Gluten Cross-Reactivity: How your body can still think you’re eating gluten even after giving it up.
NOTE: An updated version of this post can be found here.
For those 20% of us with celiac disease or gluten-intolerance/sensitivity (whether diagnosed or not), it is critical to understand the concept of gluten cross-reactivity. Essentially, when your body creates antibodies against gluten, those same antibodies also recognize proteins in other foods. When you eat those foods, even though they don’t contain gluten, your body reacts as though they do. You can do a fantastic job of remaining completely gluten-free but still suffer all of the symptoms of gluten consumption—because your body still thinks you are eating gluten. This is a very important piece of information that I was missing until recently.
Proteins are made of long chains of amino acids (small proteins may only be 50 amino acids long whereas large proteins may be 2000 amino acids long) and it is the specific sequence of these amino acids that determines what kind of protein is formed. These amino acid chains are folded, kinked and buckled in extremely complex ways, which gives a protein its ‘structure’. This folding/structure is integral to the function of the protein.
An antibody is a Y shaped protein produced by immune cells in your body. Each tip of the Y contains the region of the antibody (called the paratope) that can bind to a specific sequence of amino acids (called the epitope) that are a part of the protein that the antibody recognizes/binds to (called the antigen). The classic analogy is that the antibody is like a lock and a 15-20 amino acid section of a protein/antigen is the key. There are 5 classes (or isotypes) of antibodies, each with distinctive functions in the body. The IgE class of antibodies are responsible for allergic reactions; for example, when someone goes into anaphylaxis after eating shellfish. The two classes IgG and IgA are critical for protecting us from invading pathogens but are also responsible for food sensitivities/intolerances. Both IgA and IgG antibodies are secreted by immune cells into the circulation, lymph, various fluids of the body (like saliva!) and tissues themselves. And both IgG and IgA antibodies are found in high concentrations in the tissues and fluids surrounding the gut (this is part of why the gut is considered our primary defense against infection).
The formation of antibodies against an antigen (whether this is an invading pathogen or a food) is an extremely complex process. When antibodies are being formed against a protein, the antibodies recognize specific (and short) sequences of amino acids in that protein. Depending on how the antigenic protein is folded, certain amino acid sequences in that protein are more likely to be the target of new antibody formation than others, simply because of the location of that sequence in the structure of the protein. Certain sequences of amino acids are more antigenic than others as well (i.e., more likely to stimulate antibody formation). This is also part of why certain foods have a higher potential to cause allergies and sensitivities.
Understanding that antibodies recognize short sequences of amino acids and not an entire protein is key to understanding the concept of cross-reactivity (and molecular mimicry, but that’s a topic for another post). It also is the reason why many different antibodies can be formed against one protein (this redundancy is important for protecting us from pathogens). Many different antibodies can also be formed against one pathogen or, more relevant to this discussion, one specific food.
So what happens in cross-reactivity? In this case the amino acid sequence that an antibody recognizes is also present in another protein from another food (in the case of molecular mimicry, that sequence is also present is a protein in the human body). There are only 20 different amino acids, so while there are millions of possible ways to link various amount of each amino acid together to form a protein, there are certain amino acid sequences that do tend to repeat in biology.
The take home message: depending on exactly what antibody or antibodies your body forms against gluten, it/they may or may not cross-react with other foods. So, not only are you sensitive to gluten, but your body now recognizes non-gluten containing foods as one and the same. Who needs to worry about this? Any of the estimated 20% of people who are gluten sensitive/intolerant or have celiac disease, i.e., have formed antibodies against gluten.
Cyrex Labs offers a simple blood test that tests for cross-reactivity to the most common culprits (Chris Kresser vouches for the high quality tests done by this company, which is good enough for me!). Here is the full list (some of these are obviously not paleo, but you might consider them cheat foods, which is why I mention them):
- Polish Wheat
- Milk (Alpha-Casein, Beta-Casein, Casomorphin, Butyrophilin, Whey Protein)
- Tapioca (a.k.a. cassava or yucca)
Just like trace amounts of gluten can cause a reaction in at least those with celiac disease (the threshold for a reaction has not been tested in non-celiac gluten sensitivity), even a small amount of these foods can perpetuate inflammation and immune responses. This is important when you think of the small amounts of soy used in so many foods and even the trace milk proteins that can be found in ghee.
If you have autoimmune disease (which has a very high correlation with gluten-sensitivity), celiac disease, gluten-sensitivity, or are simply not seeing the improvements you were hoping for by following a standard paleo diet, one or all of these foods may be the culprit. You have the choice of either cutting these foods out of your diet and seeing if you improve or get tested to see if your body produces antibodies against these foods. For me, it’s a no brainer (because it just all makes so much sense now!): I have to stop eating chocolate (sniff), fermented foods like sauerkraut and kombucha (because of the yeast content), eggs, and tapioca. I am very happy to report dramatic improvement in my lichen planus lesions in just four days! (and as much as I miss chocolate and kombucha, it’s worth it!)
A great overview of proteins and antibodies (and source of protein folding image): http://publications.nigms.nih.gov/structlife/chapter1.html
A fairly technical review of food IgG-mediated food sensitivities: http://www.usbiotek.com/Downloads/information/criticalReview.pdf
Cyrex Labs Array 4: http://www.cyrexlabs.com/CyrexTestsArrays/tabid/136/Default.aspx
Image of antibody binding taken from http://classes.midlandstech.edu/carterp/Courses/bio225/chap17/ss2.htm