In the present study we have analyzed the changes in the expressed antibody repertoire and in temporal fluctuations of antibody levels in serum that followed infusion of normal IgG (IVIg) in a patient with autoimmune thyroiditis. Administration of IVIg resulted in the stimulation of IgM production, in alterations of expressed antibody activity in serum that could not merely be accounted for by the passive transfer of antibody specificities contained in IVIg, in transient down-regulation of B cells clones expressing a specific disease-related idiotype and in the increase in serum in recipient’s autoantibodies specifically reactive with F(ab′)2 fragments of IVIg. In addition, infusion of IVIg shifted the pattern of spontaneous fluctuations of autoantibody activities in the patient’s serum from a pattern indicative of disconnected events in the immune network to a pattern similar to that which is consistently observed in healthy controls. These results suggest that normal IgG may modulate autoreactivity by selecting expressed antibody repertoire through V region-dependent interactions with antibodies.

Key words: autoimmunity, IgG, intravenous immunoglobulin (IVIg), immune networks

This paper considers current concepts of autoimmunity and concludes with a discussion on the need for viable alternatives. It is argued that, if a century of ‘horror autotoxicus’ and over 30 years of active research based on ‘clonal deletion’ models have failed to contribute solutions to the problem, these notions are probably inadequate. Instead, it is proposed that pathological states of autoimmunity should be considered as deviations from normal autoreactivity which is a central property of the immune system. It follows that the study of autoimmune physiology is necessary to the understanding of pathology. Furthermore, the discrimination between destructive immune responses and physiological, self-directed immune activities is thought to be a systemic property based on a particular network organization, rather than the result of isolated clonal properties. These views suggest novel strategies in basic and clinical approaches to autoimmunity, more particularly the possibility of manipulating physiological autoreactivity to compensate diseases which are not of immunological origin.

According to a classical, antigen-driven view of the immune system, autoimmunity is due to the presence of self-reactive lymphocyte clones which have not been eliminated. However, computer simulations of the immune network show that the greater the degree of connectivity of a clone, the greater its degree of tolerance to chronic antigenic stimulation. This tolerance does not correspond to an absence of response on the part of the system as a whole. On the contrary, stimulation by a ‘tolerogenic antigen’ results in widespread modification and overall activation of the whole network. This suggests that on an autopoietic network view of the immune system, autoimmunity arises not because of the presence of self-reactive clones, which is completely normal, but because such clones are inadequately connected to the network. This amounts to a complete reversal in perspective, whose significance for the clinical treatment of autoimmunity and the future of immunology is discussed.