IVIG with antiMAG IgM or PDN posted by Ken 1/6/06

Given current knowledge, is there a good explanation why IVIG does not work well for AntiMAG IgM neuropathy?
Norbert – this isn’t a really solid answer because the mechanisms by which IVIG work aren’t fully understood. But I think this is reasonable based on what we do know.

First – back to some basic immunology. As you know, there are different classes of antibodies: IgM, IgG, IgA, IgE, and IgD. The class is determined by the “heavy chain” (antibodies all have heavy and light chains). The heavy chain is a protein which is roughly 25% “variable region”, and 75% “constant region”. The variable region is the part of the antibody that binds to antigen, and it is called variable because there are so many different protein sequences. The variable region, or binding site, can actually be the same for antibodies of different classes.

The constant region of the antibody determines which class it is. There is a distinct sequence for the mu chain (which makes IgM), for the gamma chains (IgG), for the alpha chains (IgA), and so on. While the role of the variable region is to bind antigen, the role of the constant region is to stabilize the protein, to connect to the light chains, etc., and to bind to receptors on cells like macrophages and granulocytes. These receptors are called Fc receptors (Fc is for constant fragment).

Most of the time antibodies work by (a) binding to antigen on one end of the protein and (b) binding to an Fc receptor on the other end of the protein. Binding to the Fc receptor activates all sorts of cells and can lead to release of molecules that cause inflammation, to activation of phagocytic cells that engulf whatever the antibody is binding to, and other immune mechanisms.

The antibodies in IVIG are primarily IgG class – that is the class of most normal serum antibodies. One action of IVIG is to downregulate Fc receptors – for the IgG class. There have been other proposed mechanisms for IVIG action and some or all might be a part of the package. But it seems that most of the mechanisms are related to the massive infusion of a lot of IgG constant regions, and are not due to specific antigen binding properties of the IVIG. You can see that it will not have the same effect on IgM specific receptors because there is not a lot of IgM class antibodies being infused.

I think this is why it is important to figure out whether someone has a pathogenic IgM causing the disease (and so less likely to respond to IVIG), vs. someone with typical CIDP that happens to have a benign IgM spike in their serum.

My speculation is that there are also patients where the disease doesn’t involve a lot of antibody production; that it is primarily T cell or NKT cell mediated, and that those patients are also IVIG unresponsive. The clinical literature has noted that patients with a longer course of disease tend to be less responsive to IVIG, and it may be that for typical CIDP (unlike anti-MAG IgM) the antibody component decreases over time and the T cell component becomes predominant.