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produce joint disease. Secondly, the relationship between RF and disease is not one to one. Thirdly, ing complement activation. the putative pathogenic eVects of immune complexes Perhaps the most important aspect of this hypothesis were considered chiefly in terms of complement is that it refocuses attention on the possibility that activation. By 1990, cytokines such as tumour necrosis permanent interruption of autoantibody production factor alpha ( TNF-a) had come to be considered the might eVectively cure the disease. We propose that this more important mediators in the joint, and therapeutic might be possible. trials using cytokine blockade have reinforced that Much of the hypothesis is based on conventional view [7]. immunological dogma. Although large IgM-based As early as 1983, it had been shown that immune immune complexes may form in the circulation of RA, complexes, including those derived from RF, could these should bind complement and be cleared via stimulate macrophages to produce soluble factors (i.e. complement receptors. As reviewed by Davies [14], cytokines) capable of inducing extracellular matrix large complexes may cause problems in systemic lupus degradation [8]. It seemed likely that the complexes primarily because the complement system is defective. were binding to IgG Fc receptors ( FccR), but not Kunkel and colleagues identified smaller complexes in until 10 yr later had work by Fanger, Lydyard, the circulation in RA, chiefly in the form of IgG RF Huizinga, van de Winkel and others led to a clear self-associating dimers [4]. These small complexes fix understanding of the structure and function of these complement very poorly [15]. IgG dimers are also receptors [9‐11]. Moreover, only recently has it been small enough to be expected to gain significant access established that synovial intima is a highly specialized to the extravascular space and allow interaction with immunological microenvironment which includes an tissue macrophages. unusual pattern of FccR expression [12, 13].

Rheumatoid arthritis: the predictable effect of small immune complexes in which antibody is also antigen