HLA genes and types of gluten damage

[sarkin]

I've been thinking about Gloria's comment on my Enterolab results (that she was surprised I'm double-DQ2, since I seem to be doing pretty well and tolerating a lot of foods). I reviewed the slides Tex linked to yesterday (http://www.enterolab.com/Lecture/Lecturenew/frame.htm - slide 15 mentions that DQ2, DQ8 seem to cause small-bowel gluten damage, where other subtypes are more likely to affect other organs).

And then I was thinking about Zizzle's posts about research regarding DQ2s and autoimmunity. Z, I guess I've been assuming that once gluten is removed, and the gut heals, those risks considerably reduce; and if we had never eaten gluten in the first place, our risks would be no greater than anyone else's for other autoimmune syndromes. I was thinking also about your comment about the celiac vaccine - that this is something that affects your every waking moment, and that would make it more worth the risk than other vaccines. I don't feel affected every waking moment (I sure did when I was flaring, of course!). I hope that stops being true for you soon, too.

I don't believe there's anything 'broken' about DQ2/8 genes, other than the ability to ingest gluten... and it seems highly possible to me that the variant goes the other way - that the normal human condition is gluten intolerance, and some people have a variation that makes gluten less damaging.

I guess I'm saying, maybe the only reason why the 0201 and other DQ2 folks have more food intolerances is because of the heightened sensitivity, and the increased damage to the small intestine (leading to more problems resulting from leaky gut, over a longer period of time, and affecting other systems).

That still doesn't explain my relative luck, or why I might have (perhaps) less small-intestine damage. It's true that I had been eating "less" gluten for some time, before the MC came back and I learned about the gluten connection. But as I had not removed gluten entirely, I would imagine that conferred only a very small advantage, if any. I've read that high-fructose corn syrup can also loosen those tight-cell junctions in the gut, but I'm not the only one here consuming virtually none of that stuff, I'm sure.

Those were my late-night thoughts last night - I'd be curious whether others have thoughts about connections, either between HLA DQ subtypes and symptoms, or specific food intolerances, or number of food intolerances. It seems to me that this is one area where the random luck would kick in - depending what triggers we come upon in life (Rx, pathogen, etc.), that could affect which non-gut systems become symptomatic?

All this could partially explain why so many of us with red-flag genetics have relatives walking around washing down pizza with a beer, and maybe complaining about migraines or backaches, but not obviously suffering MC or celiac.

I'm sorry this got so long. I feel as though I haven't quite said anything, yet. But I feel as though I might be about to ;)

Love,
Sara

[tex]

Hi Sara,

You've written a thought-provoking post. Remember that everyone, (and I do mean everyone), responds to the ingestion of gluten by producing zonulin, (the protein that apparently has the primary function of opening the tight junctions in the epithelia of the intestines). This statement is based on research endorsed by none other than Dr. Fasano, himself, (though he seems to be downplaying this discovery in his official professional position on gluten-sensitivity/celiac disease). Note that the following article, (which we've discussed before), was published over 5 years ago, (and it has Dr. Fasano's name on it), and yet the celiac world continues to pretty much ignore this important discovery.

CONCLUSIONS:

Based on our results, we concluded that gliadin activates zonulin signaling irrespective of the genetic expression of autoimmunity, leading to increased intestinal permeability to macromolecules.

http://www.ncbi.nlm.nih.gov/pubmed/16635908

What this means, is that no one in the world should be eating gluten, because everyone has a negative reaction to it. The successful persistence of gluten as a basic foodstock in the diet of most people, is due to the fact that in the absence of the DQ2 or DQ3 genes, the potential of zonulin to modulate the tight junctions, is somehow apparently limited by some unknown factor. As Dr. Fine has described, though, (and as we have found, by personal experience), the DQ1 genes, also appear to cancel the ability of that unknown, mysterious factor that limits the potential effect of zonulin. In fact, it appears that only the DQ4 genes allow an individual to be exempt from the effects of that automatic zonulin response to gluten, (and I'm just guessing about that - I may be overlooking something there, because the DQ4 genes are associated with other autoimmune disesases). IOW, if gluten is ingested, zonulin is still produced, but in the absence of DQ1, DQ2, and DQ3 genes, zonulin is somehow inhibited from inducing the tight junctions to open, or rather, they don't open quite as far. Of course, very, very few people in the world do not have either DQ1, DQ2, or DQ3 genes, meaning that in fact, it is rare for someone to not be vulnerable to gluten sensitivity, (rather than the other way around, as the celiac "experts" claim).

Similar to what happens during the development of any of the classic allergies, for anyone who has any of those genes, continued exposure to gluten in the diet will lead to increasing loss of integrity of the tight junctions, as they are continually assaulted by zonulin, so that the threshold for each successive episode is subsequently lowered, eventually reaching a point where exposure to even trace amounts of gluten will result in the tight junctions being opened wide, and they will tend to remain open on a chronic basis. That's the etiology of the leaky gut syndrome.

So I guess what I'm trying to say, is that while we might have what some authorities consider to be a "rare" disease, we certainly do not have a rare genetic arrangement - not by any stretch of the imagination. What is actually rare, is individuals who do not exhibit a negative reaction to gluten, in the form of zonulin production. I'm beginning to wonder if they might be so rare as to not even exist at all.

Thanks for inspiring me to think a little, this morning.

Love,
Tex

[Gloria]

Sara,

Here's a quote from Enterolab:

And according to my more recent research, when DQ1,1 or DQ3,3 are present together, the reactions are even stronger than having one of these genes alone (like DQ2,2, DQ2,8, or DQ8,8 can portend a more severe form of celiac disease).

It seems that I mistakenly reasoned that double DQ genes automatically meant more food sensitivities, but this statement seems to distinguish between the types of double DQ genes:

According to Dr. Fine, having double DQ genes means that the severity of reactions will be stronger. I have DQ1,1 genes, which means I will have more numerous food sensitivities (I've read that, but am not sure where), but your DQ2,2 means that you have a more severe form of celiac disease. That makes sense to me because I've never suffered from the cramping and pain that is associated with celiac. Neither have I had fatigue or headaches. My primary symptoms have always been mouth sores, gas, diarrhea and bloating. I am grateful for that.

Gloria

[sarkin]

Gloria,

That's interesting. I have one celiac DQ2 (0201)and one non-celiac, but gluten sensitive DQ2 (0202). There are so many permutations and possible combinations... I have never been Dx with true celiac, and I wonder whether my blood AGA would have come up positive, if one had been done when I was at my sickest. I thought if was interesting that I had elevated anti-tissue transglutaminase antibodies, but no fat malabsorption. I took that to mean that the small intestine was, at least somewhat, managing to do its work of assimilating nutrition.

I did not include the interpretation they sent with that test, but here's how that reads for my combo of subtypes:

Interpretation Of HLA-DQ Testing: HLA-DQB1 gene analysis reveals that you have one of the main genes that predisposes to gluten sensitivity and celiac sprue (HLA-DQB1*0201 or HLA-DQB1*0302). Each of your offspring has a 50% chance of receiving this gene from you, and at least one of your parents passed it to you. You also have a second gene that by itself can rarely be associated with celiac sprue (HLA-DQ2 other than by HLA-DQB1*0201), and when associated with one of the main celiac genes, strengthens the predisposition to getting the disease, and with more severe manifestations. Having one celiac gene and one gluten sensitive gene, means that each of your parents, and all of your children (if you have them) will possess at least one copy of a gluten sensitive gene. Having two copies also means there is an even stronger predisposition to gluten sensitivity than having one gene and the resultant immunologic gluten sensitivity or celiac sprue may be more severe. This test was developed and its performance characteristics determined by the American Red Cross - Northeast Division. It has not been cleared or approved by the U.S. Food and Drug Administration.

I think the precise way it all shakes out is not so easily predicted from genetics alone. So: I *am* more strongly predisposed to gluten sensitivity; my resultant GS or celiac *may be* more severe. (And maybe it is, and my small intestine is a war zone; or maybe I cut out the gluten in the nick of time.) He states shortly before that as well that it's the predisposition to getting celiac that's strengthened - what actually tips someone over from predisposed to disease must be limitlessly difficult to know/predict/guess.

And, as Tex has pointed out in the past, now that I've axed gluten, dairy, and eggs, along with a few other things for good measure, my next sensitivity may be just waiting to pop up. I could have a non-IgA-mediated response to a food lurking right around the corner... not to mention all the foods not included on that limited list.

So far all these quotes are from Dr. Fine, one way or another. I wonder whether the celiac-only researchers notice a difference between DQ2/2, 2/8, or 8/8 patients, and those with only one 'official' celiac gene.

[tex]

but your DQ2,2 means that you have a more severe form of celiac disease.

Yes, but that can only apply if she actually has celiac disease, which so far, has not been diagnosed. Or am I wrong?

Edit: Oops. I see that Sara has already clarified this.

Thanks.

Tex

[sarkin]

Tex,

You have remembered correctly. It seems unlikely to me that I would have had true celiac all this time and gotten away with that seeming remission for so long. Looking back, during that MC-symptom-free period, I probably had a day of D here and there, but never once had days of relentless watery D I had when first Dx with MC - and again when it recurred in March.

However, I can't exclude the possibility that I do have undiagnosed celiac. I have never had a small-intestine biopsy or endoscopy. Nor do I feel inclined to subject myself to one, quite honestly. I think I know exactly what I need to know about my relationship with gluten, and we're quits for good.

--S

[sarkin]

Gloria & Tex,

I just burst out laughing, because I realized that our latest round of discussion here basically means there's no particular credit I can take for my healthy eating, or my strict adherence to a *F diet these past few months, or my general good looks or sweet nature, or anything else, to account for my seeming ability to eat a reasonable number of foods safely *at the moment*.

There's just no shortcut, not even the steep 'shortcut' of super-paleo organic 90+%-homemade eating. I can't explain why that strikes me as hilarious.

Tex, thanks for your help and links and patience as I get my mind around these topics. As you've no doubt realized, this is the general area of thought where I got hung up a ways back, and PM'd you because I just couldn't get over my dawning understanding that there really is no such thing as absolute, unconditional gluten tolerance. I honestly think it's possible that my inability to get past "gobsmacked" to this point was due to brain fog, earlier in my recovery.

It does seem to me that some genetic predispositions make it more likely that gluten grains can be used as a starvation or emergency food - just the sort of thing you'd want in a storage grain. (Maybe even hunter gatherers nibbled a little here and there - when the good gathering season was at an end, at the time of year we now call "harvest time.")

And maybe if cereal grains were used more that way, instead of as an enormous percentage of consumed calories, maybe *some* people who are *somewhat* gluten sensitive would be less likely to tip over into symptomatic gluten-caused illness. I still believe that zonulin confers some health advantage to humans, or it wouldn't be activated in each and every one of us in the presence of gluten. And cholera. From this I have two conclusions: maybe there was some selective advantage to the more easily triggered, stronger zonulin reactions, such as those among us DQ2 & DQ8 types - like faster immune response mounted against pathogens, including but not limited to cholera.... AND - a drug that stops zonulin from doing is "job" is a potentially dangerous thing, with regard to some coming plague or other. Or some other duty that biological process is already performing.

The problem is not the zonulin. It's the gluten.

Hope to be clearer, and more research-and-reference-oriented, about this line of thinking soon,

Sara

[tex]

The problem is not the zonulin. It's the gluten.

Exactly! And that's why I'm not inclined to get on board praising Dr. Fasano's "cheap fix" for zonulin, in the form of a pill. Just like most doctors seem to prefer to do, he's treating a symptom, instead of treating the disease. And why is he choosing to treat a symptom? Because it's much more profitable than treating the disease. It's not as healthy for his patients/customers as treating the disease would be, but it will make his bank account extremely healthy.

It does seem to me that some genetic predispositions make it more likely that gluten grains can be used as a starvation or emergency food - just the sort of thing you'd want in a storage grain.

You probably didn't even realize how profound that statement was, when you wrote it, (or maybe you did), but you have defined exactly how wheat got to be such an ingrained, (pardon the pun), part of our diet. Grains and beans were such a successful innovation in the diets of our ancestors, precisely because of their storage potential, and the security that they offered, for preventing starvation when hard times came along, (and you can bet that hard times came along with some regularity back in those days, because when they ran out of something, they were out of it. Period. If they had a crop failure, they had better have an extra year's supply in storage, or the jig could be up. The fact that grains could be stored for years, if necessary, made them an indispensable part of the diet, and almost surely saved the necks of entire civilizations at various times in history. When something saves you from starvation, you tend to never question it's value. It is precious above all else. Over time, surely this raised grains to the level of sort of a deity, in the eyes of survivors.

But more than that, your observation certainly addresses the status of grains most eloquently, as far as we're concerned here on this board. Henceforth, many of us will view grains for what they actually are - anti-starvation, emergency food, and nothing more. If our ancestors had maintained that viewpoint, throughout history, we wouldn't be in the mess we're in now. Somewhere along the line, (probably very early on, because grains became popular after wild game and other natural foods, became scarce), grains were transformed from the status of emergency food, into a daily staple, and that's what cooked our collective goose.

Thanks for such inspiring thoughts. You're on a roll today.

Love,
Tex

[sarkin]

Thanks, Tex. I don't think I have (nor am likely to have soon) nearly as full an appreciation of the true nature of these storage grains as you do, given your knowledge of their role in our lives, even outside of your obvious personal history with gluten & MC.

I saw an article today about an Egyptian mummy, who they discovered on MRI had artery disease. They were theorizing that because she was wealthy, she must have eaten more meat and butter... and I was thinking, NO, she had more pastry ;)

There would be no celiac 'disease' if it weren't for (hugely excessive) use of grains, of course. I can't understand why it's considered so burdensome to avoid eating something toxic. No wonder people can't put down the soda and fries - the very people who nag us about healthy eating would rather drug a patient than suggest they make a pretty simple (not necessarily easy) diet modification. In fact, it wouldn't even be a modification, if the process didn't start out with getting folks addicted to the portability, storability, and cakiness of these so-ubiquitous products. I have found the adjustment not all that difficult. Yes, I like some foods that contain gluten, and they sure are available literally on every street corner. But no, I don't want to feel gruesomely sick, and take on severe risk of additional gruesome health outcomes.

Who would, if they understood that that's really the choice? (Sure, a very few severely gluten-addicted or otherwise emotionally fragile people would make the other choice, but I think very, very few.)

I like the context you've laid out. And it's a shame that for most of us here, and many others - more daily - the use of gluten grains as an emergency food is now definitively ruled out. We're not likely to need starvation rations any time soon, fortunately. But it's interesting that the very use they'd be good for is now broken by the mis-use on such a grand scale.

L,
S

[Martha]

I think the reason it's considered so burdensome to avoid eating something toxic is that most people don't believe that gluten is toxic.

As much as we affirm each other on this board, and believe that gluten is damaging us, we are on the fringe of what is generally considered reality. If most doctors don't think gluten is damaging, except to the few people diagnosed with celiac disease, why would the general public think so?

I have to constantly stop myself from suggesting to anyone who complains of a physical problem that they would be helped by avoiding gluten. Even though I think it's true in many cases.

[MBombardier]

Yeah, I've mentioned before that I could make myself as obnoxious as an ex-smoker is to smokers in the lives of some around me, especially two sisters I know who struggle with A-L-L sorts of health problems and seem to always feel just horrible but only "limit' gluten.

[Zizzle]

Amen, Marliss. My mother, sister and MIL are all "limiting gluten" based on my dire warnings about their health and obvious symptoms (massive bloating after eating, anyone?). What the heck is the point?!? Of course I'm limiting gluten in my kids, but they are not symptomatic yet. Maybe I'm wasting my time there too.