New Atmosphere, New Vision: Gibson and Whittemore Kick Off Invest in ME Conference 2016
Mark Berry reports on Dr. Gibson's introduction and Dr. Whittemore's keynote speech, at the 11th Invest in ME International ME Conference in London.
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Dr De Meirlier APRIL and BAFF IgA study

Discussion in 'Latest ME/CFS Research' started by JaimeS, May 31, 2016.

  1. JaimeS

    JaimeS Senior Member

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    Full title:

    Failure of gut-associated pDCs to express membrane bound APRIL and BAFF prevents their ability to promote low-affinity IgA expression in ME/CFS


    1. Vincent C Lombardi1,
    2. Svetlana F Khaiboullina1,
    3. Kenny L De Meirleir1,
    4. Tanja Mijatovic2 and
    5. Jan Hulstaert3

    Well, hello Dr. De Meirlier!

    Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous illness characterized by a number of comorbid conditions; gastrointestinal (GI) dysregulation make up one subgroup of this disease.

    IgA is the most abundant antibody isotype found in mucosal secretions including the gut. In a process of class switch recombination (CSR), that relies on the interaction of plasmacytoid dendritic cells (pDCs) with B cells, in a T cell independent (TI) manner, low-affinity IgA are produced that limit the adhesion of commensal bacteria to intestinal epithelia without neutralizing them.

    These low-affinity antibodies also limit bacterial overgrowth and potential bacterial translocation thus maintaining gut homeostasis. This process is known as “immune exclusion”.

    Two ligands on the surface of pDCs that are obligatory for the process; the membrane bound form of APRIL and BAFF. The upregulation of APRIL and BAFF on the surface of pDCs is dependent on low-level expression of type I interferon (IFN) which is produced by intestinal stromal cells in response to Toll-like receptor (TLR) engagement.

    Previous studies suggest that peripheral pDCs are significantly lower in subjects with ME/CFS when compared to controls and studies conducted by us further suggest these cells likely redistribute from the periphery to the gut. We have observed that, in contrast to controls, gut-associated pDCs in subjects with ME/CFS lack APRIL and BAFF expression.

    These data support a model of gut pathology in ME/CFS whereby dysregulated pDCs fail to promote the production of low-affinity IgA through the process of TI activation of B cells, thereby leading to bacterial overgrowth, dysbiosis, bacterial translocation and systemic immune activation.


    I broke up the text! Here is the link.

    Sorry to spam you all; a lot of studies in my inbox this morning.

    -J
     
  2. A.B.

    A.B. Senior Member

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    Anecdotally, most patients here seem to report low secretory IgA. I'm one of the patients with very high secretory IgA though, and my gut is still messed up.
     
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  3. JaimeS

    JaimeS Senior Member

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    I am one of those with low IgA, and when I spoke to KDM, he agreed this was very common in PWME. However, he's talking here not about a lowered number for IgA, but a decreased functionality. Not enough of the right sort of IgA, not just low IgA in general... though that may also contribute to overall pathology.
     
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  4. msf

    msf Senior Member

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    This sounds plausible to me, but it looks like it is just a meeting abstract - I guess we will have to wait for the results they talk about in the abstract to be published in a study.
     
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  5. Keith Geraghty

    Keith Geraghty Senior Member

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    I would be interested in IGG sub-class def also --- I have a theory that sufferers either have a gentic weaknesses to some pathogens that wont cause long term illness for most, or the pathogen causes changes in antibodies due to chronicity eg low NK cells is one, I suspect others
     
  6. msf

    msf Senior Member

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    This abstract is about IgA and the gut, there have been other articles about IgG subclasses and ME (the recent Fluge and Mella one comes to mind).
     
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  7. Research 1st

    Research 1st Severe ME, POTS & MCAS.

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    RE: Secretory IgA levels and testing

    If I remember correctly, active infection on the day of the test can elevate secretory IgA results, potentially resulting in a false 'normal' level of saliva test IgA which one might expect or 'hope' to be low.

    To add to complexity, levels of blood/saliva/stool Iga can all be different from one another. If you're on a 'search' for IgA levels in your body, it's thus probably prudent to have a whole look at the Iga system at different areas of your body before (potentially prematurely) concluding it's all normal due to relying on test data from one normal test, at one point in time.

    As JaimeS said, a normal result still doesn't give you information about the IgA 'function' just the level.
     
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  8. jepps

    jepps Senior Member

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    Viral infection changes gene expressions:

    https://med.stanford.edu/news/all-n...leave-a-signature-on-human-immune-system.html

     
  9. jepps

    jepps Senior Member

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    Bifidobacterium breve M-16V could induce mucosal lgA-expression:

    http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0089511

     
    Daffodil likes this.
  10. Daffodil

    Daffodil Senior Member

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    hi all. i just read this BAFF APRIL article and it is a little over my head. Can someone explain what they are saying?

    Thanks
     
    Kalliope likes this.
  11. Kalliope

    Kalliope Senior Member

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  12. msf

    msf Senior Member

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    )Basically, the article (or whatever you call it) is saying that they have found that the normal chain by which the gut stops ´bacterial overgrowth, dysbiosis, bacterial translocation and systemic immune activation´ has been broken or damaged in people with ME.

    This chain, according to the article, should work like this:


    1. ´type I interferon (IFN)...is produced by intestinal stromal cells in response to Toll-like receptor (TLR) engagement´ (by bacterial endotoxins).
    2. APRIL and BAFF are therefore upregulated on the surface of plasmacytoid dendritic cells (PDCs)
    3. the article isn´t specific about the mechanism (class-switch recombination?) by which this step happens, but PDCs then combine with B cells to produce low-affinity IgA.
    4. the low-affinity IgA ´limit the adhesion of commensal bacteria to intestinal epithelia without neutralizing them,´ preventing bacterial overgrowth, etc.

    According to the article, the authors have observed that step 2 isn´t working properly in ME patients. Now, the problem could either be in the PDCs themselves, or it could be in an earlier step (i.e. step 1).

    I don´t think there is much of link to the Fluge and Mella study, they were measuring APRIL and BAFF in the blood, whereas this article is referring to what is happening in the gut (although they do say that PDCs are decreased in the blood and are redistributed to the gut).
     
    Last edited: Jun 22, 2017
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  13. mariovitali

    mariovitali Senior Member

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  14. msf

    msf Senior Member

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    Could be, although it may be the case that they are decreased somewhere in the body with any chronic disease. Note that PDCs were low in the periphery but high iin the gut, according to the study authors.
     
    MEMum likes this.
  15. mariovitali

    mariovitali Senior Member

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    I am not sure whether this is a coincidence but i find it extremely interesting that the following paper mentions TYRO3, MERTK, LXR, Interferon I, Lupus and Dendritic cells (DCs) :




    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892226/

    Regarding MERTK, TYRO3, GAS6 (all Vitamin K-related Genes), LXR please have a look at the following post


    http://forums.phoenixrising.me/index.php?threads/machine-learning-assisted-research-on-cfs.51283/


    The same algorithms also suggest that Liver disease may be an important element of CFS/ME

    http://algogenomics.blogspot.com/2017/05/results-from-classification-analysis.html

    @JaimeS Great info there, Thank you
     
    Last edited: Jun 22, 2017
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  16. mariovitali

    mariovitali Senior Member

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    B Cells, Unfolded Protein Response, Endoplasmic Reticulum and pDCs :


    The unfolded protein response in immunity and inflammation



    Since i have ignorance about the subject of SNPs i choose not to say too much. However XBP1 was not chosen randomly here.


    http://www.nature.com/nri/journal/v16/n8/fig_tab/nri.2016.62_F2.html
     

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