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Title: B cells, Bach2 and immune deficiency
Author: O'Brien, Charlotte Rose
ISNI:       0000 0004 7232 6974
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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B cell defects in HIV-1 infection are characterised by increased frequency of immature cell subsets, loss of memory cells, and hypergammaglobulinemia. There is increasing evidence that the capacity of B cells to secrete cytokines (IL-10) or express proteins (Bach2), may inhibit the T cell inflammatory response, which is believed to contribute to progressive immune deficiency in HIV-1. The aims were to determine if HIV-1 affects the capacity of B cells to express IL-10, TNF-α, and Bach2, and if alterations in cytokines and Bach2 expression were linked to T cell activation. An increase in immature B cell subsets and plasmablasts was found in HIV-1+ individuals, and was reversed by anti-retroviral therapy (ART). B cell proliferation and activation markers were increased in ART naïve individuals. However, TLR, T cell independent and dependent stimulation failed to increase expression of the co-stimulatory molecules, CD80 and CD86, or immunoglobulin synthesis, compared to healthy controls and HIV-1 patients on ART. No difference in the capacity of B cells to secrete IL-10 and TNF-α was noted in the study groups, and there was no association with markers of T cell activation. The results of flow cytometric Bach2 staining were unreliable. Analysis of B cell phenotype and function was undertaken in a patient with a history of chest infections and diarrhoea, and a heterozygous mutation in Bach2, c.T71C, was detected using whole exome sequencing. The patient did not have class-switched memory B cells, and decreased synthesis of immunoglobulins and cytokines. The immune findings supported the clinical phenotype of common variable immunodeficiency (CVID), which was confirmed by genetic correction experiments conducted by collaborators in the USA. In conclusion, HIV-1+ ART naïve patients retain the capacity to secrete cytokines despite a reduction in immunoglobulin synthesis. Mutation in Bach2 affects B cell maturation and function, and is implicated in the development of CVID.
Supervisor: Kelleher, Peter Sponsor: Westminster Medical School Research Trust ; Chelsea & Westminster Healthcare
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral