Autoantibody/ Immune complex mediated inflammatory mechanisms
The main focus of the group is to determine the role that the Fcγ receptors (FcγRs) play in the development and severity of human autoimmunity, in order to determine if they are a potential therapeutic target. Investigation of the IgG/Fcγ Receptors (FcγRs) in the context of RA pathogenesis has been a major research focus over recent years. In common with other segmental duplications, the complex evolutionary history of the FCGR genetic locus has hampered the accurate mapping and SNP analyses undertaken as part of the Human Genome and International HapMap Projects. Our previous work has consistently identified a genetic association between the FCGR genetic locus and RA, particularly nodular RA.
New strategies for SNP detection and genotyping have had to be developed to enable a fine-mapping study of this region in theYorkshire Early Arthritis Cohorts, which is currently underway. Investigation of the FCGR locus is also relevant to a wide-variety of other autoantibody and immune complex-mediated disorders. The importance of this locus in contributing to the therapeutic efficacy of biological agents with an intact Fc region remains to be elucidated for the rheumatic disorders. Multi-centre collaborations have been established to obtain sufficiently large cohorts to expand this work further.
In addition to the immunogenetic studies, a range of functional assays have been developed to evaluate modulation of various FcγR effector functions in specific inflammatory diseases and to ultimately determine the functionality of novel SNPs.
As a clinician I also maintain an active interest in inflammatory eye disorders, including Behçets Disease, the mechanisms of action non-response to biological therapies and the Hereditary Connective Tissue Diseases.
Figure 1.
Morgan AW, Robinson JI, Barrett JH, Martin J, Walker A, Babbage SJ et al. Association of FCGR2A and FCGR2A-FCGR3A haplotypes with susceptibility to giant cell arteritis. Arthritis Res Ther 2006; 8:R109.
Morgan AW, Barrett JH, Griffiths B, Subramanian D, Robinson JI, Keyte VH et al. Analysis of Fcγ Receptor haplotypes in rheumatoid arthritis. FCGR3A remains a major susceptibility gene at this locus with an additional contribution from FCGR3B. Arthritis Res Ther 2006; 8:R5.
Morgan AW, Griffiths B, Ponchel F, Montague BMN, Ali M, Gardner PP et al. Fcγ receptor type IIIA is associated with rheumatoid arthritis in two distinct ethnic groups. Arthritis Rheum 2000; 43:2328-2334.