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The stochastic pattern of onset of rheumatoid arthritis (RA) suggests that it is initiated not by an external stimulus but by random genesis of new antibody species by immunoglobulin gene mutation [1]. Most autoantibody-committed B cells probably die from a lack of T cell help and from a follicle-centre suicide signal from uncomplexed self antigen. IgG rheumatoid factor (RF)-committed B cells may, in contrast, self-perpetuate, using their antibody product both to obtain nonspecific T cell help and, as self-associated complexes, to provide a positive survival signal in follicle centres. They should also facilitate survival of clones committed to production of RF of other classes.

Molecular modelling indicates that IgG1 RF-based complexes, comprising not more than two or three IgG molecules, should evade complement clearance, cross endothelium, and access tissue macrophages [2]. Recent work indicates that, of the three IgG Fc receptors on macrophages only FcγRIIIa will induce TNFα release in response to complexes of this size [3]. FcγRIIIa is expressed at high level only on macrophages in tissues targeted by rheumatoid arthritis and, in dermis, only at sites where nodules form [4]. The dominant involvement of synovium probably reflects the sensitivity of synovial fibroblasts to TNFα and the resulting tendency to synovial lymphoid metaplasia with local antibody production [5].

If IgG RFs are responsible both for their own production and for clinical disease, deletion of IgG RF-committed B cells should produce long term-remission. Initial results from a phase-I therapeutic trial of B cell depletion will be presented.

References

1. Edwards JCW, Cambridge G, Abrahams VM: Do self-perpetuating B lymphocytes drive human autoimmune disease?

   Immunology 1999, 97:1868-1896. Publisher Full Text

2. Edwards JCW, Sutton BJ, Grimmett J, Abrahams VM: Rheumatoid factor stereochemistry analysed by real space modelling.

   Arthritis Rheum 1998, (suppl):S84.

3. Abrahams VM, Cambridge G, Lydyard PM, Edwards JCW: FcRIIIa mediates tumour necrosis factor alpha secretion by human monocytes.

   Arthritis Rheum 1998, (suppl):S345.

4. Bhatia A, Blades S, Cambridge G, Edwards JCW: Differential distribution of FcγRIIIa in normal human tissues.

   Immunology 1998, 94:56-63. PubMed Abstract | Publisher Full Text

5. Edwards JCW, Leigh RD, Cambridge G: Expression of molecules involved in B lymphocyte survival and differentiation by synovial fibroblasts.

   Clin Exp Immunol 1997, 108:407-414. PubMed Abstract | Publisher Full Text

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