Dimer Formation in Immunoglobulin Preparations and Speculations on the Mechanism of Action of Intravenous Immune Globulin in Autoimmune Diseases

Abstract

IgG dimers occurring in therapeutic Ig preparations have been characterized as Id-anti-Id, in that the sites of interaction are localized to the distal tips of the Fab arms. The observation that such dimers are prevalent in Ig or Igi.v. prepared from large plasma pools, but absent in preparations from a single individual, supports the notion that the individual immune repertoire is small with respect to the species repertoire. A crude mathematical model that attempts to relate Id-dimer content to the number of donors is presented. This model suggests that Id-pairs may be much more prevalent in Ig than is reflected by the Id-dimer content, inasmuch as the concentrations of the individual Ids and anti-Ids may limit the equilibrium level of dimer. The model further suggests that the antibody diversity in Ig derived from thousands of donors may be representative of the species repertoire; hence, virtually all specificities, including anti-Id specificities, will be included. Because Ig is derived from normal healthy donors, it should be relatively free of pathogenic autoantibodies. However, there is no reason to suspect that anti-Ids to such autoantibodies would not occur, and indeed the presence of such anti-Ids has been demonstrated. Several mechanisms have been proposed by which such anti-Ids might ameliorate autoimmune disease. They may directly inhibit the binding of autoantibody to its target antigen, or they may target for destruction those cells expressing or secreting autoantibody. It may well be that anti-Ids play no role in the mechanism of action of Igi.v. in autoimmune disease. Such appears to have been demonstrated, for example, in the treatment of ITP. There is an obvious need for additional studies in order to elucidate the mechanism of action of Igi.v. in various autoimmune diseases. Experimental animal models of autoimmune disease, such as the mouse model for systemic lupus erythematosus (Mozes et al. 1993), might be very useful in this regard. Finally, it needs to be emphasized that the usefulness of high doses of Igi.v. in many autoimmune diseases remains to be established by controlled clinical trials. Because Igi.v. is a limited resource, and one which cannot be produced through biotechnological advances (at least in the foreseeable future), its widespread use should be restricted to the treatment of diseases for which efficacy has been demonstrated. To do otherwise might deprive appropriate patients of a valuable therapy.

Inhibition of maturation and function of dendritic cells by intravenous immunoglobulin

“…However, as reported earlier, the therapeutic efficiency of IVIg preparations may depend on the dimers of IgG. 48,49 We observed an inhibitory effect on DC function by monomer-enriched fractions of IVIg, but it is possible that dimer-enriched IVIg preparations may exert similar or even stronger effects on DCs.…”

“…47 IVIg preparations contain variable amounts of monomers and dimers. 48 The IVIg preparation (Sandoglobulin) used in the present study contained largely monomeric forms of IgG. However, as reported earlier, the therapeutic efficiency of IVIg preparations may depend on the dimers of IgG.…”

Intravenous immunoglobulins induce the in vitro differentiation of human B lymphocytes and the secretion of IgG

“…Although the origin of autoimmune diseases remains enigmatic, defects in immunoregulatory mechanisms are assumed to play a central role [3][4][5] and many authors consider that a failure in V-region connectivity is responsible for the emergence of pathologic autoantibodies. [6][7][8][9][10] Following treatment with IVIGs, the improvement in the patient's health is often characterized by a diminution of the level and activity of pathologic autoimmune antibodies. [11][12][13] Many mechanisms have been proposed to explain the beneficial effects of IVIGs but their exact mode of action remains unclear in most diseases.…”

The Impact of Protein Binding on Antibacterial Activities of Antibiotics is more than Predicted by Considering its Numerical Value Alone: Impact of Preparative and Incubation Methods on Different Pharmacodynamic Endpoints of ß-Lactams, Macrolides, or Fluoroquinolones Against Gram-positive and Gram-negative Bacteria-Part I

“…Changes in the pH of the test media have a significant effect on in vitro activities of macrolides, fluoroquinolones and aminoglycosides but leaving ß-lactams unaffected [25][26][27][28][29]. Furthermore, storage time and freeze-thaw cycles affect the stability of some serum proteins including albumin [30][31][32] and exposure of serum to heat as used for complement inactivation induced conformational changes of serum proteins affecting their interaction with bacterial membranes and antigens [33][34][35][36][37][38][39].…”