Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.796003
Title: Genetic and B cell functional studies of X-linked immunodeficiencies
Author: Lau, Yu Lung
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1988
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Abstract:
Eight types of X-linked immunodeficiency diseases have been described. In this thesis, I will focus on four, viz X-linked agammaglobulinaemia (XLA), X-linked severe combined immunodeficiency (X-linked SCID), Wiskott-Aldrich syndrome (WAS) and X-linked hyperimmuno-globulinaemia M (X-linked hyperlgM). Their clinical features, treatment and prognosis as well as cellular and genetic aspects are reviewed in Chapter 1; followed by objectives of the studies presented in this thesis, viz localization of the gene loci of XLA and X-linked SCID, clinical application of the linked DNA probes in families with XLA and identification of the B cell defects in patients with XLA and WAS. The practical issues of collecting patients and families for linkage analysis, as well as their immunological profiles and pedigrees are given in Chapter 2. Various laboratory techniques employed in these studies are detailed in Chapter 3. There are five sections in Chapter 4, which is on the genetic studies of XLA. Section one reviews the principle of linkage analysis, genetic heterogeneity and restriction fragment length polymorphism (RFLP) . Results of the genetic localization of XLA to Xq21.3-q22 are presented in section two. Evidence of non-allelic genetic heterogeneity in XLA is presented in section three, followed by the analysis of all the family data of XLA in the literature in order to estimate the proportion of families unlinked to Xq21.3-q22, which is probably 10-20%. The posterior probability of each family being linked to Xq21.3-q22 is also estimated. Section four describes the clinical application of the two linked probes, S21 and pXG12, in the genetic counselling of thirteen families with XLA; as well as developing a method of risk calculation allowing for non-allelic genetic heterogeneity. Seven obligate carriers under the age of 45 can all be offered prenatal diagnosis. Of the thirty-four females at risk of being carriers, seventeen have their risks increased, fifteen decreased and two unchanged by the RFLP results. Eleven of the seventeen women whose risks were increased are under 45 years of age and seven of them can be offered prenatal diagnosis. Successful predictions have been made in a newborn male infant and a male fetus at risk of being affected with XLA. Section five presents the evidence that X-linked hyperlgM is not an allelic genetic disease with XLA. Chapter 5 presents the results of the genetic localization of X-linked SCID to Xqll-ql3 and the clinical application of the linked probe, cpX73, in carrier detection. The results of the functional studies of Epstein-Barr virus (EBV) tranformed B cell lines from patients with XLA and WAS are presented in Chapter 6. B cell lines from patients with WAS did not differ from normal B cell lines in any of the functional assays I have used. However, differences were found in B cells from patients with XLA. EBV-transformed B cell lines from patients with XLA did not proliferate in response to KGl-a supernatant and they did not produce IgG in the presence or absence of various B cell growth and differentiation factors. Finally, Chapter 7 summarises the two approaches of investigations adopted in this thesis, which are applicable in investigating any diseases of single gene defect; future directions are also speculated.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.796003  DOI: Not available
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