Immunoglobulins and the regulation of autoimmunity through the immune network.

Beneficial effects of the administration of intravenous immunoglobulins (IVIg) have now been reported in a large number of autoimmune diseases, whether mediated by autoantibodies or by autoaggressive T cells. We have proposed that the immunoregulatory effect of IVIg in autoimmune disease is dependent on the selection of the recipient's immune repertoires by the variable (V) region reactivities of infused immunoglobulins. Thus IVIg contains antibodies reactive with idiotypes of natural and disease-related autoantibodies and surface immunoglobulins of B cells; IVIg also contains antibodies reactive with the idiotype, framework and constant regions of the beta chain of the alpha beta T cell receptor. Infusion of IVIg results in transient or long lasting suppression of specific autoantibody clones in vivo and in stimulation of a distinct subset of B cells reactive with the F(ab')2 fragments of IVIg Infusion of IVIg alters the general "architecture" of the network as assessed by studying the kinetic patterns of spontaneous fluctuations of natural autoantibodies in serum. Infusion of normal mouse Ig in healthy adult mice selects expressed immune repertoire by removing late pre-B and B cells in the bone marrow, mostly those expressing D proximal Vh genes, and by activating distinct subsets of B cells and CD4+ T cells in the spleen. Although dependent on the V region reactivities (composition) or injected preparations, these effects probably also require that the infused immunoglobulin contains an intact Fc moiety. If one considers the effect of IVIg on the structure, function and dynamics of the immune network IVIg may be viewed as a substitutive therapy for the quantitative/qualitative defects in network regulation that are associated with autoimmune diseases.