The research group has an interest in the role of autoantibodies in autoimmunity and mechanisms of tissue targeting.
Rheumatoid Arthritis
Recent work has been focussed upon testing a hypothetical model for the pathogenesis of rheumatoid arthritis. Patients with rheumatoid arthritis have small circulating immune complexes of IgG rheumatoid factor. Briefly, the model suggests that unlike larger immune complexes, small IgG rheumatoid factor complexes, because of their size, will escape complement clearance from the circulation and cross endothelium. Once in the tissues these small complexes will be able to acess tissue macrophages. These complexes may then activate these macrophages by crosslinking surface immunoglobulin receptors, causing the release of proinflammatory meditors such as tumour necrosis factor alpha, interleukin-1 and reactive oxygen species.
 | Physical model of IgG rheumatoid factor dimer x15,000,000 |
There are three human receptors for IgG Fc; FcgRI (CD64), FcgRII (CD32) and FcgRIII (CD16). Monocytes and macrophages generally express FcgRI and FcgRII, however, FcgRIIIa expressed is more restricted. We have found that FcgRIIIa expression by macrophages is limited to only a few tissues in the normal individual. Moreover, the sites of FcgRIIIa expression correlate with the sites of pathology seen in patients with rheumatoid arthritis.
Therefore, is seems likely that small complexes of IgG rheumatoid factors may selectively bind FcgRIIIa (which binds small complexes very well) and subsequently activate tissue macrophages. This would explain the tissue targeting seen in rheumatoid arthritis. Recent work has shown that human monocyte-derived macrophages can be actived to release TNFa, IL-1a and reactive oxygen species through FcgRIIIIa but not FcgRI or FcgRII when two or three receptors are specifically cross-linked.
Current projects include the investigation of why macrophages at only certain sites express FcgRIIIa and the development of a novel method for the detection and measurement of small circulating IgG rheumatoid factor complexes in patients with rheumatoid arthritis.
Publications
Edwards JCW, Leigh RD, Cambridge G. Expression of molecules involved in B lymphocyte survival and differentiation by synovial fibroblasts. Clin-Exp-Immunol 1997;108:407-14.
Edwards JCW, Blades S, Cambridge G. Restricted expression of FcgRIII (CD16) in synovium and dermis: implications of tissue targeting in rheumatoid arthritis (RA). Clin Exp Immunol 1997;108:401-406.
Bhatia AS, Blades S, Cambridge G, Edwards JCW. Differential distribution of FcgRIIIa in normal human tissues and co-localisation with DAF and fibrillin-1. Immunology 1998; 94:56-63.
Edwards JCW, Cambridge G. Rheumatoid arthritis: the predictable effect of small immune complexes in which antibody is also antigen.Br J Rheumatol. 1998;37:126-30.