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Investigating the antibody-independent functions of B lymphocytes 10.17863/CAM.40748 Inaba, Akimichi Clatworthy, Menna B cells are critical for the generation of antibody, but there is increasing evidence that they have a broader functional remit: For example, innate B1a cells are a critical source of granulocyte macrophage colony-stimulating factor (GM-CSF) during Gram-negative sepsis, inducing neutrophil expansion and mobilisation to limit bacteraemia. B cells can also regulate immune responses via the production of cytokines such as IL-10, and this can inhibit deleterious autoimmune and alloimmune responses in murine models. Here I investigated whether B cells may play a pathogenic role in the sterile inflammation associated with acute kidney injury (AKI), coordinating a systemic response in which neutrophils and inflammatory monocytes are mobilised from the bone marrow to the injured kidney. We found that during murine models of AKI, neutrophils exit the bone marrow and increase in the blood and kidneys. This neutrophil mobilisation was tightly correlated to the severity of AKI. B cells were recruited to the kidney in a CD11b-dependent manner and produced CCL7 to attract inflammatory monocytes. The absence of Siglec-G, an inhibitory receptor expressed in innate B1a cells, exacerbates AKI in murine models. Conversely, concomitant administration of a Siglec-G agonist, sialic acid (Neu5AC), ameliorated AKI and reduced renal neutrophil infiltration. These data suggest that manipulation of innate B cells may be a viable therapeutic strategy in AKI. In the second part of the thesis, I investigated whether IL-10-producing regulatory B cells could be induced in humans in vivo. Transcriptomic analysis demonstrated that IL-10 producing human B cells expressed transcripts of all components of the IL-2 receptor (CD25, CD122 and CD132). We found that surface CD25 was upregulated on a subset of mouse and human B cells following stimulation with toll-like receptor (TLR) agonists and CD40L, rendering these cells receptive to IL-2. The addition of IL-2 to these activated B cells significantly augmented IL-10 production, whilst pro-inflammatory cytokines such as IL-6 and tumour necrosis factor alpha (TNF-α) were unchanged, resulting in a skewing of B cells towards a regulatory phenotype. Consequently, co-culture of IL-2-treated B cells with activated CD4 cells led to a reduction in T cell production of TNF-α. In vivo, in mice and patients treated with low dose IL-2, we observed a significant increase in IL-10-producing B cells. Together, our data suggest that low dose IL-2 may be a useful strategy to promote the generation of regulatory B cells in vivo. University of Cambridge 2019-07-01 Thesis Doctoral Doctor of Philosophy (PhD) en The PhD was funded by a Medical Research Council Clinical Research Training Fellowship. https://www.repository.cam.ac.uk/handle/1810/293635 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/eadb8401-1873-48ec-bd76-1ac1ad8a9ff7/download 9cacecc3eff8a7a0b0aa3379996e594e https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/a7c3bb10-b292-41f0-b718-af723d8451e8/download 87eda9de84448d1f82354d60eee3eb5f https://www.rioxx.net/licenses/all-rights-reserved/ B cells Regulatory B cells B lymphocytes Acute kidney injury Autoimmune disease Diabetes mellitus CCL7 SIGLEC-G Sialic acid IL-10 IL10 IL-2 IL2