Clark, Paula Anne; (1996) Molecular and cellular studies of X-linked severe combined immunodeficiency. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

X-linked severe combined immunodeficiency (XSCID) is characterised by a failure of both humoral and cellular immunity resulting in recurrent and opportunistic infections. Affected individuals have no T cells and normal or elevated numbers of B cells, indicating a defect in T cell development. At the start of this study the gene involved in XSCID had been mapped to the region Xq 13.1-21.1. In an attempt to reduce the extent of this region, the positions of polymorphic microsatellite loci, mapping to Xq 13.2-21.1, were refined. In 1993 the gene responsible for XSCID was cloned and identified as the IL-2 receptor γ chain which was also found to be a subunit of the IL-4, IL-7, IL-9 and IL- 15 receptors and denoted γc. This new information made it possible to screen a number of XSCID patients for mutations in the γc gene using single strand conformation polymorphism (SSCP) analysis. Mutations were identified in 14 individuals and this information has also aided carrier status assignment in a number of families. Expression of mutant γc at both the mRNA and surface protein levels was investigated in a number of EBV transformed B cell lines and also primary lymphocytes from patients. Surface expression as detected by a monoclonal antibody appeared to be disrupted in the majority of XSCID cases studied. Since the γc chain is a subunit of the IL-7 receptor and IL-7 is known to have a role in T cell development, an assay for IL-7 receptor function in XSCID patients was developed. This assay utilised a whole blood culture system and IL-6 production by monocytes in response to IL-7 was measured. The preliminary results obtained may help to elucidate the role of the γc chain in T cell development. The work presented here reflects the advancement of this field from gene cloning to the development of an understanding of the role of the XSCID gene product in both the normal and disease states.

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