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12/19/19

What is Gluten and Why Should I Care?

If I had a dollar for every time I’ve heard someone (including myself at one point) say that the whole gluten thing has no veracity then I would have many a dollar. In all seriousness though, the anti-gluten movement has gained so much momentum in modern healthcare and is the cause of a lot of controversy and confusion that needs to be ironed out and understood. In modern medicine there are three categories of gluten related disorders: Autoimmune, Hypersensitive Allergy, and Immune-Mediated – which is where most of the population falls. I will focus on the autoimmune and immune-mediated classifications.

Autoimmune

So, by now a majority of the population is aware of what Celiac disease is, which is crazy because ten years ago no one except those afflicted by it were privy to its existence. Even so, the pathogenesis and physiology of the disease was shrouded in a grim veil for many years following its initial discovery in the late 1800’s, with its ties to gluten only surfacing in the 1940’s. Now it is known that different serum biomarkers are indicative of different autoimmune diseases relating to gluten. For example, the tissue-transglutaminases (tTGs) and endomysial antigen are indicative of diseases like celiac, dermatitis herpetiformis, and gluten ataxia; however, there is a large genetic component of celiac that is immune-response independent, so to speak. The literature shows that people with alterations in the alleles for the human leukocyte antigen (HLA) DQ2, an MHC II molecule, have a greater chance of developing the disease and that 90% of celiac cases present positive for this genetic variation. In this variation, the binding site on the receptor has a higher affinity for gliadin-like peptides, which then of course gets presented to CD4 helper T-cells and you know the cascade from there. There is increasing evidence for the development of autoimmunity secondary to immune- mediated gluten (and other dietary protein) sensitivity, but that is for the next section. 



Immune Mediated

In recent years there has been a massive surge of people claiming to be gluten intolerant and that going gluten free changed their lives, and with that came the stampede of controversy surrounding the legitimacy of the whole thing. Well I’m here to tell you that based on the available literature, non-celiac gluten sensitivity (NCGS) is definitely a real phenomenon. Whenever ANYONE eats gluten there is an immediate increase in intestinal permeability, which allows dietary and pathogenic antigens allowance from the intestinal lumen into the mucosal layer where dendritic cells and macrophages process and present them to naïve B and T cells in lymph nodes. Now, even in a person that has good oral tolerance and a sufficient immune balance, they will mount a response to these foreign molecules and stimulate T and B cell lines from them; therefore, it is safe to say that consumption of gluten is inflammatory at the least. IgA is the first to be produced in the submucosa, which then migrate to lymph nodes where IgG and IgM are manufactured. So, you might have the question, if gluten is inflammatory across the board then why do some people do just fine with it? This is a difficult question to answer mechanistically, but essentially it is this: different people react to everything differently – no immune system is the same. Some people have a greater inherent ability to control inflammation, TH1/TH2 polarization, auto-antigen recognition, and so on. However, it is still important to realize that it is inflammatory nonetheless, so perhaps you are okay for the moment until something like a head injury occurs or an infectious disease sets in that takes a silently primed immune system into a full-fledged attack on everything ever tagged.

Conclusion

Once you know the story it is actually pretty easy to explain to anyone, here is a synopsis of what the literature has to say about it.

1. Gliadin induces intestinal permeability in both control and gluten sensitive groups.

2. Genetic variants of the HLA DQ genes predispose gliadin-sensitive T lymphocytes in the lamina propria.

3. Dietary proteins and peptides (like gliadin) that leak through the not-so-tight junctions leads to subsequent phagocytosis of said molecules. Dendritic cell activation results in the release of proinflammatory cytokines that further perpetuate immune vigilance. These cells migrate to lymph nodes and present the antigen.

4. Antigen presentation leads to antibody production and cytotoxic T cell migration to the organ of origin.

5. Although not covered in this article, multiple food peptides have epitope cross reactivity with human tissues; optical density studies show that anti-gliadin antibodies (AGA) specifically cross- react with GAD-65, hepatocytes, asialoganlioside, myelin basic protein, and adrenal tissue.

Consuming gluten is risky business because even if you are asymptomatic the physiology is still present. Inflammation will occur and the risk for a leaky gut and its sequela will increase with it. In the future I will go over more of the interactions that occur with foods other than just gluten, but since this is such a heated topic I figured it was a good place to start.

References

Aziz, I., Branchi, F., & Sanders, D. (2015). The rise and fall of gluten. Proceedings of The Nutrition Society, 74(03), 221-226. http://dx.doi.org/10.1017/s0029665115000038

Czaja-Bulsa, G. (2015). Non-coeliac gluten sensitivity †“A new disease with gluten intolerance. Clinical Nutrition, 34(2), 189-194. http://dx.doi.org/10.1016/j.clnu.2014.08.012

Di Sabatino, A., Volta, U., Salvatore, C., Biancheri, P., Caio, G., & De Giorgio, R. et al. (2015). Small Amounts of Gluten in Subjects with Suspected Nonceliac Gluten Sensitivity: A Randomized, Double-Blind, Placebo-Controlled, Cross-Over Trial. Clinical Gastroenterology and Hepatology, 13(9), 1604-1612.e3. http://dx.doi.org/10.1016/j.cgh.2015.01.029

Hollon, J., Puppa, E., Greenwald, B., Goldberg, E., Guerrerio, A., & Fasano, A. (2015). Effect of Gliadin on Permeability of Intestinal Biopsy Explants from Celiac Disease Patients and Patients with Non- Celiac Gluten Sensitivity. Nutrients, 7(3), 1565-1576. http://dx.doi.org/10.3390/nu7031565

Michã«lsson, G., Kristjánsson, G., Pihl Lundin, I., & Hagforsen, E. (2007). Palmoplantar pustulosis and gluten sensitivity: a study of serum antibodies against gliadin and tissue transglutaminase, the duodenal mucosa and effects of gluten-free diet. Br J Dermatol, 156(4), 659-666. http://dx.doi.org/10.1111/j.1365-2133.2006.07725.x

Murray, J. (2011). Gluten sensitivity: from gut to brain. Yearbook of Gastroenterology, 2011, 205-206. http://dx.doi.org/10.1016/j.ygas.2011.08.021

Salden, B., Monserrat, V., Troost, F., Bruins, M., Edens, L., & Bartholomaỹ©, R. et al. (2015). Randomised clinical study: Aspergillus niger-derived enzyme digests gluten in the stomach of healthy volunteers. Alimentary Pharmacology & Therapeutics, 42(3), 273-285. http://dx.doi.org/10.1111/apt.13266

Sollid, L., Qiao, S., Anderson, R., Gianfrani, C., & Koning, F. (2012). Nomenclature and listing of celiac disease relevant gluten T-cell epitopes restricted by HLA-DQ molecules. Immunogenetics, 64(6), 455-460. http://dx.doi.org/10.1007/s00251-012-0599-z

Vojdani, A. (2011). The Characterization of the Repertoire of Wheat Antigens and Peptides Involved in the Humoral Immune Responses in Patients with Gluten Sensitivity and Crohn's Disease. ISRN

Allergy, 2011, 1-12. http://dx.doi.org/10.5402/2011/950104 Vojdani, A., & Tarash, I. (2013). Cross-Reaction between Gliadin and Different Food and Tissue Antigens. FNS, 04(01), 20-32. http://dx.doi.org/10.4236/fns.2013.41005

Vojdani, A. (2013). For the assessment of intestinal permeability, size matters. Alternative Therapies in Health and Medicine, 19(1), 12.

Vojdani, A. (2015). The evolution of food immune reactivity testing: Why immunoglobulin G or immunoglobulin A antibody for food may not be reproducible from one lab to another. Alternative Therapies in Health and Medicine, 21 Suppl 1, 8.

Vojdani, A. (2015). Molecular mimicry as a mechanism for food immune reactivities and autoimmunity. Alternative Therapies in Health and Medicine, 21 Suppl 1, 34.

Vojdani, A. (2013). Enhanced testing for gluten and food sensitivity The Townsend Letter Group.

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