What have poppies and fields got to do with the cause of MS?

W
It took a while for me to truly understand why the poppy is so important to people living in the UK. The poppy is a symbol of remembrance, i.e. to observe and never forget. 



Why are fields and poppies relevant to MS? 



The study below supports anecdotal clinical evidence of many of my clinical mentors and, now as I have gotten older, my own clinical experience; if you have an MS relapse, or attack, in one particular area of the brain or spinal cord you are more likely to have subsequent attacks in this area. I refer to this as the so-called field effect, i.e. something locally in a specific anatomical area triggers recurrent attacks in the same site. 

What underlies the field effect? One explanation is that the area that is damaged by the initial attack is more likely to trigger autoimmune responses in future as a result of the local up-regulation of so-called second, or danger, costimulatory signals. The latter occurs in response to the factor produced as part of the initial inflammatory event. For T-cells to become activated they need an antigen-specific signal via the T-cell receptor and additional signal via co-stimulation.


Another hypothesis, which I favour, is that there is something in the field that triggers relapses. Possibly a virus, like an isolated seed or flower in a field of wheat? Why do I say this? Firstly, when MSers were treated with interferon-gamma, a cytokine that stimulates immune responses, they all had relapses. The interesting thing about these interferon-gamma-induced relapses is that they occurred in sites previously affected by MS. When I discussed this observation with the late Hillel Panitch, who was the principal investigator on the gamma-interferon trial, he thought that this observation was a fundamental observation and was telling us something important about MS. 

Another observation that supports the abnormal field hypothesis is the rebound post-natalizumab. This suggests that whilst you keep T and B cells out of the nervous system with natalizumab the field (brain and spinal cord) becomes more abnormal and when you let these cells back in they detect the abnormal field and run amok trying to clear the field of the offending agent. This is what happens with IRIS (immune reconstitution inflammatory syndrome) and PML. When natalizumab is washed out the immune system finds the JC virus and tries to clear it by initiating an inflammatory process. Some of us think that rebound post natalizumab is simply IRIS in response to the virus that causes MS.

Another observation comes from serial MRI studies that have shown subtle changes in the white matter many weeks or months before a gadolinium-enhancing lesion appears. This suggests that the primary pathology is something in the nervous system that takes weeks or months to trigger a focal inflammatory lesion. The challenge for us all is to find out what this field abnormality is. I think the best chance we have of doing this is to study the brains of pwMS on natalizumab. To do this we will need someone with MS to die whilst on natalizumab treatment and to donate their brain to a unit with the necessary techniques to look for viruses. I think this will work because the viral load is likely to be higher in the absence of inflammation. This is why it is so important for pwMS to donate their brains for medical research.

If you are interested in more musing about the field hypothesis please read a previous post on the subject.



Epub: Willis et al. Site-specific clinical disease onset in multiple sclerosis. Eur J Neurol. 2014 Sep 8. doi: 10.1111/ene.12564.

BACKGROUND AND PURPOSE: MS is a chronic inflammatory disorder of the central nervous system characterized by acute episodes of neurological dysfunction thought to reflect focal areas of demyelination occurring in clinically eloquent areas. These symptomatic relapses are generally considered to be random clinical events occurring without discernible pattern. The hypothesis that relapses may follow a predetermined sequence and may provide insights into underlying pathological processes was investigated.

METHODS: Employing prospective clinical database data from 1482 MSers who had experienced one or more consecutive relapses were analysed. Using regression analysis, site and symptom of index event were compared with those of first relapse.

RESULTS: It is demonstrated that following disease ignition subsequent relapses may not be random events but dependent on characteristics of the index event. All anatomical sites were more likely to be affected in the first relapse if that site had been involved in the index event with a similar association observed when comparing by symptoms.

CONCLUSION: These findings have importance in understanding the evolution of the disease and predicting individual disease progression and may aid with patient counselling and management.

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

3 comments

  • If it is an endogenous virus within the brain that is being recognized, then there should be more antivirals under investigation. Ectrims didn't work, and viral TK inhibitors don't work, but that doesn't mean that other antivirals targeting different viral pathways shouldn't be investigated, especially considering the inverse relationship between HAART therapy and lower incidence of MS in HIV patients. Or the med student who self medicated herself with combivir. If EBV and other endogenous retroviruses are there sprouting new poppies, then use some directed DNA analogues that will hit the DNA viruses and stop them from replicating. And it should easily be an add-on therapy- you don't have to sacrifice normal Ocrevus or Tsybari to still test the anti virals. Said it before- test combivir yesterday.

  • It could also be that during development something like a vitamin D deficiency caused subtle changes in specific areas of the CNS which are later attacked by the immune system as they go wrong. Another possibility is that it is just random chance those areas are attacked. I like the research that did simulation of the immune system attacking the CNS; approximately 15% of the areas where in places that would not give an immediate response physical manifestation. Basically if shows that 15% of the time you would get a PPMS like disease.

By Prof G

Translate

Categories

Recent Posts

Recent Comments

Archives