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CTLA4 Mutations & Orencia?

Discussion in 'General ME/CFS Discussion' started by Tiger_Eyze, Feb 27, 2017.

  1. Tiger_Eyze

    Tiger_Eyze

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    Hi all,

    Have a theory I would like to run by anyone willing to read it (hopefully @nandixon @Valentijn would be willing to lend their expertise):

    Do you think CFS could be due to CTLA4 mutations?

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4668597/

    From what I've seen and read, a lot of CFS/ME patients have both autoimmunity and CVID-like immune deficiency. CFS also tends to run in families with autoimmune histories.

    CTLA4 mutations appear to be in the 1-2% prevalence range, I think.

    From the paper above, it looks like the immune dysregulation caused by CTLA4 is autosomal dominant with variable penetrance because 2 functional copies of CTLA4 are required for Tregs to actually be able to supress T cell activity. So even having one bad copy can make a person's Treg cells somewhat useless at preventing autoimmune disease.

    Thus with bad CTLA4 function, you get persistence and proliferation of autoreactive T cells in several target organs and induction of an array of auto-antibodies by B Cells.

    This would fit with why Rituxan works well in a good chunk of CFS patients, but isn't curative. The autoreactive B cells will keep being made and activated as long as auto-reactive T cells are still there.

    Unfortunately, even killing the autoreactive T cells once over won't be curative if CTLA4 is to blame, because the Tregs (although normal or even increased in number) are powerless to inactivate any new autoreactive Tcells that crop up.

    There are 2 CTLA4 protein replacement products out there, currently used for RA -- Orencia (Abetacept) is one of them.

    Orancia was used to successfully treat a girl with multiple autoimmune diseases found to have a novel CTLA4 mutation who wasn't responding to immune suppressive medications
    (http://www.sciencedirect.com/science/article/pii/S0091674915012610).

    Orencia can take 3-6mos to affect joint symptoms...which is curiously similar to how long Rituxan takes to work in CFS patients. Interestingly, Orencia anecdotally relieves fatigue in RA patients quite well, and often faster than it relieves their joint pain.

    Has anyone with CFS been on Orencia? If so, what has your experience been?

    And does anyone know their CTLA4 mutation status?

    (A search for CTLA4 on the forums yielded a few 23&me results showing at least one bad CTLA4 copy. I have 2 mutated copies.)

    I ask because Orencia is cheaper than Rituxan and would theoretically treat the root cause of the disease (if due to ctla4), possibly fixing the autoimmunity and immune deficiency.

    Thanks in advance for your input!
     
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  2. nandixon

    nandixon Senior Member

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    @Tiger_Eyze That makes sense that defects in CTLA4 could be exacerbating or contributing to the disease in at least some ME/CFS patients. As far as CTLA4 mutations fundamentally causing ME/CFS, though, I would think this would only be a small subset as this should have already been found.

    Trying Orencia (abatacept) in ME/CFS does seem worthwhile to me. @Nielk may have tried this already possibly.(?)

    (FWIW, I'm heterozygous for rs231777 out of the 6 SNPs 23andMe tested for on their older v3 chip.)
     
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  3. wastwater

    wastwater Senior Member

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    I see that foxp3 gets mentioned in the paper and IPEX is immune dysregulation connected to foxp3
     
    Last edited: Feb 27, 2017
  4. Tiger_Eyze

    Tiger_Eyze

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    Heres my rambling theory on why a link between CTLA4 mutations and CFS/ME may have gone unnoticed:

    It doesn't seem like the extent of the autoimmunity that just one mutated copy of CTLA4 can cause was really appreciated until the past 3 years or so.

    CTLA4 mutations had been linked separately to Hashimotos, MS, Celiac, and a CVID-like immune deficiency, but it wasn't until more recently that all of those diagnoses were recognized to be parts of the same spectrum of an "immune dysregulation syndrome" comparable in scope to mutations in FOXP3 and AIRE (which cause IPEX syndrome and APS/APECED respectively).

    Plus, since CTLA4 mutations are autosomal dominant, there is a decent chance they could be behind more clinical syndromes than previously thought.
     
  5. wastwater

    wastwater Senior Member

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    A lot of the fox genes are tumour surpressors,I wondered if ME/cfs is an anti cancer deficiency.
     
  6. Nielk

    Nielk

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    Orencia was the next drug that my rheumatologist wanted me to try. My insurance company denied coverage. I'm still fighting with them.
     
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  7. nandixon

    nandixon Senior Member

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    Hutan likes this.

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