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“Tight junction function” might sound like a song from Schoolhouse Rock, but it’s a topic that explains a great deal about our immune system and the increasing prevalence of autoimmune disorders. The tight junction (TJ) is an essential element of our intestinal structure, and is part of the body’s defenses against bacteria and toxins. About 70% of the body’s immune system resides in the gut, mostly as lymphatic cells. To prevent the immune system from being overtaxed, the TJ restricts access to these cells. The TJ is a matrix of interlocking proteins that open and close tiny pores between cells. The proteins form a hexagonal pattern, similar to chicken wire. Substances can pass through the intestinal wall, either through cell membranes, or between cells, using a the pores (gaps in the chicken wire). Pores help the body absorb nutrients, but must be selective. They use an electrostatic charge to filter out large particles, and to bind cells close together. Zonulins are messenger proteins that signal the pores to open. When zonulins are released, they bind to specific chemical receptors in the intestinal wall. These receptors tell the body to add a phosphoryl group to one of the proteins in the matrix. This deactivates the protein, disassembling the TJ’s hexagonal structure (like cutting a strand of the chicken wire.) The lymphatic cells address molecules that pass through the TJ, and may mark them as antigens (dangerous substances). The “danger” flag may go up on molecules larger in size than the normal dimension of the pores (typical of bacterial infections), known toxins, or a sudden flood of material that is new to the lymphatic cells in the gut. The immune system remembers each antigen and attacks it when it reappears. While this is an effective way to keep out bacteria and toxins, the problem is overkill. When the TJ is leaky (TJ dysfunction is also known as “leaky gut”), the body attacks all substances marked as antigens, even otherwise benign foods. This stresses the immune system, creating inflammation. Inflammation damages the TJ further, loosening it to admit new substances. This creates a vicious cycle, making the TJ even more permeable. This explains why Celiacs who recently had a gluten exposure tend to become sensitive to other foods they are eating during the time they are suffering from leaky gut. Those foods are passing through the loosened pores, and being marked as antigens. But why do the TJs fail to begin with? Everyone releases some zonulin in response to gluten, but those with a gene for Celiac disease release far more zonulin (two standard deviations above the norm, well beyond coincidence). Bacterial infections can also trigger zonulin release. Some industrial food additives are also zonulin triggers. They include nanoparticles (such as titanium dioxide – check your toothpaste and chewing gum ingredients), microbial transglutaminase (“meat glue”), salt nanowires, organic solvents, and emulsifiers. These new ingredients are increasingly common in the U.S. food supply. If they sound inscrutable, it’s for good reason; they’re not naturally occurring. Elevated zonulin levels and TJ permeability are associated with Celiac disease and Type 1 Diabetes. (A drug that reduces zonulin production also protects against damage to insulin-producing cells in Type 1 Diabetes patients.) Overproduction of zonulin is also found in those with Crohn’s disease, schizophrenia, and chronic kidney disease, and other disorders. The intestinal tight junction, and damage to it, is strongly associated with various autoimmune diseases. We are just beginning to understand the role of this important system in modulating health, and the factors that cause it to fail. Sources Anderson, J.M., and C.M. Van Itallie. (2009). Physiology and function of the tight junction. Cold Spring Harb Perspect Biol; 1:a002584. doi: 10.1101/cshperspect.a002584 Brandner, J.M., M. Zorn-Kruppa, T. Yoshida, I. Moll, L.A. Beck, and A. De Benedetto. (2015). Epidermal tight junctions in health and disease. Tissue Barriers 3:1-2, e974451; January-June 2015. doi: 10.4161/21688370.2014.974451 Fassiano, A. (2012). Zonulin, regulation of tight junctions, and autoimmune diseases. Ann N Y Acad Sci. 2012 July; 1258(1): 25–33. doi:10.1111/j.1749-6632.2012.06538.x Khaleghi, S., J.M. Ju, A. Lamba and J.A. Murray. (2016). The potential utility of tight junction regulation in celiac disease: focus on larazotide acetate. Ther Adv Gastroenterol 9(1): 37–49. doi: 10.1177/1756283X15616576 Lerner, A., and T. Matthias. (2015). Changes in intestinal tight junction permeability associated with industrial food additives explain the rising incidence of autoimmune disease. Autoimmunity Reviews 14 (2015) 479–489. doi:10.1016/j.autrev.2015.01.009 Vighi, G., F. Marcucci, L. Sensi, G. Di Cara, and F. Frati. (2008). Allergy and the gastrointestinal system. Clinical and Experimental Immunology, 153 (Suppl. 1): 3–6. doi:10.1111/j.1365-2249.2008.03713.x
Celiac.com 02/05/2018 - TIMP-GLIA, a new nanoparticle-based celiac disease treatment currently under development by Cour Pharmaceuticals, has received Fast Track Designation from the US Food and Drug Administration (FDA). Phase 1 studies to assess the safety and tolerability of TIMP-GLIA are currently underway in the United States. TIMP-GLIA works in part by encapsulating a component of wheat within a nanoparticle. The treatment has resulted in gluten tolerance in numerous animal models. By encasing components of gluten proteins in a nanoparticle, Cour is hoping that the gluten will remain unrecognized by the body's immune system, at least until immune tolerance can be generated through non-inflammatory antigen presentation. The FDA created the fast track process to speed development, review and commercialization of drugs that target serious conditions and fill an unmet medical need. Fast Track Designation puts Cour in a "prime position to advance an innovative new approach for the treatment of Celiac Disease," said John J. Puisis, CEO of Cour Pharmaceuticals. Cour is investigating TIMP-GLIA as part of an effort to reprogram the body's immune system so patients develop a tolerance to gluten as a non-threatening substance and ultimately to reduce or reverse celiac disease without the need for immune suppressing drugs. Cour's approach is designed to work by encasing a component of wheat in a nanoparticle, and introducing that particle into a celiac disease patient. If it works as designed, the gluten will remain unrecognized by the body's immune system until tolerance can be achieved through non-inflammatory antigen presentation. The phase 1 clinical trial for TIMP-GLIA study is being conducted at centers in the United States. The objective of the study is to assess the safety and tolerability of TIMP-GLIA when administered intravenously (IV) as a single dose at ascending dose levels and as a repeat dose in subjects with celiac disease. All in all, this is another of many bold and encouraging efforts to treat or cure celiac disease that have arisen in the last few years. Look for news of success or failure over then next few years. Source: Pharmabiz.com