Cross-Reactivity Discussion

[NoGlutenCooties]

There have been some discussions regarding the possibility of cross-reactivity – the theory that the body can mistake certain proteins for the gluten protein and react as if it has encountered gluten.  I know some are fairly adamant that this theory has not been medically proven and I am not suggesting that it has been.  I’m just opening this up for discussion because I find it very interesting.

 

I found this article on how the immune system works.  While it is not a cited, professionally recognized source it does appear to be accurate and a very thorough account of the immune system in layman's terms that are easy to understand: Open Original Shared Link

 

The posting includes this section on antibodies:

 

Antibodies

Antibodies (also referred to as immunoglobulins and gammaglobulins) are produced by white blood cells. They are Y-shaped proteins that each respond to a specific antigen (bacteria, virus or toxin). Each antibody has a special section (at the tips of the two branches of the Y) that is sensitive to a specific antigen and binds to it in some way. When an antibody binds to a toxin it is called an antitoxin (if the toxin comes from some form of venom, it is called an antivenin). The binding generally disables the chemical action of the toxin. When an antibody binds to the outer coat of a virus particle or the cell wall of a bacterium it can stop their movement through cell walls. Or a large number of antibodies can bind to an invader and signal to the complement system that the invader needs to be removed. 

Antibodies come in five classes: 
Immunoglobulin A (IgA) 
Immunoglobulin D (IgD) 
Immunoglobulin E (IgE) 
Immunoglobulin G (IgG) 
Immunoglobulin M (IgM)

 

 

WebMD describes one possible cause of Crohn’s Disease: Open Original Shared Link

“For some reason, though, people with Crohn's disease have an immune system that reacts inappropriately. The immune system may be defending the body against helpful microbes by mistake.”

 

 

This website has a more scientific explanation of how the antigen-antibody interaction works: Open Original Shared Link

Regarding cross-reactivity, they explain it this way: 

“Cross reactivity refers to the ability of an individual antibody combining site to react with more than one antigenic determinant or the ability of a population of antibody molecules to react with more than one antigen. Figure 5 illustrates how cross reactions can arise. Cross reactions arise because the cross reacting antigen shares an epitope in common with the immunizing antigen or because it has an epitope which is structurally similar to one on the immunizing antigen (multispecificity).”

 

 

Again, this is just a theory – not scientifically proven.  However, this sounds very feasible to me.  If the immune can mistake one bacteria for another why could it not also mistake one protein for another?  Especially when you consider that having Celiac Disease by definition indicates that the immune system is somehow compromised and/or not working exactly as it should.

[greenbeanie]

I am also interested in this topic. My understanding is that cross-reactivity of food proteins in IgE-mediated food allergies is well-established, but I don't know what that means for celiac, since it's not an allergy. I have a latex allergy and also react to some (but not all) of the cross-reactive fruits; this is known as "latex-fruit syndrome". My daughter is also allergic to latex and had to do a food challenge with banana because her allergist thought she was at high risk for a severe cross-reaction there. Here's one PubMed article that discusses it, and a simple search pulls up tons more:

Open Original Shared Link

My allergist has a whole chart of foods that are known to cross-react with birch pollen, ragweed, and other environmental allergens. These are all IgE-mediated reactions. Some people seem to have trouble with the related foods, especially during pollen season, while others don't. I know there's been a lot of controversy on these boards about whether anything cross-reacts with gluten - and to be clear, I'm not making any claims about that one way or another. Allergists only seem interested in IgE-mediated reactions (understandably enough), so maybe the phenomena doesn't work the same for autoimmune reactions against gluten.

This issue has confounded my own diagnosis, though. I initially had a positive skin prick test for wheat allergy. I was told I was allergic to wheat, and I stopped eating it and immediately felt better. The she ran an allergy IgE blood test and it was negative, plus I started cooking with barley flour instead of wheat and got sick again from that too. So the allergist revised her opinion, retracted the wheat allergy diagnosis, and sent me to GI (which led to a celiac work-up). Her explanation is that I'm very allergic to grass pollen, and she said my wheat skin prick test was a false positive because wheat cross-reacts with grass pollen. Importantly, she said it's not necessarily the gluten protein in wheat that seemed to be causing me problems - wheat and barley contain other proteins too, so I could be reacting to a different protein in them. Anyhow, the current status is that my GI is totally convinced that I have a wheat allergy, while my allergist is convinced that my symptoms (and improvements on a gluten-free diet) are much more indicative of celiac. Either way I can't eat wheat or barley, of course, but I wish there was a clearer answer about the cross-reactivity possibility.

[dilettantesteph]

To pursue this idea further, look at the protein sequence in gluten that is responsible for the reaction.   Where are proteins most likely to be found with a similar structure?  Avenin in oats is one.  Oats are closely related to wheat, barley and rye.  Look at the genetic relationships between plants.  The closeness of this genetic relationship tells us something about the similarity of proteins formed by the plants.  See if the ones that might be cross reacting are more or less closely related than ones that don't cross react.  For example, coffee is one that is often given as likely to cross react.  Look at the genetic relationship between coffee and wheat.  Look at how many plants are more closely related than that one.  Now look at the fact that barley has been found as a contaminate in coffee.  Open Original Shared Link The most likely source of a reaction with coffee seems obvious to me.

[Gemini]

I think there are too many people overthinking everything about a disease which already is well established as far as causes, treatment and recovery.  From what I have seen and read, all of the cross reactivity stuff is coming from the off the wall section of the so called medical establishment and most of them have been chiropractors or others who have not studied Celiac Disease very well.  Don't get me wrong...chiropractors have their merit and I have a very good one myself but I wouldn't ask him or seek medical advice from him on autoimmune GI issues.

 

The fact is, most people who put the time and effort into learning as much as they can about Celiac and follow the diet as they should, will recover well and go on to live completely normal lives. I have met many people who haven't even learned the basics about how the digestive system works, yet fall for information put out onto the internet by quacks. There are also established reasons why some do not do as well and the variables are many, so figuring it all out can take awhile. I also do not believe the food supply...the reputable company, gluten-free food supply, is as contaminated as some think it is because if that were the case, no one would heal. I am pretty sensitive to trace gluten and yet I do well and rarely, if ever, take a hit but there are reasons for that. It no doubt is hard work to accomplish this but I think this is why so many diagnosed Celiacs do recover well.  You just don't hear from them like you would someone who is having problems. In almost 9 years gluten free, I have to say coffee has never glutened me and I drink it daily.  If cross reactivity and contamination of the product really was an issue, I think many more Celiacs would not be able to tolerate it and that just isn't happening.

There aren't even any warnings from reputable Celiac organizations on the coffee contamination issue or cross reactivity and they have done a good job of making clear to Celiac Nation what is safe for us to eat and what is not. 

 

When I see doctors who make it their life's work to study Celiac, like Fasano or Green, come out and say that cross reactivity could be an issue so let's study it more, I will be open to hear what they have to say.  But coming from a chiropractor who makes money off of convincing people you can have a gluten reaction to coffee or that drinking milk as a Celiac can lead to depression and suicide is just plain ridiculous.  Another charlatan who uses fear to sell stuff.....just what we need!

 

 

[kareng]

A story from the international celiac Symposium. They are serving only gluten-free food for breakfast, lunch and snacks and the opening reception. So we are all sitting there one morning, drinking our coffee, and the docs are talking about Celiac myths. When the nonsense about coffee " cross- reacting" came up, everyone had a good laugh.

Like Steph said - it might make sense for something like oats, that is biologically similar, but things like coffee are so very different. In fact, a certain dubious lab that likes to sell the cross- reactivity theory is admitting that those tests they ran were wrong. They ran them on some kind of instant coffee with cc of wheat or barley - so of course it " reacted like gluten". When they tested whole bean coffee or other brands - no " cross- reaction". I think these " doctors" pick coffee because it will get them the most attention and publicity, good or bad. I'm not mentioning names because I don't want to give them anymore Internet presence on here.

[kareng]

Once again, I will link to what the Celiac Disease center at the univ of Chicago says. I realize some people won't read it or, for some reason, believe it, but I'll try again. . To me, its a better place to get medical info than a chiropractor or " natural doctor" or a " nutritionist" - none of which are usually MDs or DOs.

Open Original Shared Link

"What’s with all the talk about certain types of food causing “cross-reactivity?”

There is not yet reliable data about cross-reactivity. As for the alleged possibility that many gluten-free foods or drinks (such as coffee, milk, orange juice, etc.) would trigger symptoms in celiac individuals due to hidden antigens mimicking gluten or cross-reacting with anti-gluten antibodies, it must be clearly stated that this is all false information, devoid of any scientific basis, and must be rejected as untrue."

Open Original Shared Link

"Is there evidence of cross-reactivity (such as, any foods that do not contain gluten but cause gluten-like reactions in the body)?

We aren’t familiar with any foods that show evidence of cross-reactivity."

[answerseeker]

I am also interested in this topic. My understanding is that cross-reactivity of food proteins in IgE-mediated food allergies is well-established, but I don't know what that means for celiac, since it's not an allergy. I have a latex allergy and also react to some (but not all) of the cross-reactive fruits; this is known as "latex-fruit syndrome". My daughter is also allergic to latex and had to do a food challenge with banana because her allergist thought she was at high risk for a severe cross-reaction there. Here's one PubMed article that discusses it, and a simple search pulls up tons more:

Open Original Shared Link

My allergist has a whole chart of foods that are known to cross-react with birch pollen, ragweed, and other environmental allergens. These are all IgE-mediated reactions. Some people seem to have trouble with the related foods, especially during pollen season, while others don't. I know there's been a lot of controversy on these boards about whether anything cross-reacts with gluten - and to be clear, I'm not making any claims about that one way or another. Allergists only seem interested in IgE-mediated reactions (understandably enough), so maybe the phenomena doesn't work the same for autoimmune reactions against gluten.

This issue has confounded my own diagnosis, though. I initially had a positive skin prick test for wheat allergy. I was told I was allergic to wheat, and I stopped eating it and immediately felt better. The she ran an allergy IgE blood test and it was negative, plus I started cooking with barley flour instead of wheat and got sick again from that too. So the allergist revised her opinion, retracted the wheat allergy diagnosis, and sent me to GI (which led to a celiac work-up). Her explanation is that I'm very allergic to grass pollen, and she said my wheat skin prick test was a false positive because wheat cross-reacts with grass pollen. Importantly, she said it's not necessarily the gluten protein in wheat that seemed to be causing me problems - wheat and barley contain other proteins too, so I could be reacting to a different protein in them. Anyhow, the current status is that my GI is totally convinced that I have a wheat allergy, while my allergist is convinced that my symptoms (and improvements on a gluten-free diet) are much more indicative of celiac. Either way I can't eat wheat or barley, of course, but I wish there was a clearer answer about the cross-reactivity possibility.

my allergist also warns me against certain fruits.

[kareng]

celiac Disease is not an allergy, so the same things may not apply.

[Gemini]

I am also interested in this topic. My understanding is that cross-reactivity of food proteins in IgE-mediated food allergies is well-established, but I don't know what that means for celiac, since it's not an allergy. I have a latex allergy and also react to some (but not all) of the cross-reactive fruits; this is known as "latex-fruit syndrome". My daughter is also allergic to latex and had to do a food challenge with banana because her allergist thought she was at high risk for a severe cross-reaction there. Here's one PubMed article that discusses it, and a simple search pulls up tons more:

Open Original Shared Link

My allergist has a whole chart of foods that are known to cross-react with birch pollen, ragweed, and other environmental allergens. These are all IgE-mediated reactions. Some people seem to have trouble with the related foods, especially during pollen season, while others don't. I know there's been a lot of controversy on these boards about whether anything cross-reacts with gluten - and to be clear, I'm not making any claims about that one way or another. Allergists only seem interested in IgE-mediated reactions (understandably enough), so maybe the phenomena doesn't work the same for autoimmune reactions against gluten.

This issue has confounded my own diagnosis, though. I initially had a positive skin prick test for wheat allergy. I was told I was allergic to wheat, and I stopped eating it and immediately felt better. The she ran an allergy IgE blood test and it was negative, plus I started cooking with barley flour instead of wheat and got sick again from that too. So the allergist revised her opinion, retracted the wheat allergy diagnosis, and sent me to GI (which led to a celiac work-up). Her explanation is that I'm very allergic to grass pollen, and she said my wheat skin prick test was a false positive because wheat cross-reacts with grass pollen. Importantly, she said it's not necessarily the gluten protein in wheat that seemed to be causing me problems - wheat and barley contain other proteins too, so I could be reacting to a different protein in them. Anyhow, the current status is that my GI is totally convinced that I have a wheat allergy, while my allergist is convinced that my symptoms (and improvements on a gluten-free diet) are much more indicative of celiac. Either way I can't eat wheat or barley, of course, but I wish there was a clearer answer about the cross-reactivity possibility.

Your last paragraph says it all......if you got sick when you introduced barley and then improved on the gluten-free diet, then clearly you have Celiac.  You would also improve, allergy wise, on the gluten-free diet because that completely erradicates wheat from your diet also.....but you would still get sick, as a Celiac, from barley if you were just wheat free. This is not rocket science and I fail to understand why doctors get so confused over this. 

 

I am also allergic to grasses, some trees and mold but have never had food allergy testing. Now that I have followed a strict gluten-free diet for almost 9 years, the only food that causes me grief besides the Celiac 3 is milk......but I am lactose intolerant so that is not an allergy.  What it boils down to is that an allergy is a different animal than an intolerance so this cross reactivity theory cannot be applied the same way between the two conditions. I think all food intolerances, except Celiac, are not autoimmune based at all. They generally occur due to a lack of an enzyme or a reaction to chemicals and other things added to the food.

[dilettantesteph]

 In fact, a certain dubious lab that likes to sell the cross- reactivity theory is admitting that those tests they ran were wrong. They ran them on some kind of instant coffee with cc of wheat or barley - so of course it " reacted like gluten". When they tested whole bean coffee or other brands - no " cross- reaction".

 

I would love to see a link for that!  Do you have it.  You can pm me with it if you don't want to give them presence here.  Know what I've heard?  Often when people see a report that says that something is wrong or doesn't work, later when they recall it, they remember it as being right.  You've got the right idea not wanting to give them presence.  Shoot, I can't figure out the right google search terms to get that information to come up.

[dilettantesteph]

 In almost 9 years gluten free, I have to say coffee has never glutened me and I drink it daily.  If cross reactivity and contamination of the product really was an issue, I think many more Celiacs would not be able to tolerate it and that just isn't happening.

 

Gemini, you and I go back and forth on this contamination issue.  I just wanted to say that I agree with you that sensitive celiacs like you can drink coffee with no issues.  I brought up the coffee contamination issue to say that if you react to coffee it is much more likely to be from contamination (which has been shown to exist) than from cross reactivity (which has not been shown to exist).  I'm guessing that a study of coffees in general would show that the large majority are uncontaminated or many more celiacs would react to coffee.  A way to avoid the possibility of contamination, if one is concerned, is to buy whole beans.

[kareng]

I would love to see a link for that!  Do you have it.  You can pm me with it if you don't want to give them presence here.  Know what I've heard?  Often when people see a report that says that something is wrong or doesn't work, later when they recall it, they remember it as being right.  You've got the right idea not wanting to give them presence.  Shoot, I can't figure out the right google search terms to get that information to come up.

Sorry. Maybe I shouldn't have put that on here. It's something they told me, in person and showed me some " research" results (notebook) at ICDS. Somehow, they still thought it made their point on Cross- reactivity. I argued in circles with them while a doctor looked on and tried not to laugh. If I get a chance, they gave me a thumb drive and I'll look and see if its on that.

[NoGlutenCooties]

To pursue this idea further, look at the protein sequence in gluten that is responsible for the reaction.   Where are proteins most likely to be found with a similar structure?  Avenin in oats is one.  Oats are closely related to wheat, barley and rye.  Look at the genetic relationships between plants.  The closeness of this genetic relationship tells us something about the similarity of proteins formed by the plants.  See if the ones that might be cross reacting are more or less closely related than ones that don't cross react.  For example, coffee is one that is often given as likely to cross react.  Look at the genetic relationship between coffee and wheat.  Look at how many plants are more closely related than that one.  Now look at the fact that barley has been found as a contaminate in coffee.  Open Original Shared Link The most likely source of a reaction with coffee seems obvious to me.

 

I agree that for cross-reactivity to occur that the two antigens - or in the case of Celiac, proteins - must be sufficiently similar to confuse the immune system.  It would be much more likely for a reaction to occur with oats, than say coffee or some other food that is even more dissimilar.

[NoGlutenCooties]

The medical profession does recognize that autoimmune disorders may be caused by the body confusing normal cells in the body with the antigen that first triggered the antibody reaction in the first place:

 

"The cause of autoimmune diseases is unknown, but it appears that there is an inherited predisposition in many cases. In a few types of autoimmune disease (such as Open Original Shared Link), a Open Original Shared Link or infection with Open Original Shared Link triggers an immune response and the antibodies or T-cells attack normal cells because some part of their structure resembles a part of the infecting Open Original Shared Link."

 Open Original Shared Link

 

I don't think it is such a leap to think that the immune system could also confuse one protein for another that is very similar.  To cite someone who claims cross-reactivity between gluten and orange-juice is disingenuous.  But if there can be potential cross-reactivity between say oats and gluten, then why could it not also exist with other similar proteins?  I also do not agree with the "don't confuse the newbies" comment... I'm a newbie when it comes to Celiac but I'm not a newbie when it comes to paying attention to what I'm eating and what's going into my body and I see value in fully understanding what all might be going on.  As long as the discussion is clear that this is just a discussion and not scientific fact I not only do not see the harm, but I see a definite potential benefit.

 

I find it ironic that people use the "doctors laugh at it" argument to say that cross-reactivity could not possibly exist.  Doctors in the past did not acknowledge that Celiac existed either.

[kareng]

The medical profession does recognize that autoimmune disorders may be caused by the body confusing normal cells in the body with the antigen that first triggered the antibody reaction in the first place:

"The cause of autoimmune diseases is unknown, but it appears that there is an inherited predisposition in many cases. In a few types of autoimmune disease (such as Open Original Shared Link), a Open Original Shared Link or infection with Open Original Shared Link triggers an immune response and the antibodies or T-cells attack normal cells because some part of their structure resembles a part of the infecting Open Original Shared Link."

Open Original Shared Link

I don't think it is such a leap to think that the immune system could also confuse one protein for another that is very similar. To cite someone who claims cross-reactivity between gluten and orange-juice is disingenuous. But if there can be potential cross-reactivity between say oats and gluten, then why could it not also exist with other similar proteins? I also do not agree with the "don't confuse the newbies" comment... I'm a newbie when it comes to Celiac but I'm not a newbie when it comes to paying attention to what I'm eating and what's going into my body and I see value in fully understanding what all might be going on. As long as the discussion is clear that this is just a discussion and not scientific fact I not only do not see the harm, but I see a definite potential benefit.

I find it ironic that people use the "doctors laugh at it" argument to say that cross-reactivity could not possibly exist. Doctors in the past did not acknowledge that Celiac existed either.

If everyone is drinking coffee and coffee cross- reactivity comes up - it is funny.

And I have provided info from legitimate sources many times, including this thread, but I realize some don't choose to read them or believe them over some Internet blog by a " home economist" or " natural doctor"

[Gemini]

Gemini, you and I go back and forth on this contamination issue.  I just wanted to say that I agree with you that sensitive celiacs like you can drink coffee with no issues.  I brought up the coffee contamination issue to say that if you react to coffee it is much more likely to be from contamination (which has been shown to exist) than from cross reactivity (which has not been shown to exist).  I'm guessing that a study of coffees in general would show that the large majority are uncontaminated or many more celiacs would react to coffee.  A way to avoid the possibility of contamination, if one is concerned, is to buy whole beans.

I think when people react to coffee, it's most likely from the fact that coffee is very acidic and can bother people without Celiac Disease. Caffeine is also an issue for many and can make a normal gut feel really bad.  I cannot drink coffee on an empty stomach but if I drink it with food, not a problem. I also buy whole beans only and grind them at home because I think it makes for a more flavorful cup of coffee. I would tend to agree with you that if a person buys ground coffee, from a company that also produces other products (grains) then it could possibly be cc'd with other stuff.  I tend to just stick with companies that take Celiac seriously and are dedicated because I really hate getting sick....not worth it to me.

[GFinDC]

Some sites suggest that caffeine can lead to adrenal fatigue.  This article doesn't address adrenal fatigue.  But it does say that caffeine can raise cortisol levels.  Even after a period of adjustment to the caffeine, the amount of cortisol is higher than normal.  So, not  really a cross reactivity issue at all.  But possibly a link to adrenal issues.  Just thot it was interesting and related to the coffee discussion.

 

Caffeine Stimulation of Cortisol Secretion Across the Waking Hours in Relation to Caffeine Intake Levels

Open Original Shared Link

 

Objective

Caffeine increases cortisol secretion in people at rest or undergoing mental stress. It is not known whether tolerance develops in this response with daily intake of caffeine in the diet. We therefore tested the cortisol response to caffeine challenge after controlled levels of caffeine intake.

 

Results

After 5 days of caffeine abstinence, caffeine challenge doses caused a robust increase in cortisol across the test day (p < .0001). In contrast, 5 days of caffeine intake at 300 mg/day and 600 mg/day abolished the cortisol response to the initial 9:00 AM caffeine dose, although cortisol levels were again elevated between 1:00 PM and 7:00 PM (p = .02 to .002) after the second caffeine dose taken at 1:00 PM. Cortisol levels declined to control levels during the evening sampling period.

Conclusion

Cortisol responses to caffeine are reduced, but not eliminated, in healthy young men and women who consume caffeine on a daily basis.

[greenbeanie]

I was just doing a PubMed search for something different and happened to come across the recent articles below. Their conclusions are fairly tentative, but the initial results are quite interesting. The full text of the 2013 article is available for free if anyone's inclined to read the details. One of them does specifically look at a DQ2/DQ8 connection. [Note: I'm relatively new to this and didn't recognize the names of the researchers involved, and I have no idea at all what coffee article others were alluding to earlier or who conducted the disreputable studies...but I trust that someone will let me know if I've inadvertently posted a reference to discredited research!]

Open Original Shared Link

Abstract: Celiac disease (celiac disease) is an autoimmune-mediated enteropathy triggered by dietary gluten in genetically prone individuals. The current treatment for celiac disease is a strict lifelong gluten-free diet. However, in some celiac disease patients following a strict gluten-free diet, the symptoms do not remit. These cases may be refractory celiac disease or due to gluten contamination; however, the lack of response could be related to other dietary ingredients, such as maize, which is one of the most common alternatives to wheat used in the gluten-free diet. In some celiac disease patients, as a rare event, peptides from maize prolamins couldinduce a celiac-like immune response by similar or alternative pathogenic mechanisms to those used by wheat gluten peptides. This is supported by several shared features between wheat and maize prolamins and by some experimental results. Given that gluten peptides induce an immune response of the intestinal mucosa both in vivo and in vitro, peptides from maize prolamins could also be tested to determine whether they also inducea cellular immune response. Hypothetically, maize prolamins could be harmful for a very limited subgroup of celiac disease patients, especially those that are non-responsive, and if it is confirmed, they should follow, in addition to a gluten-free, a maize-free diet.

Open Original Shared Link

Abstract : Maize is used as an alternative to wheat to elaborate food stuffs for celiac patients in a gluten-free diet.However, some maize prolamins (zeins) contain amino acid sequences that resemble the wheat gluten immunodominant peptides and their integrity after gastrointestinal proteolysisis unknown. In this study, the celiac IgA-immunoreactivity to zeins from raw or nixtamalized grains, before and after peptic/tryptic digestion was evaluated and their possible immunogenicity was investigated by in silico methods.IgA from some celiac patients with HLA-DQ2 or DQ8 haplotypes recognized two alpha-zeins even after peptic/ tryptic proteolysis. However, digestion affected zeins after denaturation, reduction, and alkylation, used for identification of prolamins as alpha-zein A20 and A30 by MS/MS sequencing. An in silico analysis indicated that other zeins contain similar sequences, or sequences that may bind even better to the HLA-DQ2/DQ8 molecules compared to the already identified ones. Results concur to indicate that relative abundance of these zeins, along with factors affecting their resistance to proteolysis, may be of paramount clinical relevance, and the use of maize in the formulation and preparation of gluten-free foods must be reevaluated in some cases of celiac disease.

Just to clarify my earlier comments, I am fully aware that celiac is not an allergy and that allergies are very different from autoimmune reactions. My point was simply that a certain type of immune system cross-reaction between different plant proteins has been clearly established for allergies (even for some proteins from plants that aren't all that closely related taxonomically, but that have similar protein structures). So it doesn't seem unreasonable to me to wonder whether there may be other types of immune system cross-reactions that we don't fully understand yet. Only time will tell, and I will be interested to see whether these preliminary results hold up as more studies are done.