Celiac disease is one of the few autoimmune disorders that we can treat effectively and with few side-effects; however, our understanding of its pathogenesis is, as it is for most autoimmune disorders, lacking. Although the DQ2 and DQ8 HLA-class II types, the same ones related to Type-I Diabetes predisposition, contribute approximately 40% of the susceptibility for this disorder (I really don’t understand how statisticians get these numbers, but there is an apparent consensus on this one) and other, known gene loci may contribute another 2-3% of the risk, the majority of the susceptibility for this disorder appears to be environmentally-related (1). *I think I should point out – in TIDM, very specific alleles with HLA-DQ and –DR have been identified related to this disease, however this is not the case with Celiac. We still aren’t sure which specific alleles with DQ and DR are important in Celiac, or if that matters at all.
Environmental factors that may contribute include the amount and quality of gluten fed to babies early in life. Babies that are fed high-gluten diets during and after weaning are more likely to develop Celiac, especially if the grains they are fed contain more of the “toxic” epitopes related to autoimmunity (2). Furthermore, breastfeeding has (again) been shown to be extremely beneficial by promoting the growth of benevolent “friends” in the duodenum and jejunum, who help to process large carbohydrates as well as to keep mean bacteria out. You can almost think of them as bouncers for your tight-junctions!
What a segue – genes related to tight-junction regulation are emerging as a potentially crucial factor in Celiac development (2). In particular is the protein Zonulin, which was discovered as an analog to the Vibrio cholerae enterotoxin Zot. This protein reversibly permeabilizes the tight junctions between intestinal epithelial cells (IECs) via cytoskeletal rearrangements, allowing luminal antigen to bypass transcytosis and cross into the lamina propria, where antigens such as gluten can be altered into immunogens. In vitro experiments using cultured biopsies from Celiac patients showed sustained, rather than transient, increases in zonulin production compared to normal controls when the tissues were exposed to gliadin peptides. [Type-I Diabetics also have elevated levels of serum zonulin, and it appears to be a major player in the autoimmunity seen in Bio-Breeding Diabetic-Prone rats] (2).
Furthermore, zonulin-expression appears to be mediated by innate chemokine receptors on the luminal, not basolateral, side of the intestinal epithelium, in particular the receptor CXCR3. In patients with Celiac, CXCR3 appears to be activated by luminal gluten, which then leads to zonulin production via the MyD88 pathway. This may cause a sustained increase in intestinal permeability, which leads to the inflammatory destruction characteristic Celiac Disease. The zonulin pathway may also be a major player in Type-I Diabetes and other inflammatory bowel diseases, however the genetic and environmental modulators that cause differential development of these disorders is still not understood.
Citations:
- Barisani, D et al Celiac Disease: From Pathogenesis to Novel Therapies. Gastroenterology 2009;137:1912-33
- Fasano, A et al Tight Junctions, Intestinal Permeability, and Autoimmunity: Celiac Disease and Type I Diabetes Paradigms. Ann NY Acad Sci 2009 May;1165:195-205
Interesting post. I didn't know that breast milk was good for the child's health for this reason too. How does breast milk encourage growth of "friends" in the gut? (And by friends I assume you meant commensal bacteria?) Does it pass from the mother in the milk itself, and/or are there substances in the milk that encourage growth?
ReplyDeleteThe mechanism for this is still unclear, but some of the theories include things like regulating pH balance in the gut lining, which would favor growth of commensal bacteria over invaders, and passive immunization with IgA, which would quickly sequester any non-commensal bacteria that appear. Mother's milk is, I believe, sterile when it's expressed, so the bacteria would be coming in on other things and either encouraged or discouraged to proliferate by the components of the milk.
ReplyDeleteMother's milk has a wide-range of potential benefits that haven't yet been vetted in the lab, but I'm convinced that breastfeeding for at least 6mo and ideally up to 12mo is one of the most important things a mother can do to help her children off to a good start.