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Non-celiacs Show Interleukin 15 Production when Challenged with Gliadin Peptides

Celiac.com 08/06/2009 - A study by a team of Spanish researchers puts the world on notice that gluten may trigger adverse reactions in both celiacs and non-celiacs alike. The research team was made up of E. Arranz, D. Bernardo, L. Fernandez-Salazar, J. A. Garrote and their colleague S. Riestra, all doctors based in Spain.

According to the current medical wisdom, innate immunity to gluten plays a critical role in the development of celiac disease (CD).

This innate immune response is caused by a reaction to the ‘toxic’ gluten peptides that is mediated by interleukin (IL) 15, like the 19-mer through a DQ2-independent mechanism, and which causes epithelial stress and triggers the intraepithelial lymphocytes to turn into natural killer (NK)-like cells, which then causes enterocyte apoptosis and a compromised permeability of the cells lining of the gut…and, violà, celiac disease!

It is by breaching this lining that immuno-dominant peptides, such as the 33-mer peptide, come into contact with the lamina propria, which triggers adaptive immunity.

The innate specific response in celiac disease has been pretty well documented, but until recently, no one had described any differential factors between people with celiac disease and those without.

Since the toxic 19-mer triggers its damaging effects through a DQ2-independent mechanism, doctors wondered whether the innate immune response was common in both people with and without celiac disease, and whether the adaptive response is emblematic only of susceptible people with celiac disease.

A team of researchers recently set out to determine just that, beginning with biopsies from at least three patients with celiac disease who were observing a gluten-free diet and three patients who are free of celiac disease. The research team consisted of D. Bernardo, L. Fernandez-Salazar, J. A. Garrote and their colleague S. Riestra, all based in Spain.

The team applied crude gliadin, the gliadin synthetic 19-mer and deaminated 33-mer peptides to the biopsy tissue after discarding the presence of lipopolysaccharide.

They did this at concentrations of 100 mg/ml for 3 hours to mimic what are considered the standard timing and concentration in the digestive tract after a routine meal.

The research team then washed the specimens and cultured them for 21 hours in new clean culture medium to assess whether an innate stimulus is reflected by an adaptive response.

Here’s some technical jargon:

Each sample cultured in basal medium served as an internal control. Innate immune mediators IL15 and nitrites were measured by western blot in the biopsy protein extract along with a Griess reagent system in the 3 h supernatants respectively. mRNA levels of adaptive immunity mediators like signal transducers and activators of transcription (STAT) 1, STAT3, tumour necrosis factor a, interferon (IFN) c, IL23 (p19), IL27 (p28) and IL12 (p35) were determined by real-time polymerase chain reaction using b actine levels as house-keeping.

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Compared with the basal culture, all of the patients were challenged with the gliadin solution, and all of the patients, both those with and those without celiac disease on a gluten free diet, showed IL15 production, which indicates an immune reaction is taking place.

More importantly, the IL15-mediated response in patients without celiac disease was triggered, in three of six cases, by the same toxic 19-mer gliadin peptide and, in five of six cases, by the 33-mer gliadin peptide as in those with celiac disease.

Significantly, none of the basal cultures showed this result, though the ‘‘non-toxic’’ immuno-dominant 33-mer did induce an innate response that was un-foreseen.

Interestingly, one patient with celiac disease and on a gluten-free diet, and three patients without celiac disease, who were also on gluten-free diets, all showed the IL15 response, which was confirmed by western blot analysis. This discounts an intracellular and non-biologically active IL15 response in patients without celiac disease.

The gliadin-challenged patients with celiac disease who were on a GFD, showed increased nitrite levels, which those without celiac disease did not show. Following the biopsy mRNA isolation, only patients with celiac disease showed modifications to what are called adaptive mediators (STAT1, STAT3, IFNc).

The basal samples of those celiac patients on a gluten-free diet showed
IFNc mRNA levels that were 80 times higher than basal samples of those without celiac disease (p value 0.002), along with a slightly higher production of nitrites (p value 0.052).

This appears to be the first time that researchers have described an IL15-mediated innate response to gliadin and gliadin peptides in people without celiac disease, as well as the first time they have described an IL15-mediated innate response to the ‘non-toxic’ deaminated immuno-dominant 33-mer peptide.

What this all means is that, for the first time, scientists have documented harmful effects of gluten on people without celiac disease. This hypothesis seems to be born out by the fact that all individuals who took place in the study, both those with and those without celiac disease, showed an innate immune response to gluten, though only those with celiac disease showed an adaptive immune response to gluten.

Clearly, before doctors can draw any hard and fast conclusions, they will need to do more studies on larger groups.

The research team also suggests that people with celiac disease have a lower threshold for triggering an adaptive TH1 response than do non-celiacs, and that people with celiac disease need to be DQ2 positive.

The reason for the differences in threshold levels between celiacs and non-celiacs might be tied to the fact that celiac patients show higher basal levels of immune mediators, such as IFNc mRNA, compared to those without celiac disease. That’s one possibility.

The difference in threshold levels might also have to do with some kind of defect in permeability of the gut membrane in those with celiac disease, or even a greater IL15-sensitivity response under equal stimulus, which might be mediated by a higher density of IL15 receptor in patients with celiac disease.

Gut 2007;56:889–890

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7 Responses:

 
Frances Garcia,MD
Rating: ratingfullratingfullratingfullratingfullratingempty Unrated
said this on
10 Aug 2009 9:13:41 AM PDT
Very intresting but may be difficult to understand unless you are an immunologist or a physician

 
lindaoden
Rating: ratingfullratingfullratingfullratingfullratingempty Unrated
said this on
14 Aug 2009 1:07:46 PM PDT
Maybe not, especially, among celiac patients who are used to reading about their condition. I understood 99% of this adequately, and certainly sufficiently to grasp the significance of the study and the newsworthiness of the findings.

 
Dee
Rating: ratingfullratingfullratingfullratingemptyratingempty Unrated
said this on
10 Aug 2009 7:12:42 PM PDT
It would be nice to read an article without having to look up definitions to all the words. There are people out there who are not science majors, etc. However, after looking all this up, it was pretty interesting. Thank you.

 
admin
( Author)
said this on
11 Aug 2009 7:57:25 PM PDT
Many of the words you see in our articles are actually links to the definitions--we have a site glossary that defines many of the key terms using in our articles...it is a work in progress.

 
Gloria Brown
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said this on
11 Aug 2009 6:42:48 AM PDT
Great article!

 
Teresa Huffman
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said this on
11 Aug 2009 12:44:31 PM PDT
ITS GOOD TO READ ABOUT WHAT THEY ARE FINDING WITH PEOPLE WITH CELIAC.

 
Sandy
Rating: ratingfullratingfullratingfullratingfullratingfull Unrated
said this on
11 Aug 2009 3:38:41 PM PDT
very interesting study!




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Ugg, tell me about I thought I had bad gut bacteria for years. Carbs would just make be bloat and distend, sugars, rice, any kind of grain. Figured out in Feb, it was UC and that the sugars in carbs caused flare ups....I realize I am blessed I can nuts, I eat nut based breads, muffins, cakes etc, using stevia, monk fruit, and xylitol for sweeteners since they do not trigger the flare ups. >.> I am also addicted eating sugar free jams made with extracts, and a universal pectin that reacts with calcium water instead of sugar so I can use monk fruit to sweeten. (Cheaper to make this for my fruit cravings to buying sugar free jams) I also found a noodle by miracle noodles that is carb free they also make a rice sub...I use them in recreating dishes I used to eat all the time. NOTE the fiber in them is not tolerable to some people. But might look into it as a alternative. I think I did a post not to long ago about different forms of noodles and how to make them or get them for those with similar issues one of hte more intiruging ones is using eggs or egg whites mixed up and cooked on low eat in a pan into a thin sheet then cutting into noodles or using nordic wear microwave plates to make them. .....I recently found you can mix konjac flour, eggwhites, and hemp protein, up pour into one of those plates and cook into a tortilla. check my profile for my food issues lol list is huge, at least you can eat meats?

Hi guys, I am newly diagnosed celiac. I found out about a week and a half ago, and have been gluten free for 5 weeks (I stopped after the biopsy was taken). I never really suspected celiac, so it was quite a surprise, but when I started reading about it it made a lot of sense in terms of symptoms etc. I am 34 yr old female, my main symptom was lack of energy for as long as I can remember, blood tests only ever showed low iron (not quite anaemic) but supplements never made a difference (now I know why!). For the last 5 years I have also had constipation, bloating and gas, but I put it down to stress or bad diet and if I am honest because it was a bit of an embarrassing issue to talk about I became complacent. As this is all very new to me, I feel like I have so many questions so thought I would put some here and if anyone has any input or advice from their experience that would be great! I will probably also post more in depth questions in the relevant sub-forums - For those in the UK, how long did it take you to speak with a dietician. The letter with my diagnosis was sent on 12 April and said I had been referred but I haven't heard anything - I am interested to know whether other celiacs/strict GFers ever eat foods which say "may contain traces of..." or "made in a factory which processes...." etc. So far I have avoided anything which says "may contain" or "not suitable for celiacs due to..." but I did eat something which said "made in a factory" (Walkers crisps) as they were the only option but then I felt guilty after! - What procedures do you take when eating out, i.e. do you only go to places which are certified by Coeliac UK (if you're in the UK), do you find speaking with the waiter etc actually helps? I have eaten out a few times since being gluten-free and feel like I am being a bit difficult when I bring it up and that they don't really understand. I am lucky to be in London so there are lots of certified restaurants, but even in Pizza Express I didn't think that the waiter really understood. - For those who had energy/tiredness problems before, how long did it take you to notice a difference? The only difference I have so far noticed is I am now more regular toilet wise and have had very little bloating/gas. - I have always had low iron which is most likely due to celiac but also as I don't eat meat (I do eat fish), I am hoping now that iron supplements will help now so have been taking the gluten-free Floradix for the last week. Anyone noticed a difference in this after stopping gluten? Thanks anyone for taking the time to read, and feel free to put any general advice you have Rachel

BOBS RED mill makes an all purpose flour with no rice try Quinoa flour buckwheat flour tapioca chic pea flour coconut flour almond meal ground into a flour flax meal all these things make great " toast" and healthy alternatives to too much rice flour yummy

Oh yeah. I'm 6 months in and still have bad days, even though I know I'm not eating gluten. It takes a long time to heal. I have been on here a lot in the past 6 months venting because I didn't feel good. I just posted today about how tired I still am. Everyone has basically said the same thing - give it time. Be patient. It can take a long time. Some people said it can take a year. Hang in there.

Ok, so I have another question for all of you professional Celiacs. I read an article recently that talked about a study that was done on people with Celiac's disease, which said that some of them (a small number) had high levels of arsenic in their systems because of all of the rice products that they eat. Now, I don't eat a ton of rice, but we do have gluten-free pasta a couple times a week, my son and I like rice Chex, and I know there's brown rice flour in the pizza crusts I use and in the gluten-free bread that I eat. How worried about arsenic poisoning do we need to be? I'm not downing rice at every meal but I do eat it daily, I'm sure. I rarely eat rice, rice. Usually it's the rice flour that's in things. Is this one more thing to keep me up at night? Because now I'm like, "Oh this is great. I'm trading gluten for arsenic." I need to eat carbs. If I just eat fruits and veggies and meat I'll lose weight which stresses me out. I want to be able to eat toast with peanut butter and eggs but I worry my toast is killing me. Am I being a little dramatic.