For more than two decades, the IntraVenous administration of high doses of IgG pooled from the Plasma of healthy donors (Immune Globulin therapy, also known as "IVIg") has benefited patients with a variety of AutoImmune Disorders.
Although its mechanism of action is not known, Immune Globulin is accepted as an effective and convenient alternative to Plasmapheresis.
For treating diseases that are thought to be mediated by pathogenic AutoAntiBodies or Immune complexes. (1)
It is used increasingly to treat Neurologic Diseases such as inflammatory DeMyelinating Neuropathies, Multifocal Motor Neuropathy, Inflammatory Myopathies, Myasthenia Gravis, and the Lambert-Eaton Syndrome.
The efficacy of Immune Globulin therapy has formally been proved only for the Guillain-Barre Syndrome and chronic inflammatory DeMyelinating PolyNeuropathies, (1,2).
But reports of new applications continue to appear, such as the use of this therapy for intractable childhood Seizures (Rasmussen's Encephalitis). (1)
Numerous mechanisms have been proposed to explain the beneficial action of high doses of normal IgG in AntiBody-mediated Disorders, but none satisfactorily explain all clinical situations.
For example, therapeutic concentrations of IgG have been shown to block Fc receptors on Phagocytes and on Cellular Effectors of AntiBody-dependent cytotoxicity. (1)
These receptors bind to the stem (Fc region) of the Y-shaped IgG molecule. The Fc region mediates the effector properties of the molecule but not its Immunologic specificity, which depends on the two extended arms of the Y.
Blockade of Fc receptors is a plausible mechanism for ameliorating the Cytopenia of Idiopathic Thrombocytopenic Purpura and the destruction of Myelin in the Guillain-Barre Syndrome. (1)
But, it is unlikely to explain how an elevation of Serum IgG brought about by treatment with Immune Globulin relieves the chronic blockade of Synaptic transmission in Myasthenia Gravis, which is mediated by pathogenic IgG.
But is independent of Fc receptor-bearing Effector Cells (with the possible exception of inflammatory Myasthenia Gravis occurring as a Paraneoplastic complication of Thymoma).
Various ImmunoModulatory properties have been attributed to pooled preparations of IgG, (1) including regulatory properties of AntiIdiotypic AntiBodies and effects on Cytokine synthesis and on receptors for Cytokines and Complement.
There is no persuasive evidence that any of these postulated mechanisms account for the therapeutic benefits.
In 1964 Sell and Fahey observed that the Plasma concentration of IgG determined its fractional rate of catabolism, (3).
But the mechanism for the concentration-dependent elimination of IgG from Plasma was not understood until very recently.
We think that acceleration of the rate of IgG catabolism is the most plausible unifying explanation for the beneficial action of high doses of exogenous IgG in AntiBody-mediated AutoImmune Disorders. (4)
Such a process would eliminate individual IgG molecules in direct proportion to their relative concentration in Plasma.
Recent studies in mice with a targeted "knockout" of the Gene encoding beta2-MicroGlobulin, a subunit of the Class I Major-Histocompatibility-Complex protein.
Unexpectedly revealed the mechanism by which Plasma IgG concentrations regulate the rate of IgG catabolism. (5,6)
Mutant mice lacking beta2-MicroGlobulin had extremely low Serum levels of IgG.
Immunization of these mice with model Antigens did not evoke a sustained increase in Serum IgG, but IgM responses were normal.
The low Serum level of IgG in these mutant mice is attributed to the loss of a previously unrecognized transport receptor for IgG, named FcRn.
Normally, IgG that enters cells through the process of PinoCytosis is protected from Catabolism by binding to FcRn.
The receptor was initially identified in neonatal intestinal Epithelium (and is therefore called FcRn, for Fc receptor of the neonate), and beta2-MicroGlobulin is a critical subunit of the receptor. (6)
The discovery of FcRn validated a hypothesis that Brambell et al. proposed 35 years ago (7):
IgG that is picked up by cells from Plasma binds to a protective receptor in EndoCytotic Vesicles and subsequently returns intact to the circulation.
IgG binds maximally to its protective receptor - FcRn - in the Acidic conditions of the Endosome.
Without this protective mechanism, IgG would pass to the Lysosome and be degraded.
Several groups have recently demonstrated that FcRn is a protective receptor that prevents the Catabolism of IgG. (5)
In states of HypergammaGlobulinemia, this receptor is presumably saturated, permitting the degradation of IgG to occur in proportion to its total concentration in Plasma.
The IgG receptor known as FcRn is found in many adult tissues, including skin, muscle, and intestinal Epithelium.
Its high level of expression in Vascular Endothelial Cells suggests that these cells are a major site of IgG catabolism. (6)
Although most information has been obtained from studies in rodents, a human homologue of FcRn has been identified. (6)
The discovery that FcRn regulates Plasma IgG levels should open pharmacologic avenues for depleting IgG as a treatment for AntiBody-mediated AutoImmune Diseases.
Instead of using large quantities of exogenous IgG to accelerate the degradation of IgG, the same effect could be achieved by pharmacologic agents that target FcRn.
The apparent synergism between Immune Globulin therapy and treatment with high doses of MethylPrednisolone in patients with the Guillain-Barre Syndrome (1) is consistent with this idea.
Because GlucoCorticoids down-regulate the expression of FcRn messenger RNA. (9)
Novel strategies for the depletion of IgG might include the use of neutralizing MonoClonal AntiBodies that are designed to modify FcRn covalently.
The use of synthetic Ligands with a higher affinity than IgG for the receptor and that would thus saturate FcRn, and the use of antisense nucleotides to down-regulate the expression of FcRn.
In theory, all these strategies should increase the Catabolism of circulating IgG and therefore reduce the levels of pathogenic AutoAntiBodies.