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The role of immunoglobulin receptors in the pathogenesis of rheumatoid arthritis

Abrahams, Vikki Martyne; (2000) The role of immunoglobulin receptors in the pathogenesis of rheumatoid arthritis. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Historically, a key immunological feature of rheumatoid arthritis is the presence of small circulating immunoglobulin G (IgG) rheumatoid factor-based immune complexes. More recently, tumour necrosis factor alpha (TNFα) has been shown to be an important mediator of inflammation in rheumatoid arthritis. The aim of this thesis was to test a hypothetical model outlining an effector mechanism for inflammation in rheumatoid arthritis. This model predicts that small immune complexes comprising self-associating IgG rheumatoid factors, owing to their small size, evade complement-mediated clearance from the circulation and access tissue macrophages. These complexes may initiate inflammation within synovium by binding to one of three immunoglobulin receptors for IgG (FcγR). Unlike FcγRI and FcγRII, FcγRIIIa expression by macrophages correlates with the location of synovitis and extra-articular features in patients with rheumatoid arthritis. Selective FcγRIIIa crosslinking by IgG rheumatoid factor complexes may trigger macrophage activation and the subsequent production of proinflammatory mediators such as TNFα. Murine IgG anti-FcγR monoclonal antibodies (mAb) to each FcγR were used as surrogates for small immune complexes. Of the three anti-FcγR mAb, only that directed against FcγRIIIa triggered adhered monocytes to release TNFα, IL-1α and reactive oxygen species. This confirmed previous evidence that for signalling, FcγRI and FcγRII require multiple receptor aggregation. Further findings indicated anti-FcγRIII mAb- induced TNFα release to be dependent on crosslinking of either three FcγRIIIa receptors, or two receptors where one FcγRIIIa bound an IgG Fc fragment. Small, soluble human IgG anti-NIP mAb immune complexes were also able to trigger adhered monocytes to release TNFα in a subclass dependent manner. Moreover, although this TNFα response was found to be dependent upon both FcγRII and FcγRIIIa, FcγRIIIa appeared to play a dominant role. The findings of this thesis support the hypothesis that small IgG rheumatoid factor based immune complexes may trigger the production of TNFα and other proinflammatory mediators from macrophages in rheumatoid arthritis, and implicate an important role for FcγRIIIa.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The role of immunoglobulin receptors in the pathogenesis of rheumatoid arthritis
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; Arthritis
URI: https://discovery.ucl.ac.uk/id/eprint/10114457
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