Behçet’s Disease in the United Kingdom: Genetic Risk Factors and Ophthalmic Manifestations

Abstract

This thesis focuses on clinical manifestations and genetic risk factors in a cohort of individuals with Behçet’s Disease (BD) from the United Kingdom (UK). Chapter 1 outlines the history of BD and discusses the spectrum of clinical presentations. The history of human leukocyte antigen B*51 (HLA-B*51) associations in BD is covered and current knowledge of other genetic associations explored. The relevance of the killer immunoglobulin-like receptor 3DL1/S1 (KIR3DL1/S1) and its ligand, the Bw4 epitope, is discussed and current knowledge of KIR3DL1/S1 biology is reviewed. Chapter 2 outlines the materials and methods used in the following chapters. Results are described in Chapters 3, 4 and 5. Chapter 3 explores established genetic associations in BD between HLA –A and –B, and the MHC Class I Polypeptide-Related Sequence A (MICA). Here, the concept of ancestry informative markers (AIMs) is introduced, with a view to reducing heterogeneity caused by population admixture. I confirm the importance of HLA-B*51 in the UK cohort and in a subgroup made up of individuals of European ancestry. The allele MICA*009, is also confirmed as a risk factor for BD, however, its association is likely to be caused by strong linkage disequilibrium to HLA-B. Chapter 4 investigates alleles of KIR3DL1/S1 and their associations in BD. In this chapter, the construction of ‘functional genotypes’ to estimate KIR3DL1/S1 expression phenotype is discussed. The combination of a low-expressing KIR3DL1 allotype and KIR3DS1 was found to increase the risk of disease, whereas a high-expressing KIR3DL1 allotype in combination with a KIR3DL1-null allotype decreases the risk of disease. The phenotype of circulating Natural killer (NK) and CD8 T cells is then explored. Low percentages of NK cells were present in PBMC analysed from individuals with BD. Furthermore, KIR3DL1 and KIR3DS1 were expressed at much lower levels than expected. The creation of target cell lines to test the functional effects of the KIR3DL1/S1 ‘functional genotypes’ is then discussed. I was unable to find any significant differences in degranulation provoked by HLA-B*51, B*52 or B*35+ target cells. Chapter 5 describes the results of a prospective survey of ophthalmic manifestations of BD in the UK. The incidence of ophthalmic BD is 0.04 per 100,000 in the UK. Patient demographics and geography are discussed in detail in this chapter. Chapter 6 draws together the findings from the Thesis and Chapter 7 discusses limitations and further work.