Reseach themes
Ocular Immunology, Behcet’s Disease, Immunogenetics
Research activity
Behcet’s Disease (BD)
In Behcet’s Disease, in collaboration with colleagues in Birmingham (PI Murray), London (Prof MR Stanford, King’s College and Prof Farida Fortune, Queen Mary’s College) and Professor Rob Moots (University of Liverpool, Graham has identified several single nucleotide polymorphisms (SNP) including those associated with increased production of tumour necrosis factor, and Factor V Leiden, both linked to severe vascular disease (retinal occlusion), and MHC class I-related protein MICA*009, which I have postulated is involved in control and licensing of NK cells (see below). Recently, Graham has analysed SNP in PTPN22 and CTLA-4, two genes regarded as genetic masterswitches for autoimmunity, and found that CTLA-4 SNP were not associated with BD, while PTPN22 620W was inversely associated. These results support the view that BD is an autoinflammatory condition and not autoimmune. Recent work has focussed on the evolutionary aspect of gene mutations in BD.
Ocular Immunology
Research has focussed on the effect of the ocular microenvironment on macrophage activation by Toll-like receptor ligands, to address the conditions in which immune privilege may be maintained or broken. In related studies, in collaboration with Miss Si Rauz (Institute of Inflammation and Ageing) the effect of TLR signalling on antimicrobial defensins and chemokine production by corneal epithelial cells is being addressed. The effects of TLR stimulation are being analysed in the presence of both cortisol and vitamin D3 production to investigate interaction between these endogenous (protective) and exogenous (inflammatory pathways. The results have shown for the first time that corneal epithelial cells can make active vitamin D3, while fibroblasts make active cortisol, but that neither affects TLR stimulation.
On the cellular side with in collaboration with Professor Farida Fortune, Professor Miles Stanford and Dr Harry Petrushkin, Graham has investigated the functional relevance of the HLA-MICA coexpression identified by his genetic studies in BD. The results show that while a differential response of inhibition of killing in patients compared to controls. This may have an important effect on NK cell function and we are currently sequencing the molecules involved in NK control.