Thursday, 10 September 2015

Beware when the tail wags the dog

Miller NM, Wang J, Tan Y, Dittel BN.Anti-inflammatory mechanisms of IFN-γ studied in experimental autoimmune encephalomyelitis reveal neutrophils as a potential target in multiple sclerosis. Front Neurosci. 2015;9:287. doi: 10.3389/fnins.2015.00287. eCollection 2015.Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) mediated by T helper (h)1 and/or Th17 CD4 T cells that drive inflammatory lesion development along with demyelination and neuronal damage. Defects in immune regulatory mechanisms are thought to play a role in the pathogenesis of MS. While an early clinical trial indicated that IFN-γ administration was detrimental to MS, studies in the mouse model of MS, experimental autoimmune encephalomyelitis (EAE), indicated that IFN-γ exhibits a number of anti-inflammatory properties within the CNS. These mechanisms include inhibition of IL-17 production, induction of regulatory T cells, T cell apoptosis and regulation of chemokine production. Mice deficient in IFN-γ or its receptor were instrumental in deciphering the anti-inflammatory properties of IFN-γ in the CNS. In particular, they revealed that IFN-γ is a major regulator of neutrophil recruitment into the CNS, which by a variety of mechanisms including disruption of the blood-brain-barrier (BBB) and production of reactive oxygen species are thought to contribute to the onset and progression of EAE. Neutrophils were also shown to be instrumental in EAE relapses. To date neutrophils have not been appreciated as a driver of MS, but more recently based largely on strong EAE data this view is being reevaluated by some investigators in the field.

EAE is heavilily criticized my many. However it has given the MS world many ideas. Often it has been let down where the study of EAE drives what happens in MS, rather than first looking at MS and then working out what to study in EAE.

There have been a number of heroic failures to translate treatments from EAE into MS. One of those is the apparent worsening of MS after gamma interferon verses the amelioration of EAE.

The mouse EAEers have realised that their lesions are full of neutrophils and are now doing their bit to convince the MS world that it is a disease of neutrophils......Will they succeed? It depends on the advocates.  

Mousers convinced the world that cytokines have a clear cut TH1, bad TH2 good and when that fell down TH17 is bad..all the time knowing that human cytokine biology was much more blurred. Really TH = all bad even the TH2 best to have none of them.

In this paper they suggest because of such strong EAE data we should go back and re-investigate interferons.....really?...Would you be willing to try interferon gamma with the past history? Someone very brave maybe.

Maybe there is a point in NMO, where the pathologists tell us that their are neutrophils in the CNS. 

However, whilst mouse EAE may have neutrophils, histological evidence shows us that MS doesn't....Should we believe the pathologists?.  Will they change their tune.They can't seem to make their mind up:-)

However histological evidence also shows us that rat EAE, guinea pig EAE, marmoset EAE isn't a disease of neutrophils either. 

It is a mouse thing and this has been known for donkies years by anyone working in the skin field. I would recommend a book by Polak written in 1970's where it discusses the short coming of mouse hypersensitivity reactions compared to those in guinea pigs and humans.

If you look in some mouse strains the infiltrate can be over 80% neutrophils (e.g. HA mice) in other strains it is less than 5%. TH17-induced EAE has neutrophils, therefore MS must be neutrophil mediated mustn't it? 

However, if we let the tail (EAE) wag the dog (MS), this is where things go astray. I am not saying that neutrophils have no function in MS or EAE for that matter, just make the mouseEAEers put the work in outside mouse EAE, before thinking about human studies.

2 comments:

  1. This discussion of neutrophils appears to be the same confusion that occurs with cytokines, what are the cytokines that are actually involved in triggering process of MS? Someone actually looking at IL-4 ... I remember a previous publication here the blog that spoke of a study on the ratio of neutrophils and leukocytes as an indicator of an inflammatory process ...

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    1. Which cytokine is involved....we can saythings such as IL-7 and IL-2 because they are in the genes that link to MS susceptibility

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