Evidence against oligoclonal bands being important?

As you may realise, I am sometimes critical of my colleagues who tend to follow dogma, without question.

This of course does me no favours with my colleagues. Maybe I should just say everything is "Great" or "Super", like I'm part of  some 1970s Sitcom :-0

For many, many years my colleagues have been hunting for the autoantigen in MS. They have got nowhere fast and we have seen more false dawns than I've had tequila sunrises.

MD2 has stuck his neck out and has suggested that we are wasting our time hunting for the causative antibody.

Indeed MD2 has suggested that the antibodies produced in the CNS are not inert and that they may simply bind to microglia via their tails rather than their heads that bind to their targets. These would serve to stimulate the microglia possibly to maintain a damaging phenotype that could drive degeneration in damaged nerves.


Paper

Pryce G, Baker D. Oligoclonal bands in multiple sclerosis; Functional significance and therapeutic implications. Does the specificity matter? Mult Scler Relat Disord. 2018;25:131-137.
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So you set up an idea and you don't try to prove it but you try to disprove it. This is called Popperian Science, after Karl Popper.

Therefore, thanks to one of the readers who did some reading and found this paper. 

It is a case of some one with MS who had a B cell cancer. They were given a stem cell cell transplant (HSCT) and they became oligoclonal band negative. However, disease activity continued.

Therefore, oligoclonal bands can't be a driver of progression, can they?


Paper


BACKGROUND:Allogeneic hematopoietic cell transplantation (allo-HCT) has been proposed as treatment for multiple sclerosis (MS) and other autoimmune diseases.
AIMS:To describe the effects of allo-HCT on the course of MS in a 49-year-old woman with longstanding progressive MS who was treated with allo-HCT for follicular lymphoma.
METHODS:Non-myeloablative conditioning allo-HCT, examination for IgG oligoclonal bands and measurement of CXCL13 and matrix metalloproteinase-9 (MMP-9) concentration in the cerebrospinal fluid (CSF).
RESULTS:Despite the disappearance of oligoclonal bands in CSF, disease progression and CSF inflammation was observed.
CONCLUSIONS:We hypothesize that CXCL13 and MMP-9 detected in CSF may reflect ongoing, pathogenic immune activation even after the eradication of intrathecal IgG synthesis. This suggests that progressive MS may depend more on innate than on adaptive immune activation.

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Maybe, but we have to figure out what could be happening before we give up on the idea. In this study the person had a B cell lymphoma and is treated with cyclophosphamide (CNS penetrant) and fludarabine (CNS penetrant) immunosuppressive agents capable of killing dividing (B) cells. The lymphoma is put under control and the person does a stem cell transplant. 

The transplant then starts to attack the body (Graft verses host disease). This means that the graft will attack anything that expresses transplantion antigens called the human leucocyte antigens (HLA) or major histocompatibility complex (MHC) antigens. 

B cells express high amounts of both class I and class II MHC and so will be targeted by the new immune system coming from the transplant. This could easily destroy B cells in the CNS that produce oligoclonal bands, especially as the MS would have made the CNS more leaky to immune cells. Also because of the MS, nerve cells sometimes express MHC class I and so could get attacked and damage too.

Indeed the graft immune system can target and kill any host cell expressing MHC class II and MHC class I antigens. These (MHC class I) are expressed by the skin and other tissues, which why the graft verse host disease occurs can be easily visible (I'd show you a picture but it is rather gross and will put you off your food). 

To treat this the person gets more immunosuppression  (cyclosporin A, mycophenylate) including anti-TNF. This latter agent has been associated with triggering the development of MS in some people.


This person started developing new lesions (i.e. sub-clinical relapsing MS), but when tested they had become oligoclonal band negative. But would this mean that the cells causing graft verses host disease were entering the CNS and causing damage. Could this be the cause of the lesions? However, it could certainly cause the production of cytokines that keep microglia activated, meaning that you don't need oligoclonal bands to do this job.

However, the the person was having spinal cord lesions and their movement got worse.  They got graft verses host disease again and this goes chronic for months before it is put under control. 

Then the person gets tacrolimus, or FK506, which is an immunosuppressive agent. Although this may have neuroprotective potential,  it can also cause neurological problems in some people. Is this part of the problem and the worsening of neurological problems for this person? I don't know. However there are a lot of confounding possibilities so that we can not be sure if this kills off the B cell ideas.

The idea but forward by MD2 was that activated microglia may be a central part of progressive MS. There are probably different routes to achieve this.  In this study they find CXCL13 (CXCL13 is a small chemokine  that chemokine is selectively chemotactic for B cells , such as memory B cells, by interacting with chemokine receptor CXCR5) and MMP9 (a metalloprotease associated with inflammation) Would we want this.

Do you have any ideas, I may be talking tosh.

Keep the anti views coming.

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