Immunoglobulins are antibodies synthesized by B lymphocytes – plasma cells that can recognize a broad spectrum of specific antigenic determinants, constituting the basis of the humoral immune response. The unique structure of the immunoglobulin molecule ensures the large repertoire of specificities of the antibodies. Intravenous immunoglobulin (IVIG) products are derived from the pooled human plasma of thousands of donors, ensuring that the IVIG preparation contains a wide diversity of antibody repertoire with the whole array of variable (antigen-binding) regions of antibodies in normal serum. Immune antibodies are critical for replacement therapy in the treatment of primary immunodeficiency disorders (PID), and have been used for more than 25 years. Most IVIG preparations consist of intact immunoglobulin (Ig)G molecules with a half-life of 3 weeks and with trace amounts of IgA, soluble CD4, CD8, human leucocyte antigen (HLA) molecules and certain cytokines [1]. IgG subclasses (IgG1, IgG2, IgG3 and IgG4) in IVIG products have a distribution similar to that found in normal human plasma [2].
The functional activities of IgG molecules, such as bactericidal effect mediated by complement, viral neutralization, inactivation of toxins and opsonization, are important for the development of an effective immune response against a large range of microorganisms and their toxic products. The Fc fragment of the IgG molecule is critical for many of the clinical beneficial effects seen in IVIG therapy. The Fc IgG portion of the immune antibodies allows them to interact with and signal through Fcγ receptors on B cells and cells of the phagocytic system and with Fc-binding plasma proteins, which is necessary for the activation of complement and for the clearance of microorganisms [3].
IVIG products may also trigger powerful immunomodulatory and anti-inflammatory effects in different diseases. The mechanisms involved in the immunomodulatory effects of the IVIG infusions are dependent upon the interaction between the Fc portion of infused IgG with the Fcγ receptors on the surface of target cells (macrophages, B cells, natural killer cells, plasma cells, eosinophils, neutrophils and platelets) or with the variable regions of antibodies in the preparation [4]. These interactions with immune cells can either up-regulate or down-regulate inflammatory and immune responses. The immunoregulatory function of IVIG explains the beneficial effects seen in syndromes associated with PID, as well as in inflammatory and autoimmune disorders. The blockade of Fcγ receptors on macrophages is one mechanism implicated in the beneficial effect of IVIG in autoantibody-mediated cytopenias [5,6] and in inflammatory neurological disorders [7,8], probably by blocking the clearance of opsonized target cells or by suppressing antibody-dependent cell-mediated cytotoxicity, respectively. Immunoglobulins can also modulate the inflammatory response by preventing complement-mediated tissue damage or the deposition of immune complexes containing C3b [9], or by modulating the induction of anti-inflammatory cytokines and cytokine antagonists such as interleukin (IL)-1β, IL-1 receptor antagonist and tumour necrosis factor (TNF)-α. Another mechanism implicated in the immunomodulatory function of the immune globulin preparation is the provision of anti-idiotypic antibodies that can exert an immunoregulatory effect on B cells and autoantibodies. Other immunomodulatory effects of the IVIG are related to regulation of the production of helper T cell cytokines, of the apoptosis and of the functional expression of genes of the immune system [10,11].
A considerable fraction of the IVIG product contains natural autoantibodies of the IgG isotype, which are present in normal serum. Those self-reactive natural antibodies are capable of interacting with idiotypes (serologically defined elements of the variable region) of other antibodies in the IVIG preparation to form dimers with complementary idiotypes (idiotype–idiotype dimers), with antigen receptors and with molecules which are believed to be essential for the immunoregulatory effects of IVIG [12,13]. Down-regulation of deleterious autoantibody titres through idiotypic–anti-idiotypic networks is one mechanism implicated in the beneficial effect of IVIG in the management of highly sensitized patients with anti-HLA antibodies, both pre- and post-transplant [14].
Primary immunodeficiencies are a heterogeneous group of genetic disorders that affect distinct components of the innate and adaptive immune system, such as macrophages, natural killer cells, dendritic cells, neutrophils, proteins of the complement system and B and T lymphocytes. In recent years major advances in the molecular and cellular characterization of PID have demonstrated the complexity of their genetic (more than 120 distinct genes have been identified) and clinical features (more than 150 different forms of PID) and have provided new insights into the functioning and management of immune-based diseases.
Biological therapy has completely innovated the method of treatment of the chronic systemic diseases, where alteration of the immune system is the main mechanism implicated in the pathogenesis of the disease. Recent advances in biotechnology have led to the development of a new generation of human immunoglobulins, subcutaneous (Vivaglobin) and intravenous (Flebogamma 5% dual inactivation and filtration), for the treatment of PID. Immunoglobulins administered in monotherapy or in combination with monoclonal antibodies (such as anti-TNF-α or anti-CD20) and/or other immunomodulators will, in the future, be part of the standard therapy for inflammatory and immune-based disorders.
Conflicts of interest
None.
References
- 1.Lam L, Whitsett CF, McNicholl JM, Hodge TW, Hooper J. Immunologically active proteins in intravenous immunoglobulin. Lancet. 1993;342:678. doi: 10.1016/0140-6736(93)91784-j. [DOI] [PubMed] [Google Scholar]
- 2.Seite JF, Shoenfeld Y, Youinou P, Hillion S. What is the contents of the magic draft IVIg? Autoimmun Rev. 2008;7:435–9. doi: 10.1016/j.autrev.2008.04.012. [DOI] [PubMed] [Google Scholar]
- 3.Daeron M. Fc receptor biology. Annu Rev Immunol. 1997;15:203–34. doi: 10.1146/annurev.immunol.15.1.203. [DOI] [PubMed] [Google Scholar]
- 4.Samuelsson A, Towers TL, Ravetch JV. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science. 2001;291:484–6. doi: 10.1126/science.291.5503.484. [DOI] [PubMed] [Google Scholar]
- 5.Imbach P, Barandun S, d'Apuzzo V, et al. High-dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood. Lancet. 1981;1:1228–31. doi: 10.1016/s0140-6736(81)92400-4. [DOI] [PubMed] [Google Scholar]
- 6.Godeau B, Bierling P. Treatment of idiopathic thrombocytopenic purpura in adults. Presse Med. 2008;37:1292–8. doi: 10.1016/j.lpm.2008.01.027. [DOI] [PubMed] [Google Scholar]
- 7.Dalakas M IV. Ig in other autoimmune neurological disorders: current status and future prospects. J Neurol. 2008;255(Suppl 3):12–6. doi: 10.1007/s00415-008-3004-y. [DOI] [PubMed] [Google Scholar]
- 8.Kieseier BC, Meyer Zu Hörste G, Lehmann HC, Gold R, Hartung HP. Intravenous immunoglobulins in the treatment of immune neuropathies. Curr Opin Neurol. 2008;21:555–62. doi: 10.1097/WCO.0b013e32830efc03. [DOI] [PubMed] [Google Scholar]
- 9.Basta M. Ambivalent effect of immunoglobulins on the complement system: activation versus inhibition. Mol Immunol. 2008;45:4073–9. doi: 10.1016/j.molimm.2008.07.012. [DOI] [PubMed] [Google Scholar]
- 10.Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med. 2001;345:747–55. doi: 10.1056/NEJMra993360. [DOI] [PubMed] [Google Scholar]
- 11.Hartung HP. Advances in the understanding of the mechanism of action of IVIg. J Neurol. 2008;255(Suppl 3):3–6. doi: 10.1007/s00415-008-3002-0. [DOI] [PubMed] [Google Scholar]
- 12.Rossi F, Dietrich G, Kazatchkine MD. Anti-idiotypes against autoantibodies in normal immunoglobulins: evidence for network regulation of human autoimmune responses. Immunol Rev. 1989;110:135–49. doi: 10.1111/j.1600-065x.1989.tb00031.x. [DOI] [PubMed] [Google Scholar]
- 13.Rossi F, Kazatchkine MD. Antiidiotypes against autoantibodies in pooled normal human polyspecific Ig. J Immunol. 1989;143:4104–9. [PubMed] [Google Scholar]
- 14.Jordan SC, Vo AA, Peng A, Toyoda M, Tyan D. Intravenous gammaglobulin (IVIG): a novel approach to improve transplant rates and outcomes in highly HLA-sensitized patients. Am J Transplant. 2006;6:459–66. doi: 10.1111/j.1600-6143.2005.01214.x. [DOI] [PubMed] [Google Scholar]