Friday, 19 September 2014

Field hypothesis: site specific disease

What do you know about the MS field hypothesis? #MSBlog #MSResearch

"This 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. This is the so called field hypothesis, i.e. something locally in a specific anatomical area triggers recurrent attacks in the same area. 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, co-stimulatory 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 a 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 trigger relapses. Possibly a virus? 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. It was after this insight and my discussion with Hillel that led me to formulate my leprosy hypothesis about MS (more on this another time)."

"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 up the field. 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 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 MSers 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 MSers to donate their brains for medical research."

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


"Does the study below have implications for clinical practice? Possibly; we know  that MSers who have initial attacks in sensory and visual pathways that recover are more likely to have a better clinical outcome in  the long-term. The observations in the study below support this. However, I must point out that this is an average effect and does not necessarily apply to individuals."



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 MSerswho 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.

9 comments:

  1. Why alemtuzumab works then? Even if the virus in question is EBV, alemtuzumab could not deplete brain B-cells effectively

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    1. Interestingly there is a transient reactivation of lesions after alemtuzumab treatment which then resolves. Unless you believe there are B cell follicles in the brain (v contentious) then existing lymphocytes in the brain don't survive for long and alemtuzumab would prevent new ones entering the brain also around lesions the blood brain barrier is leaky and it is likely that an antibody such as alemtuzumab could enter the brain at these sites and kill of any locally surviving lymphocytes including B cells.

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  2. Please explain how the EBV viral cause and field hypotheses explain alemtuzumab and anti-CD20 therapies

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    1. Anti B cell therapies and EBV is a B cell virus

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    2. We knew that already. It doesn't answer all questions

      Is it that the B-cells that regenerate after alemtuzumab do not have the virus?
      Why the transient reactivation of old lesions after alemtuzumab?

      With rituximab: signs of fresh activity appear some months after the infusion. though CD19 is still at 0. After the next infusion things start going back to normal.

      Could it be that the B-cells that regenerate after rituximab still have the virus and why this difference from alemtuzumab?
      But as per the blood test there are still no B-cells, so why the fresh activity?
      'activity' = fatigue, old symptoms turn up more often, etc. As per the MRI (1.5T) there is no change in the brain

      (This is personal experience after 5 sets of infusion. MS was very active before rituximab)

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  3. What's the leprosy hypothesis?

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    1. I am interested as well...
      Could Profs. explain?

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    2. Sorry I will let ProfG explain this one as it is his baby not mine.

      However to get you ready there are two type of leprosy Tuberculoid Leprosy and lepromatous leprosy. Leprosy is cause by the the bacteria mycobacteria leprea. Humans can react very vigourously to it and the bacteria is very well killed but there is associated tissue damage during this and this is a problem as immune nodules (granulomas) of dead bacteria form in nerves etc. This can stop nerves functioning so maybe you cant feeland so your feet get infected when you tread on a thorn and you loose your toes as a consequence.This is immune (Th1) driven problem is tuberculoid leprosy like the guy in "papillion" the movie

      In lepromatous leprosy there is an ineffective (Th2) immune response and you are riddled with bacteria. If you get the immune response to start to become active you get a problem called erythma nodosum when you get complexes of bacteria an the new antiboy response.

      Are you still interested?

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    3. I'm not the original poster, but yes - even more so.

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