Research News: T Cells are Permanently Changed by Celiac Disease



An interesting study was published very recently showing that T-cells, a part of the immune system, are permanently changed after Celiac Disease becomes active.  The same or a similar process is also seen in bowel disease such as Ulcerative Colitis.  Celiac disease is an illness primarily of the small intestine, but is also associated with the development of bowel disease and certain types of colon cancer, as well as other chronic inflammatory, autoimmune diseases.  For the first time, we have a hint to explain why Celiac Disease can be the starting point for other illness later in life.

The article is a collaboration between prestigious universities from several countries including the following.

International Collaboration


from: https://www.ncbi.nlm.nih.gov/pubmed/30739797
  1. Committee on Immunology, University of Chicago, Chicago, IL, USA; Department of Medicine, University of Chicago, Chicago, IL, USA.
  2. Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK.

  3. Institute for Biophysical Dynamics, University of Chicago, Chicago, IL, USA; Department of Chemistry, University of Chicago, Chicago, IL, USA.

  4. Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia.

  5. Department of Medicine, University of Chicago, Chicago, IL, USA.

  6. Department of Genetics, CHU Sainte-Justine Research Center, Montreal, QC, Canada.

  7. Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.

  8. Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

  9. Celiac Disease Center, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.

  10. Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Chicago, Chicago, IL, USA; University of Chicago Celiac Disease Center, University of Chicago, Chicago, IL, USA.

  11. Department of Medicine, University of Chicago, Chicago, IL, USA; University of Chicago Celiac Disease Center, University of Chicago, Chicago, IL, USA.

  12. Institute for Biophysical Dynamics, University of Chicago, Chicago, IL, USA; Department of Chemistry, University of Chicago, Chicago, IL, USA; James Franck Institute, University of Chicago, Chicago, IL, USA.

  13. Department of Medicine, University of Chicago, Chicago, IL, USA; Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Chicago, Chicago, IL, USA.

  14. Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC, Australia.

  15. Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK; Infection and Immunity Program and Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia; Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, VIC, Australia.

  16. Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, UK. Electronic address: priced6@cardiff.ac.uk.

  17. Committee on Immunology, University of Chicago, Chicago, IL, USA; Department of Medicine, University of Chicago, Chicago, IL, USA; Department of Pathology, University of Chicago, Chicago, IL, USA. Electronic address: bjabri@bsd.uchicago.edu.

This collaboration is very much appreciated, which is why I mentioned the participants here.  Let's look at the abstract of the article.  Note that there is also a video abstract and an image available to view for free at:  https://www.cell.com/cell/fulltext/S0092-8674(18)31653-2

 The video is available for download or viewing here:  https://www.cell.com/cms/10.1016/j.cell.2018.12.039/attachment/00a4502b-f32b-4d46-9d4b-216991c1a795/mmc4.mp4

Abstract


Tissue-resident lymphocytes play a key role in immune surveillance, but it remains unclear how these inherently stable cell populations respond to chronic inflammation. In the setting of celiac disease (CeD), where exposure to dietary antigen can be controlled, gluten-induced inflammation triggered a profound depletion of naturally occurring Vγ4+/Vδ1+ intraepithelial lymphocytes (IELs) with innate cytolytic properties and specificity for the butyrophilin-like (BTNL) molecules BTNL3/BTNL8. Creation of a new niche with reduced expression of BTNL8 and loss of Vγ4+/Vδ1+ IELs was accompanied by the expansion of gluten-sensitive, interferon-γ-producing Vδ1+ IELs bearing T cell receptors (TCRs) with a shared non-germline-encoded motif that failed to recognize BTNL3/BTNL8. Exclusion of dietary gluten restored BTNL8 expression but was insufficient to reconstitute the physiological Vγ4+/Vδ1+ subset among TCRγδ+ IELs. Collectively, these data show that chronic inflammation permanently reconfigures the tissue-resident TCRγδ+ IEL compartment in CeD.

Definitions


Tissue-resident lymphocytes - Tcells, these are the cells harmed by AIDS also. I bring it up only because there are people who remember that from the news in the 1990s, I know of no connection between the two.  There are many illnesses whose features include changes in Tcell function, notably, cancer, which is associated with CeD (celiac disease). 

      In scientific articles, I've noticed that CD usually means Crohn's Disease and CeD means Celiac Disease.  It's odd though, since there are 100x more CeD patients in the world (if you compare estimates of prevalence).  Crohn's however, has more urgent and life threatening events as the disease progresses.  Maybe it's a function of how much of an emergency it is.  I tend to use CD myself, but it's just because it's easier and that's the subject of my blog. 

"where exposure to dietary antigen can be controlled" - meaning gluten is the antigen, and you can control the exposure to gluten with the gluten free diet


"gluten-induced inflammation triggered a profound depletion of naturally occurring Vγ4+/Vδ1+ intraepithelial lymphocytes (IELs) with innate cytolytic properties and specificity for the butyrophilin-like (BTNL) molecules BTNL3/BTNL8"  -------------  Wow, how do I put that in English?!   The next section discusses what those V-notations mean, for now, they're a type of Tcell.  
---- Intraepithelial means, in this case, inside the gut wall.  
---- So we're talking about Tcells that live inside the gut wall.  And more specifics about their features follow.
---- The word "cytolytic" means it's capable of killing a cell in your body.  When a cell is cancerous or other wise needs to be retired, Tcells can kill it and trigger a cleanup process. This happens thousands of times each day. 
---- Butyrophilin is a type of protein involved in immune system regulation.  That's vague, but they can either activate or deactivate immune cells.  These Tcells are specific (activated by) BTNL3 and BTNL8.  

---- BTNL3 and 8 are two from a large group of possible BTNL types. Which type is active in your body depends on which genes are currently being expressed (this touches on epigenetics quite a bit).
---- Gluten inflammation can cause a depletion of this type of Tcell.


  And now we're at the crux of the article.  The following is my interpretation of what their next points mean.

1.  Gluten reduces the expression of BTNL8, and the Tcells are therefore fewer and inactive. Injured cells aren't cleaned up and recycled as well as before. Note that this also means there is less immune response, so it can hopefully someday explain why Celiac somehow causes gut dysbiosis.  And that dysbiosis is not always cleared up after a person implements the Gluten Free Diet.

2.  The previous behavior of Tcells was replaced by a gluten sensitive type of Tcell that also produces Interferon-gamma (a cytokine that produces more inflammation).

3.  After the gluten free diet was applied, the expression of BTNL8 was restored.  However, that didn't restore the function of the Tcells which remained vigilant for gluten regardless. Therefore, they conclude that the change is permanent.

It's probable that a drug will be used someday to restore the original configuration of Tcells, but at this point, it's a victory that we know this happens. 

 

 Vγ4+/Vδ1+  Oh My!

OK, so what is this?  It's a notation that shows inflammation activation of T cells, but it needs more explanation than that.  The following paragraph may help.  It's from the British Society for Immunology.

"Gamma delta (γδ) T cells are the prototype of ‘unconventional’ T cells and represent a relatively small subset of T cells in peripheral blood. They are defined by expression of heterodimeric T-cell receptors (TCRs) composed of γ and δ chains. This sets them apart from the classical and much better known CD4+ helper T cells and CD8+ cytotoxic T cells that express αβ TCRs. The mechanism of (thymic) selection of γδ T cells is still largely unkown."

The reference to a small subset found in "peripheral blood" means, it's hard to see them from a blood test. I should say at this point that when I looked into what these cells were, a lot of the articles said "epithelial" which means the sorts of cells that line the body, such as skin, gut, thyroid, lung bronchioles, ureter, and blood vessels. Sometimes, like in endocrine glands, these cells have a secretory function (like secretion of cytokines or hormones).

Note that CD4+ helper Tcells are thought to be the ones that send out the alarm that activates Celiac Disease by triggering the production of antibodies that cause the immune system to attack the structures of the small intestine.  There's a good discussion of the various immune responses in an article about refractory (uncured by the GF diet) Celiac Disease in the unfortunate case that it progresses to AIE (Autoimmune Enteropathy).  Look under Histopathology and Pathophysiology sections. That change too, is permanent.  So in a sense we've found that there's another type of Tcell change that is also permanent. The Holy Grail would be to find a way to change them back.

The numbers 1 and 4 (in Vγ4+/Vδ1+) probably refer to the types of "herterodimeric Tcell receptors (TCRs)."  (I say probably because that's my educated guess. Corrections are welcome.) In short, each TCR type shows what sorts of things the Tcell responds to, whether that's a pathogen or an allergenic food.  The last part notes that we don't know how the thymus, a vital immune system gland, selects the types of Tcells needed.

Although we don't understand how it happens, we now know that in CeD, the Tcells become more pro-infalmmatory and this change is not likely to be reversible in the near future.

Epilogue: Is wheat a poisonous food?


There have been calls for wheat to be removed from the mass produced food supply.  It sounds bizarre at first, but the more you understand about the long term effects of Celiac, the more the thought occurs that maybe it would be best to stop subsidizing a crop that has such toxic effects on people with Celiac, and indeed, everyone.  Some of the objections to wheat aren't specific to wheat, but to plants that have defense mechanisms against being eaten, though, and this muddles the debate, because it at once, supports and dilutes the concern that wheat may be "toxic." 

And now we have even more proof that the changes caused by wheat for Celiac patients, is permanent (until we can find a way to reverse it, if ever.)

This thought also occurs with the added urgency of Non-Celiac Gluten Sensitivity (NCGS) and the much larger group of people who are affected by NCGS than are affected by Celiac Disease alone.  Monash University, one of the collaborators of the current study, has tried to show that it was actually FODMAPs that cause NCGS, but with limited success. My belief, which hasn't been proven, is that one irritation exacerbates the other.  It fits the patient experiences I've read about and my own experience. 

So, should we restructure our commercial food production system to eschew wheat, or all gluten grains?  That would be a huge undertaking and would require a lot of consensus. We'd have to exclude all gluten grains because if we just got rid of wheat, everything would be made with barley or rye to take advantage of the gluten in them.  That also means, no beer except GF beer!
However, if I told you that a plant caused illness in up to 50% of people, would you expect that food to be on the GRAS list?  GRAS is the Generally Regarded as Safe list maintained by the FDA, and used as a guide for food producers and others when choosing additives for their products. Personally I would be surprised to find it there.  But it's a bit like asphalt.  It's unthinkable to stop using it when cars depend on it so much.
I don't have an answer for this, it's a problem much larger than one blogger can fix.

 I welcome your comments. 💙

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