is an intestinal enzyme targeted by autoantibodies in celiac disease.
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A 40-year-old man comes to the office because of diarrhea and abdominal cramps. He says that he was diagnosed with celiac disease 15 years ago, but is beginning to eat gluten-containing food again because he thought that he would be able to tolerate it now. Which of the following cellular patterns would most likely be found on a biopsy of this patient's small intestine?
Content Reviewers:Rishi Desai, MD, MPH
It’s becoming more and more common to see things like “gluten-free pizza” or “gluten-free buns” and other gluten-free items at restaurants, grocery stores, or other food-based businesses.
As many as 1 in 100 people have celiac disease, although many remain undiagnosed.
Now, celiac disease is currently understood as an immune system-mediated disorder where the gluten in food triggers the body’s immune cells to attack the cells in the small intestine, as well as produce auto-antibodies against tissue transglutaminase, also found in the small intestine, as well as other tissues like the heart or the liver.
Gluten’s found in common wheats and grains, including wheat, rye and barley.
If we take a look at wheat, you’ve got your individual wheat kernels, and then inside each kernel there’s the endosperm, which has a bunch of nutrients for the seed’s embryo, mostly protein and starch, and some vitamins.
The type of protein here is gluten, the main culprit in Celiac disease.
So, if somebody with celiac disease eats a wheat-based pizza, it’s broken down in the stomach into gluten peptides ...and a whole lot of other stuff.
That other stuff is no challenge for digestion - gluten peptides, like the gliadin in wheat, however, are high in proline and glutamine, two amino acids which make it a tough little bugger to digest.
So when the undigested gluten proteins, like gliadin, get to the small intestine, they meet the intestinal mucosa, which is lined with a layer of intestinal epithelial cells.
Gluten proteins can then get across the gut epithelial cells, either between them, or through the cell, from the apical to the basolateral membrane, and get to the lamina propria, which is a thin layer than lines the gut wall.
Once there, an enzyme called tissue transglutaminase, or tTG, cuts off of an amide group from the protein.
Deamidated gluten proteins are then eaten up by macrophages and served up on its MHC class II molecules.
Remember, macrophages are in the gut and are always doing a bit of “gut sampling” where they grab proteins (which a lot of times are from foods that we’ve eaten) and show them to the immune cells.
MHC stands for Major Histocompatibility Complex and is that name of the “serving platter” for the stuff that is served up.
It’s a normal way to make sure that there are no pathogenic bacteria lurking in the gut.
Now there are a ton of different types of MHC class II “serving platters” and these serving platters are encoded by genes called human leukocyte antigen genes, or HLA genes.
These genes determine what things the MHC class II molecules “serve up”, so, for example, HLA-DR encodes for an MHC that “serves up” something different than the one HLA-DQ encodes for.
Researchers have noticed that patients with celiac disease typically have specific HLA genes, specifically HLA-DQ2 and HLA-DQ8, which code for MHC serving platters that allow deamidated gliadin to bind tightly.
And when deamidated gliadin is tightly bound to these specific MHC serving platters, that’s when the immune system kicks in.
The macrophage throws it up top and is like “hey, uh, guys?
What do you think about this molecule…?” and T helper cells, also known as CD4+ T-cells, from the immune system that recognize the gliadin zoom over and are like “Yep, I’ll take it from here”, and they release inflammatory cytokines like interferon gamma and tumor necrosis factor, which are molecules that initiate inflammation directly damaging and destroying epithelial cells in the villi of the small intestine in the process.
Of these, anti-tissue transglutaminase antibodies play a role in some of the non-digestive complications of celiac disease.
Anti-gliadin antibodies, on the other hand, don’t cause any damage; they are, however, helpful in making a diagnosis.
Finally, the helper T cells also recruit killer CD8+ T cells, which is when things get nasty.
Killer T cells are drawn to and destroy cells undergoing inflammation.
So, in short, as patients eat gluten, the immune system is stimulated and epithelial cells are destroyed.
It’s possible that the destruction of these cells lets more gliadin across the epithelium, since they’re not bunched together as tightly as they were before.