Intravenous Immunoglobulin (IVIG) is used to treat a variety of disorders. Among these conditions, a number are mediated by antibodies- such as Guillain Barre Syndrome, CIDP, Inflammatory Myositis, Multifocal Motor Neuropathy, Myasthenia Gravis & Rasmussen Syndrome.
But how do infusions of pooled antibodies from thousands of donors (each IVIG aliquot must be derived from at least a thousand donors) mitigate the consequences of pathogenic antibodies already present in the patient?
A number of mechanisms have been proposed, among them the presence of "anti-idiotype" antibodies in the infused IVIG. Thus, among the pooled antibodies, there will be a fraction that will treat the epitopes on pathogenic antibodies as "antigen" and thus neutralise them. Secondly, naive B cells binding to infused IgG through the B cell receptor will activate inhibitory ITIM motifs -"Immune Tyrosine Inhibitory Motif" and thus lead to B cell anergy. These B cells will no longer develop into memory B calls, and thus will not produce pathogenic antibodies.
While the above mechanisms are plausible, it does not explain why IVIg works well only for IgG mediated disorders such as the ones described above, but not for disorders mediated by IgM- such as MAG associated peripheral neuropathies seen in association with IgM paraprotein.
After the infusion of IVIg in subjects with pathogenic IgG antibodies such as Myasthenia Gravis, the putative IgG antibodies decline by up to 40% over a matter of several weeks. There is now sufficient evidence to suggest that this fall is due to increased degradation of these antibodies, rather than reduced production thereof.
But how does infusing IVIg increase the breakdown of intrinsic culprit antibodies?
The answer lies in a group of intracellular receptors called the "Neonatal Fc Receptor" or simply FcRn. While these were so named because they were first isolated in the gut of newborn rats, these receptors are in fact widely present in adults. The greatest concentration is in endothelial cells, but they are also found in antigen presenting cells. FcRn containing cells such as endothelial cells take up IgG by pinocytosis. In the acidic environment of endosomes-pH 6.0- FcRn binds to the Fc portion of IgG. The endosome than travels through the cell until it fuses with the cellular membrane to release the bound IgG back into the circulation. As long as sufficient FcRn receptors are available to take up circulating IgG, the effect is to recycle IgG and thus increase its half life in the circulation. However, FcRn does not bind IgM or IgA. This is the salient reason why IgG is the predominant antibody class in blood ahead of IgM and IgA- not because it's produced more, but because it is recycled repeatedly by FcRn receptors, increasing its half life, while no such thing happens with IgM or igA.
This principle is ingeniously exploited in antibody mediated diseases such as inflammatory myositides. When pooled human IVIg is infused, the "overload" of total IgG- in the infusate (more than 95% of infused IVIg is of IgG class) and intrinsic IgG- saturates the FcRn receptors. Thus, endosomal recycling is no longer possible. Instead the endosomes release pinocytosed IgG to lysosomes, where igG is degraded. Thus, infused igG leads to an overall increase in the breakdown of all IgG- including pathogenic antibodies, leading to a gradual and modest fall in the titre of pathogenic antibodies.
FcRn of course has other roles. Remember, it was first isolated in neonates. In the foetus, FcRn serves to transfer IgG across the placenta from the mother- again explaining why IgG is the only class of immunoglobulin to undergo transplacental transfer.
Recirculation of IgG has other benefits- when the amount of injected IgG is modest, i.e. the FcRn receptors are not saturated, it serves to extend the survival of monoclonal antibodies now in wide use inside the body. Again, it would not have escaped your notice that all monoclonal antibodies are of IgG class.
To summarise, FcRn explains the following observations:
1. Why IgG is the predominant class of antibody in blood
2. Infusion of IVIg reduces the level of pathogenic antibodies in humorally mediated disorders
3. Why IgG is the only class of immunoglobulin to be transferred from mother to foetus in utero
4. Why monoclonal antibodies are entirely of IgG derivation
But how do infusions of pooled antibodies from thousands of donors (each IVIG aliquot must be derived from at least a thousand donors) mitigate the consequences of pathogenic antibodies already present in the patient?
A number of mechanisms have been proposed, among them the presence of "anti-idiotype" antibodies in the infused IVIG. Thus, among the pooled antibodies, there will be a fraction that will treat the epitopes on pathogenic antibodies as "antigen" and thus neutralise them. Secondly, naive B cells binding to infused IgG through the B cell receptor will activate inhibitory ITIM motifs -"Immune Tyrosine Inhibitory Motif" and thus lead to B cell anergy. These B cells will no longer develop into memory B calls, and thus will not produce pathogenic antibodies.
While the above mechanisms are plausible, it does not explain why IVIg works well only for IgG mediated disorders such as the ones described above, but not for disorders mediated by IgM- such as MAG associated peripheral neuropathies seen in association with IgM paraprotein.
After the infusion of IVIg in subjects with pathogenic IgG antibodies such as Myasthenia Gravis, the putative IgG antibodies decline by up to 40% over a matter of several weeks. There is now sufficient evidence to suggest that this fall is due to increased degradation of these antibodies, rather than reduced production thereof.
But how does infusing IVIg increase the breakdown of intrinsic culprit antibodies?
The answer lies in a group of intracellular receptors called the "Neonatal Fc Receptor" or simply FcRn. While these were so named because they were first isolated in the gut of newborn rats, these receptors are in fact widely present in adults. The greatest concentration is in endothelial cells, but they are also found in antigen presenting cells. FcRn containing cells such as endothelial cells take up IgG by pinocytosis. In the acidic environment of endosomes-pH 6.0- FcRn binds to the Fc portion of IgG. The endosome than travels through the cell until it fuses with the cellular membrane to release the bound IgG back into the circulation. As long as sufficient FcRn receptors are available to take up circulating IgG, the effect is to recycle IgG and thus increase its half life in the circulation. However, FcRn does not bind IgM or IgA. This is the salient reason why IgG is the predominant antibody class in blood ahead of IgM and IgA- not because it's produced more, but because it is recycled repeatedly by FcRn receptors, increasing its half life, while no such thing happens with IgM or igA.
This principle is ingeniously exploited in antibody mediated diseases such as inflammatory myositides. When pooled human IVIg is infused, the "overload" of total IgG- in the infusate (more than 95% of infused IVIg is of IgG class) and intrinsic IgG- saturates the FcRn receptors. Thus, endosomal recycling is no longer possible. Instead the endosomes release pinocytosed IgG to lysosomes, where igG is degraded. Thus, infused igG leads to an overall increase in the breakdown of all IgG- including pathogenic antibodies, leading to a gradual and modest fall in the titre of pathogenic antibodies.
FcRn of course has other roles. Remember, it was first isolated in neonates. In the foetus, FcRn serves to transfer IgG across the placenta from the mother- again explaining why IgG is the only class of immunoglobulin to undergo transplacental transfer.
Recirculation of IgG has other benefits- when the amount of injected IgG is modest, i.e. the FcRn receptors are not saturated, it serves to extend the survival of monoclonal antibodies now in wide use inside the body. Again, it would not have escaped your notice that all monoclonal antibodies are of IgG class.
To summarise, FcRn explains the following observations:
1. Why IgG is the predominant class of antibody in blood
2. Infusion of IVIg reduces the level of pathogenic antibodies in humorally mediated disorders
3. Why IgG is the only class of immunoglobulin to be transferred from mother to foetus in utero
4. Why monoclonal antibodies are entirely of IgG derivation
