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Title: Essential role for inflammatory signals in the differentiation and function of regulatory B cells
Author: Rosser, E. C.
ISNI:       0000 0004 5358 7407
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2014
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Regulatory B cells (Bregs), identified by this laboratory as transitional-2 marginal zone precursor cells (T2-MZPs), restrain immune-driven diseases by inhibiting pathogenic T cell differentiation via the provision of IL-10. Despite intense investigation into their effector function, little is known regarding the cellular processes that govern Breg differentiation. Here I show that arthritic inflammation controlled by the gut-microflora promotes the differentiation of splenic Bregs. Drastic alteration of the inflammatory process imposed by anti-TNFα treatment or changes in the gut-microflora caused a deficiency in the production of IL-1β and IL-6, and concurrently in the number and functional capacity of Bregs. Furthermore, Bregs induced by IL-1β and IL-6 were critical in limiting excessive inflammatory responses, as disruption of IL-1R1 and IL-6R exclusively on B cells lead to the development of an exacerbated arthritis and reduced IL-10 production by splenic B cells. These results led to the question of how the gut-microflora influences the differentiation of splenic-Bregs? I found that splenic-T2-MZPs, expressed the gut-homing marker α4β7, and were also detectable in the mesenteric lymph nodes (MLN). Furthermore, similarly to the spleen, changes imposed on the microbiome by antibiotics treatment caused a reduction in both the number of IL-6+ cells and IL-10+Bregs in the MLN. Interestingly, further analysis revealed that MLN-T2-MZPs were not exposed to IL-1β in the MLN and were only-partially suppressive when compared to their splenic counterparts. Collectively, this data suggests a possible scenario where Breg differentiation is initiated in the MLN following exposure to gut-microbiota induced IL-6, but B cells do not become fully-committed Bregs until exposure to the combination of both IL-1β and IL-6 in the spleen.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available