond normal homeostatic limits. An additional means of regulating the plasma cell response to IL-6 is the induction of SOCS3, which curtails the duration of STAT3 signalling. The consequences of deletion of SOCS3 in the B cell lineage were investigated, revealing a subtle role for this negative regulator during the antibody response to T cell-dependent antigen.