Idiotypy and idiotypic networks: a time to redefine concepts
The administration of intravenous immunoglobulin (tVIg) has been reported to benetit patients with autoimmune disease [1]. The benefit may be transitory or long lasting. Three possible mechanisms have been proposed; (i) the IVlg preparation contains antibodies specific for a pathogen that is causative in the disease; (ii) the high levels of IgG attained result in nonspecific blockade of Fey receptors expressed on cells of the retieulo-endothelial system; (iii) the autoimmune condition results from loss of a normal regulatory pathway that is reestablished by components of the IVtg preparation. Mechanisms proposed in (i) and (ii) may be relevant to particular diseases but not to the wide spectrum of autoimmune conditions for which benefit is claimed. The mechanism most widely canvassed, under (iii), is re-establishment of immune regulation through the idiotypic network. Clearly, it is of fundamental importance and interest to examine this possibility, since, if benefit can result from application of such relatively crude preparations, appropriately targeted reagents should have dramatically improved efficacy. The paper of Barbouche et al. [2] reports that 28% of monoclonal immunoglobulins having polyreaetive autoantibody activity express cross-reactive idiotypes (CRI) and that these CRI are present in IVlg (Sandoglobulin). They suggest that the detection of CRI in this immunoglobulin preparation is consistent with the proposition that therapeutic benefit results from restoration of regulation through an idiotype network. The criteria used in Barbouche et al. to produce a polyclonal reagent recognizing CRI conform to convention, including successive absorptions on normal human polyclonal IgG immuno-affinity columns, using IgG prepared by the Cohn fractionation method. The absorbed antiserum is reported to detect CRI present in the IVlg preparation, indicating a radical difference in composition between the two polyclonal IgG preparations. Since Sandoglobulin is a refined preparation of IgG prepared by Cohn fractionation, this finding suggests that different immunoglobulin preparations may have significantly differing therapeutic potential; determined, presumably, by the donors contributing to the pool. This further underlines the need for precise analysis of the biological specificities and activities that are contained within such preparations, particularly with respect to idiotype and anti-idiotypic components. The first requirement is an understanding of the phenomenon of idiotypy and a precise definition of the terms used.