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Dr De Meirlier APRIL and BAFF IgA study

JaimeS

Senior Member
Messages
3,408
Location
Silicon Valley, CA
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
 

A.B.

Senior Member
Messages
3,780
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.
 

JaimeS

Senior Member
Messages
3,408
Location
Silicon Valley, CA
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.

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.
 

msf

Senior Member
Messages
3,650
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.
 

msf

Senior Member
Messages
3,650
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).
 

Research 1st

Severe ME, POTS & MCAS.
Messages
768
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.
 

jepps

Senior Member
Messages
519
Location
Austria
Viral infection changes gene expressions:

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

When pathogens infect the cells of the body, the infection sets off a chain reaction involving the immune system that changes the expression of hundreds of genes. Gene expression is the process by which cells extract information from the genes and render it as molecules of protein or RNA. Cells have the capacity to express more or less of each molecule, creating a pattern of expression that changes in response to external influences — including infection by viruses.
Purvesh Khatri, PhD, assistant professor of medicine, and a team of six other researchers at Stanford identified 396 human genes whose expression changes in a consistent pattern that reveals the presence of a viral infection. The pattern of changes, which they call the meta-virus signature, occurs in a range of viruses and is distinct from the pattern of gene expression in healthy people or in people with bacterial infections.
 

jepps

Senior Member
Messages
519
Location
Austria
Bifidobacterium breve M-16V could induce mucosal lgA-expression:

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

Transforming growth factor (TGF) A1 displays a broad spectrum of activities in mucosal regulation, including induction of oral tolerance, potent anti-inflammatory effects, mucosal IgA expression and effects on epithelial cell proliferation and differentiation [39]. Fujii et al reported that B. breveM-16V can up-regulate TGF-A1 signaling and may be beneficial in attenuating inflammatory and allergic reactions in preterm infants
 

Daffodil

Senior Member
Messages
5,873
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

Senior Member
Messages
367
Location
Norway

msf

Senior Member
Messages
3,650
)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).
 
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msf

Senior Member
Messages
3,650
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.
 

mariovitali

Senior Member
Messages
1,214
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) :



Furthermore, other receptors that trigger ingestion of ACs have been shown to be different for DC versus macrophages(97). Macrophages rely predominantly on Mertk, a cell surface receptor tyrosine kinase; in contrast, DCs do not utilize Mertk but rather involve other family receptors, Axl and Tyro3(97, 98). The use of Axl and Tyro3 as phagocytic receptors for the ingestion of ACs is much slower taking nearly 6 hours whereas macrophages engulf dying cells within 15–30 minutes(97). The impact of the delayed uptake of ACs by DCs is not fully known; however, despite not being used as a phagocytic receptor, Mertk appears to influence DC deactivation including downregulating IL-12 when exposed to ACs (See Figure 1)(82, 83). This illustrates the complexity of receptors engaged in clearing ACs and the multiple signaling consequences that regulate subsequent immune responses. It is plausible that defects in the downstream Mertk-signaling pathways may be occurring in some patients with SLE.


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
 
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mariovitali

Senior Member
Messages
1,214
B Cells, Unfolded Protein Response, Endoplasmic Reticulum and pDCs :


The unfolded protein response in immunity and inflammation


XBP1 is crucial for the differentiation of conventional dendritic cells (cDCs) and plasmacytoid DCs (pDCs) from immature progenitors (left). Loss of XBP1 in progenitor cells abrogates maturation and decreases DC survival.


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