Friday, 26 July 2013

Dusting off the cobwebs...An Apology

Delarasse C, Smith P, Baker D, Amor S. Novel pathogenic epitopes of myelin oligodendrocyte glycoprotein induce experimental autoimmune encephalomyelitis in C57BL/6 mice. Immunology. 2013 Jul 23. doi: 10.1111/imm.12155.

Myelin oligodendrocyte glycoprotein (MOG), a minor protein of the central nervous system myelin is recognised as a potential target in multiple sclerosis and neuromyelitis optica. The extracellular domain of MOG is commonly used in a wide range of mouse strains and other animals to induce experimental autoimmune encephalomyelitis (EAE) an autoimmune animal model of multiple sclerosis, because it is a target for antibody mediated attack. Previous studies, using selected peptides, have indicated that MOG35-55 peptide is an encephalitogenic epitope in C57BL/6 (H-2b ) mice. A more systematic analysis of both T and B responses following immunization of C57BL/6 mice with either recombinant extracellular mouse MOG protein (1-116) or with overlapping peptides spanning the whole sequence of MOG, before assessment of responses to 15mer and 23mer peptides was undertaken. The studies identified T cell responses within the MOG35-55 (extracellular domain) but also two new immunogenic and encephalitogenic T cell epitopes within residues MOG113-127 , MOG120-134 (localised in the transmembrane region) and MOG183-197 (in the second hydrophobic MOG domain). In addition residues MOG113-127 was found to be a B cell epitope, suggesting that this may be a useful adjunct for the induction of EAE as well as immunological studies in C57BL/6 mice, which is increasingly being used to study immune function through the use of transgenic and gene knockout technology.
In the world of EAE virtually all studies are now being done in C57BL/6 strain of mouse, because this is the strain on which transgenic and gene knockouts are made.

The C57BL/6 strain is about the most genetically resistant strain when it comes to EAE. 

DoctorLove discovered that myelin oligodendrocyte could induce EAE by systematically looking for regions that cause disease in the ABH and SJL mouse strains. One region that worked well in the ABH strain was the amino acids between 8 and 22 of the sequence. MOG 35-55 induced disease but it wasn't very good.

Another group plucked a few peptides out of the air and one peptide MOG35-55 induced disease in C57BL/6. 

Now the whole world uses this peptide and this mouse to find MS drugs.

Problem is, this is a bit useless as a model, it doesn't always work and if you look at it funny, your drugs stop disease. 

Whilst doing some research for a paper I came across an abstract indicated that actually MOG35-55 was not the dominant antigen and it was located elsewhere. So maybe not surprising that MOG35-55 can be variable. 

I wanted to cite this work, so I contacted the author of the abstract to see if they had or were publishing that stuff, they had submitted it.

Anyway  a couple of days later I was chatting to DoctorLove about this and it turns out that she had shown that there were more epitopes in MOG and that they were shown to induce disease. This was done by systematically looking through the sequence. 

They had presented in about 2003 but had forgotten to publish it. So now was the time to dust off the cobwebs of the old data and get it published. So we had a hunt round the world to find some old lab books and added bits of data and here it is.  

There are multiple epitopes that can induce EAE in MOG. 

This information will be useful to the C57BL/6 EAEers, but will come as a shock to one group in US........as they have been pipped to the post.............

Sorry, I did not know when I contacted you........this is the story.

However, do I still think the C57BL/6 EAE is pretty rubbish.........Em!

CoI. This study involves Team G

5 comments:

  1. Always nice to see the US pipped to the post and an impressive turnaround from submission to acceptance too!

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  2. It funny that you say the whole world uses this peptide to find drugs for MS, and this only induces EAE wit the co-administration of complete Freund's adjuvant.

    As has been recently shown, Myelin peptide based therapies adminstered transdermally have suppressive capacities on EAE and MS. Similiarly, Copaxone is based on this principle of tolerance induction. I guess there seems to be a lack of basic understanding of what drive MS.

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    Replies
    1. I think I'll sit back and let MD go to town on this!

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    2. I did not mention Freunds complete adjuvant, many people like adoptive transfer (transfer of disease with T cells) which has no Freund's adjuvant.

      Tregs and other immune tolerance mechanisms stop autoimmunity developings so you nned to be brutal to kick start the response..adjuvants do this.

      Of course the whole world does not use C57BL/6 mice there are rat labs, monkey labs, but virtually antibody working on transgenics use this strain

      As to the finding that myelin.....MS. Not sure what this has to do with this post it is totally unrelated So a post on "chalk" becomes "cheese"

      Copaxone is based on the principle of tolerance induction.....Again what has this got to do with this post?

      If copaxone induces tolerance....should you need to take it every day or every few days? Once induced, most forms of immune tolerance are robust. This only needs one or two injections to induce in my hands.

      What happens when you stop taking copaxone, does disease return or are you protected?.......

      Have these experiments been done by Teva to know if you have to take it every day.

      Is tolerance the mechanism T reg today, Th2 yesterday, MHC blocker the day before that. I have my favorites.

      The way to work out what drives MS is to stop the mechanism and see what happens, is it a virus like the ProfGs think and hope, it is immune

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  3. This is off topic since I don't know what the point of this post is but are you saying that induction of EAE is accomplished by induction of a CNS peptide without an adjuvant? Even if Tcells are transfered from animals with EAE, what causes EAE in the first place in the donor animals? Just the peptide?

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