I’m a fan of “you can’t have it both ways” and it means that if you say this is good for that you can’t say the opposite is good for that too. So if you have a good guy you want to augment it for it to be good, but if you get rid of the good guy you would think it is going to be be bad. When you are a mechanistic science you sometimes don’t think about the human condition because you are so interested proving the mechansim. Great but then you need to take a step back and ask what does this mean for the human condition the research is about.
I know people will take exeception to this and perhaps even I will agree as inflammation can be a good and a bad thing, bad in that it causes damage and good that it promotes repair.
We have focussed on the lymphocyte as a way of controlling relapsing MS, but an increasingly supported view is that microglia are a valuable target. Pharma have realized that targeting B cells may have a better chance of inhibiting MS than the T cell only approach, given the . So they have all gone chasing after B cell inhibitors. We have had a few disasters, by targeting B cell growth factors with anti-BAFF and Anti-APRIL/BAFF. These inhibit naive B cells and antibody producing plasma cells. However they are not great on memory B cells and they didn’t work in MS.
Another route was to target a B cell signalling molecules and that gave rise to the Brutons Tyrosine kinase inhibitors. Pharma hunt in packs and most MS drug manufacturers has one in clinical development and phase III trials in PPMS and relapsing MS are ongoing. We had the idea quite abit earlier and had contacted the makers of Ibrutinib, which was a first generation BTKinhibitor. However there was not enough interest in MS at that time. Maybe we were ahead of our time.
However fast forward a few years and Pharma are all over BTK ihibitiors. Some get into the brain and it is evident that BTK inhibitors can target microglia. So B cell inhibitor and microglial inhibitor, just what you want for MS. No wonder they are all making inhibitors against this molecule.
However, what is the mechanistc idea behind the BTK inhibitors B cells and microglia? Have they got it right?
In this new paper blocking microglia is not the best therapeutic idea.
Dong Y, D’Mello C, Pinsky W, Lozinski BM, Kaushik DK, Ghorbani S, Moezzi D, Brown D, Melo FC, Zandee S, Vo T, Prat A, Whitehead SN, Yong VW. Oxidized phosphatidylcholines found in multiple sclerosis lesions mediate neurodegeneration and are neutralized by microglia. Nat Neurosci. 2021 Feb 18. doi: 10.1038/s41593-021-00801-z. Neurodegeneration occurring in multiple sclerosis (MS) contributes to the progression of disability. It is therefore important to identify and neutralize the mechanisms that promote neurodegeneration in MS. Here, we report that oxidized phosphatidylcholines (OxPCs) found in MS lesions, previously identified as end-product markers of oxidative stress, are potent drivers of neurodegeneration. Cultured neurons and oligodendrocytes were killed by OxPCs, and this was ameliorated by microglia. After OxPC injection, mouse spinal cords developed focal demyelinating lesions with prominent axonal loss. The depletion of microglia that accumulated in OxPC lesions exacerbated neurodegeneration. Single-cell RNA sequencing of lesioned spinal cords identified unique subsets of TREM2high mouse microglia responding to OxPC deposition. TREM2 was detected in human MS lesions, and TREM2-/- mice exhibited worsened OxPC lesions. These results identify OxPCs as potent neurotoxins and suggest that enhancing microglia-mediated OxPC clearance via TREM2 could help prevent neurodegeneration in MS.
We also know that microglia are involved in the myelin debris clean up and so again you would not want to block microglia activity. However there are are good microglia and bad microglia just as there are good and bad T and B cells. The molecule TREM2 is highly expressed by microglia in mouse and humans and MS4A4A. Trem2 gene encodes for a protein that is part of a receptor signaling complex with TYRO protein tyrosine kinase binding protein, and that activates macrophages and dendritic cells immune response. Loss-of-function variants of the TREM2 gene are associated with Alzheimer’s Disease. It seems a soluble form of TREM2 is released in the spinal fluid in Alzheimers disease and MS involving a CD20 (MS4A1) related molecule (MS4A4A) found on microglia.
TREM-2 was expressed by a macrophage subset with known functions in clearing myelin debris and down-regulating inflammation. Therefore, the TREM2 macrophages/microglia are associated with an inhibitory effect. There are damaging molecules produced during inflammation that kills nerves and oligodendrocytes. These are taken up by microglia. So one wants to enhance them perhaps to promote repair. This is the conclusion of the paper.
I say great, but now I ask can we have it both ways because it looks like microglia also express BTK. So are BTK inhibitor going to block the good microglia. BTK inhibitors block the uptake of stuff by microglia.
What do BTK inhibitors do to memory B cells? Well. there is not much BTK on T cells so they are probably not working by T cells. BTK inhibitors however are not physical inhibitors and so is unlike ocrelizumab. BTK is important for B cell development and is involved in early B cell developement and is highly expressed by naive B cells. There is some in memory B cells but if B cells are important in MS have they already developed?
However, memory B cells have BTK and this is involved in memory B cell function.
What about myelinations. Well it seems to be good news for inhibition promoting repair. Inhibitors also inhibit MS. Therefore on balance it is evident that any negative element is outweighed by the positive element. This is the important point. The results in humans in studies that are important.
For any postives there are some negatives, e.g. some people had anaphylaxis when they got a COVID-19 but the benefit outweighs the negatives.