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Title: Autophagy in Systemic Lupus Erythematosus
Author: Clarke, Alexander James
ISNI:       0000 0004 5368 4311
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2015
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Autophagy has emerged as a critical homeostatic mechanism in lymphocytes, influencing proliferation and differentiation. I sought to explore the role of autophagy in the pathogenesis of human and murine lupus, a disease in which B cells are critical effectors of pathology. Autophagy was assessed using multiple techniques in NZB/W and control mice, and in patients with SLE compared to healthy controls. I evaluated the phenotype of the B cell compartment in Vav-Atg7-/- mice in vivo, and examined human and murine plasmablast formation following inhibition of autophagy. I found activation of autophagy in early developmental stages of B cell development in a lupus mouse model even before disease-onset, and which progressively increased with age. In human disease, again autophagy was activated compared with healthy controls, principally in naïve B cells. B cells isolated from Vav-Atg7-/- mice failed to effectively differentiate into plasma cells following stimulation in vitro. Similarly, human B cells stimulated in the presence of autophagy inhibition did not differentiate into plasmablasts. My data suggest activation of autophagy is a mechanism for survival of autoreactive B cells, and also demonstrate that it is required for plasmablast differentiation, processes that induce significant cellular stress. The implication of autophagy in two major pathogenic pathways in SLE suggests the potential to use inhibition of autophagy as a novel treatment target.
Supervisor: Vyse, Timothy James ; Cunninghame Graham, Deborah Shirey Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available