|Gluten @ Wikipedia|
So in future occasions when I talk about CD in relation to some wonderful new study, I've got this training post as mine and yours go-to reference for the condition.
If you want the long and complicated story of CD, there are plenty of peer-reviewed papers which I could suggest you read such as this one from Kagnoff* (open-access) or this one from Meresse and colleagues** (open-access). There are lots of other papers on the topic too but if you want the Mr Men version, read on.
Gluten protein and peptides
CD is a condition governed by genes and environment in pretty equal measure. I suppose it all starts with foods containing the protein gluten. Actually gluten is a bit of a catch-all word because it combines two types of protein: gliadin and glutenin. Gluten is a protein which consists of long chains of amino acids. When ingested, various enzymes go to work on chopping up the protein into those nutritious rich amino acids that our bodies so rely on. But digestion does not just see the gluten protein immediately exploded into its constituent amino acids but rather breaking the protein down chunk by chuck to form small chains of amino acids called peptides along with way.
If you're a follower of autism research and in particular the whole gluten- and casein-free dietary intervention thing, you'll probably have heard about peptides as per the opioid-excess theory*** (open-access) put forward as one explanation for why diet might 'work' for some on the autism spectrum. It's still a little bit contentious but that's perhaps a topic for another day.
Anyhow, gluten is not an easy protein to digest as per the presence of certain amino acids such as glutamine and proline in that protein chain, the chemistry of which don't like being degraded easily. So what you potentially get are quite a few peptides swimming around our gastrointestinal (GI) tract which are not completely degraded into their simplest building block form, the amino acids.
These gluten, sorry gliadin, peptides however don't just stay in the gut; some of them are also able to gain access to a part of the gut barrier called the lamina propria. Once there, something rather interesting seems to happen in cases of CD. The peptides come across something called tissue transglutaminase (tTG) something else which has cropped up on this blog with autism in mind (see here). The clue is in the name about tTG (also called TG2) and what it can do: -ase means it's an enzyme and the glutaminase bit means that it does things to the amino acid glutamine. The specific duty it does is a process called deamidation which basically involves the conversion of glutamine to glutamic acid (otherwise known as glutamate). Without getting too much into the chemistry of this process, the newly deamidated gliadin peptide is now 'super-charged' (neutral into negatively charged amino acids) in terms of its attraction (binding affinity) to molecules of the almighty MHC - major histocompatability complex or HLA in humans (see here).
DQ2 and DQ8
OK, so a quick recap. Gluten protein digested into gluten peptides. Said peptides meet and greet tTG and funny things start to happen to them.
Next in the process chain of CD is how these newly enhanced peptides from an immunogenicity point of view are met by the cells of the MHC and the sparks that fly as a result. Just in case you didn't click on my link talking about the MHC, it's all about how things are presented to the immune system and in particular, the tricky task of making sure that 'self' is not confused with 'other' by the immune system.
The genetics of CD represent the important part of this next stage of proceedings as per the HLA-DQ2 and DQ8 heterodimers; in effect the genes of CD. It's all about inheritance patterns as to whether or not a person will have two or one or no copies of these genes as a consequence of genetic zygosity.
HLA DQ2 or DQ8 molecules are part of the antigen presenting cells (APCs). Those newly enhanced gluten peptides fit nicely into the 'pocket' of the DQ2 and/or DQ8 molecules and once there activate T cells or more specifically a Th1 CD4+ response**** (open-access) focused on gliadin. This eventually leads to the release of cytokines such as IFN-γ (see here also) and TNF which then go on to damage the gut mucosa as a function of their important role in the process of inflammation.
This is quite a simplistic overview of the main processes involved in CD. As per the discussions on the Kagnoff and Meresse papers, there are still quite a few unknowns about the whole process of CD. There's also the relatively newer work coming into the science of CD such as a role for zonulin (see this post) and its 'gatekeeper' role in relation to the gut barrier and things like the wheat amylase trypsin inhibitors (thanks Jad).
The gluten-free diet
As you'll probably already know, management of CD is primarily via the use of a gluten-free diet. The theory being that if there is still no starting material (gluten) to form those peptides, even though the genetics may be there, there is nothing or only little material for tTG or the DQ2/DQ8 molecules to go to work on.
That being said, you'll probably also see a few other potential areas where other interventions might also be developed***** (open-access). So how about helping to degrade those gluten peptides? What about stopping those peptides from meeting tTG? Blocking DQ8 and DQ2 molecules? Or even reducing the release or blocking the effects of those cytokines? And the good things is that research is underway in some of these areas.
Testing for coeliac disease
Just before you go it might also be worthwhile mentioning about how one goes about testing for CD in light of some confusion in this area over the years. It's worth pointing out that an accurate diagnosis of CD relies on more than one test (see here) covering serology, gut biopsy and on occasion, genetic testing. One of the more recent professional consensus statements on testing can be seen here****** (open-access).
And finally.... please don't take my word for it, do some research yourself.
* Kagnoff MF. Celiac disease: pathogenesis of a model immunogenetic disease. J Clin Invest. 2007 Jan;117(1):41-9.
** Meresse B. et al. Celiac disease: from oral tolerance to intestinal inflammation, autoimmunity and lymphomagenesis. Mucosal Immunol. 2009 Jan;2(1):8-23. doi: 10.1038/mi.2008.75.
*** Whiteley P. et al. How Could a Gluten- and Casein-Free Diet Ameliorate Symptoms Associated with Autism Spectrum Conditions? Autism Insights 2010:2 39-53.
**** Nilsen EM. et al. Gluten induces an intestinal cytokine response strongly dominated by interferon gamma in patients with celiac disease. Gastroenterology 1999; 115: 551-563.
***** Bakshi A. et al. Emerging Therapeutic Options for Celiac Disease: Potential Alternatives to a Gluten-Free Diet. Gastroenterol Hepatol (N Y). 2012 Sep;8(9):582-588.
****** Husby S. et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition Guidelines for the Diagnosis of Coeliac Disease. JPGN. 2012; 54: 136-160.
Meresse B, Ripoche J, Heyman M, & Cerf-Bensussan N (2009). Celiac disease: from oral tolerance to intestinal inflammation, autoimmunity and lymphomagenesis. Mucosal immunology, 2 (1), 8-23 PMID: 19079330
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