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A functional analysis of HLA-DQ using transgenic models

Frater, Arlene James; (1997) A functional analysis of HLA-DQ using transgenic models. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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The aim of the work described in this thesis was to investigate the function of the human HLA class II product, HLA-DQ, by expression in transgenic mice. The specific role of HLA-DQ in the immune response has not been well understood. HLA- DQ alleles are strong markers of susceptibility in several autoimmune diseases, however, this is not mirrored by strong expression of HLA-DQ by peripheral antigen presenting cells or a high frequency of HLA-DQ restricted T cells. Isotype specific differences in HLA class II function are suggested by differences in polymorphism of the peptide binding groove and by differing upstream regulatory regions. However, functional aspects of HLA-DQ have been difficult to characterise in human cells since expression is overshadowed by HLA-DR. To this end HLA-DQ transgenic mice have been generated using constructs containing HLA-DQA1*0301/-DQB1*0302 (a marker of susceptibility to insulin dependent diabetes mellitus) and HLA-DQA1*0102/- DQB1*0602 (linked with susceptibility to multiple sclerosis) genes. Transgenic HLA- DQ expression from both genomic constructs and a cDNA cassette was characterised. The expression of the transgenes was found to be tissue and cell-type specific, occurring with a typical MHC class II distribution except for weak thymic expression in some cases. Moreover, the transgenes appeared functional. Introduction of HLA- DQ was found to correspond with V? specific expansions and Mtv specific deletions in the mouse T cell repertoire. Furthermore, the transgenic mice were capable of generating HLA-DQ restricted T cell responses on priming with a nominal antigen (ovalbumin). As an initial step towards investigation of the role of HLA-DQ in susceptibility to autoimmune disease, transgenic mice were primed with candidate autoantigens associated with multiple sclerosis or diabetes. HLA-DQ3+ mice showed increased responses to an epitope of glutamic acid decarboxylase, whilst introduction of the HLA-DQ6 trangenes lead to an alteration in the T cell responses of mice to priming with a panel of myelin basic protein peptides. It is hoped that with further characterisation these animals will provide a model to investigate in greater detail the role of HLA-DQ in the immune response and its association with susceptibility to autoimmune disease.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: A functional analysis of HLA-DQ using transgenic models
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences; Leukocyte antigens
URI: https://discovery.ucl.ac.uk/id/eprint/10100768
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