In the Daratumumab trial patients with higher baseline IGG4 levels tended to be drug responders whereas in the cyclo trial low IGG4 patients tended to be responders. Given all the caveats about low sample sizes, etc., wonder if anyone knows what might be going on here.
I don’t have any answers, but I wanted to chime in to say I find this very interesting too. I firmly believe the answers to this disease lie in a place we can’t see, or a system we fundamentally don’t understand. Often times, we don’t understand things because we’ve assumed something has no important function when it in fact it does something important. I think IgG4 fits both of these catagories nicely.
There is a bit of a cart and horse issue here as we don’t know if IgG4 declines after Dara because it is a cause or whether it declines because it’s a reaction to the cause. For instance, I’m told that IgG4 could be an attempt to inhibit over active complement. If that’s the case, then maybe high IgG4 is helpful as opposed to causative.
Another possibility I find interesting is that IgG4 could be meditating the disease. We know that IgG4 is involved in immune tolerance, and IgG4 can give rise to a number of so called IgG4 diseases though a largely unknown mechanism. The known IgG4 related diseases cause tissue damage, so that mechanism seems to be less likely in ME/CFS. However, I think IgG4’s role in immune tolerance is really intriguing. if I understand correctly, it does so by blocking host proteins and cannot cause tissue damage like a typical antibody in this role.
In the context of the Dara results, I wonder if the disease could be IgG4 mediated wherein IgG4 is blocking a signal in its immune tolerance role. So, we would have b-cell meditated disease that causes symptoms by blocking an important signal, but leaves little evidence since it does not damage tissue.
One problem with the above idea is that IgG4 disease seems to respond to Rituximab, and we know that Rituximab failed in ME/CFS. However, maybe there are enough open questions about both the Rituximab trial in ME/CFS and IgG4 diseases generally, that this problem is not fatal.
