Larochelle C et al. Immunological and pathological characterization of fatal rebound MS activity following natalizumab withdrawal. Mult Scler. 2016. pii: 1352458516641775. [Epub ahead of print]
BACKGROUND: Severe rebound multiple sclerosis (MS) activity is a life-threatening complication of natalizumab (NTZ) withdrawal, for which pathogenesis and treatment are still unclear. We report the immunological and pathological characterization of a case of central nervous system (CNS) inflammatory demyelination after NTZ discontinuation.
OBJECTIVE: To understand the pathophysiology of this neuroinflammatory condition.
METHODS: Antemortem blood and cerebrospinal fluid (CSF) analysis was compared with postmortem pathological studies, as well as with novel flow cytometry characterization of immune cells isolated from the CNS parenchyma.
RESULTS: Pathological analysis of the brain revealed the presence of innumerable active inflammatory demyelinating lesions typical of immunopathological pattern II. Monocytes/macrophages and B cells were enriched in the CNS parenchyma compared to the CSF. Numerous plasma cells were present in the lesions, but CD8 T lymphocytes were predominant in the parenchyma, as opposed to CD4 in the CSF. CNS-infiltrating lymphocytes expressed high levels of adhesion molecules, granzyme B (GzB), interferon-gamma (IFN-γ), and interleukin (IL)-17.
CONCLUSIONS: Our results underline the differences in immune cell populations between the CSF and the CNS parenchyma, and suggest that aggressive immunosuppressive therapy targeting both T and B lymphocytes is warranted to control the overwhelming CNS inflammation.
Apologies as a half-cocked,unfinished post that was launched by mistake last night at 02.30am.....It was full of spelling mistakes as does the figure below. Copaxone is obviously one of my dyslexia (as pointed out by ProfG) words......it is spelt glatiramer acetate apparently..."comming" is another and "soory" is another, as was "Micheal", I eventually learnt to spell it Michael maybe glaterimer will get same treatment
"Will the real MS stand up" was something that scientists have been asking...open your eyes is what we have been saying.
ProfG has been arguing that rebound post natalizumab is going to be one good way to find out what is driving relapsing MS. In this study one person actually died from the relapse associated with stopping natalizumab treatment.
The BartsMS team have been very clear how to switch from natalizumab to something different as it seems some neuros are not aware of the risk of rebound activity. One wonders whether this would have happened it the switch was to a more effective alternative
This is actual the MRI.
Can you see the damage of about 4 years of MS in the top row and new lesions in the next two rows some are arrowed.
When the pathology was done it was evident that typical MS lesions were present. Yes the ones full of T cells with a few B cells and antibody plasma cells thrown in. This looks just like EAE.
There were more CD8...virus destroying cells in the brain. So relapse is associated with peripheral immune cells entering the CNS and doing damage. This is the real MS that drives relapsing MS. However the lesions could have been up to 3 months old and lesion C above does not look that active (I need a close up).
However, this is the pathologists at work...remember they missed Grey Lesions for years. Have a look..you are not a pathologist but can you see grey matter lesions. (Wonder if its the same ones saying EAE is rubbish:-). You don't need a microscope. But is dogma is MS is a white matter disease which it was when I came into the field. Is it surprising that animals models don't always look like MS
What we should ask is what was the rest of the CNS like, was it full of demyelinated lesions or was it full of remyelination?
Presumably this person has been doing well on natalizumab and there would be ample time to repair old lesions. If repair is the default there should be evidence of remyelination all over the CNS.
Was this absent or missed because they are not looking for repair only damage. If this is the cases then aiming to get repair strategies is of limited value..you just need to treat early and effectively and the body does the rest.
If there were chronic demyelinated lesions then there is a real repair failure and we need repair strategies. There is not mention of the chronic lesions the lateral ventricles should be full of old lesions based on the MRI. Is figure C light blue (remyelination?) or no blue demyelinated?
Maybe ProfG /DrK can ask them to have a look?
I have heard about one case of post-natalizumab death, where the CNS was full of remyelination.
So the authors give a stock answer that there are T and B cells there so we need T and B cell therapies and there are plasma cells there.....so generic CLADRIBINE in the only current answer:-). However yesterday we had ProfG posting that anti-B therapies were working better at this than fingolimod which is partially anti-T & B.
In the text the IL-17 was in the CD8 cells, and so the bit in the abstract probably has nothing to do with Th17.
Most of what is in the CNS is probably irrelevant and is dragged in there because they have homing molecules; The trick is to sort the wheat from the chaff, but I think based on pathology and response to treatment the MS relating to relapsing disease stood up a long time ago.
The study demonstrates that white blood cells can be extracted from the CNS, and therefore we can get at their antigen receptors. Which is a step closer to finding the target. There were plenty of T cells in the lesions with a CD4 bias in the blood and CSF but half the numbers of CD8 in the CNS proper.