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Wheat Series Part 4: Home Invasion

While a home invasion is something most of us will hopefully never experience, dealing with invaders is something our bodies have to handle thousands of times each day. And just like a thief entering your house, it would seem the job of identifying the invader—bacteria and viruses—should be a simple task. But it’s not.

The immune system has to deal with dark and confusing scenarios as it tries to differentiate dangerous invaders from our own cells, beneficial microflora, and food.1-3 Fortunately, it has evolved remarkably complex systems that make it very good at determining which is which.

One food, however, is even better at breaking in and misdirecting our internal security systems: Wheat.

In the first three installments of this series on wheat, we talked about how wheat affects the three things that can cause the digestive immune system to dysfunction. The first was increased permeability (Part 2), the second was excess bacterial stress (Part 3). The third is the subject of this post: Harmful dietary antigens.

Antigens: Identifying the Invader

Antigens are critically important to our immune defenses. In fact, without them, most of our immune system wouldn’t be able to function. Which begs the question—what exactly are antigens?

They are just molecules. And not really any special type of molecule. Antigens exist in everything: bacteria, viruses, our food, even our own cells. As long as our immune cells can bind to it and identify it, it’s an antigen.4

Certain cells in our immune system, called antigen presenting cells (APCs), travel around our bodies “sampling” everything they encounter. They aren’t particular—they’re just as likely to check out our own cells as a foreign bacterium. They chew everything they sample into small molecules and present these antigens to the brains of our immune system: T Cells.4

T Cells are trained from birth not to respond to our own unique self-antigens, which makes them remarkably good at identifying anything foreign. Together, T Cells and APCs determine when an antigen isn’t itself and, more importantly, if it’s something to be worried about.5

Think of an antigen as an ID card. APCs and T Cells are the police hunting through the house for anyone who doesn’t belong. The APC is the one who takes the intruder’s ID, and the T Cell looks over their identification and decides if they belong or not.

The problem is that ID cards are easy to fake. Some viruses have evolved the ability to mimic our own antigens in an attempt evade detection.6, 7 And not everything from the outside is bad. Beneficial bacteria in our gut are foreign, but we’ve learned to live in synergy with them.2, 3, 8 Likewise, all food is technically foreign, but an immune response to everything we eat would lead to debilitating allergic reactions and worse.9-11

To deal with this extra level of complexity, our immune systems have developed two sophisticated “interrogation” techniques: co-stimulation and oral tolerance.

Co-stimulation (or the Second Signal)

Identifying an antigen as foreign isn’t enough for a T Cell to start an immune response. The T Cell must also receive an activating signal from the APC as it presents the antigen. The APC gives this second signal when it has been exposed to a large amount of the antigen or if the body is in an inflamed state.5, 12-15

Co-stimulation is the equivalent of the T Cell asking the APC, “I don’t recognize this guy, should I call in backup?” Surprisingly, the tough-guy APC generally replies, “What, this wimp? Nah, I can take him.”

Oral Tolerance

Oral tolerance is a fancy term for not reacting to food. A special type of APC, called dendritic cells (DCs), specializes in reaching into the gut to sample food particles and microflora. Most of the time it presents the antigens with the message: “This is food. Don’t do anything.”1, 12, 14 DCs work in conjunction with a special T cell called T Regulatory (Treg) cells that respond to self-antigens instead of foreigners. But unlike other T cells, when activated, Treg cells suppress the immune system.12, 16-18 Fortunately, in our bodies, these two cells are in control most of the time.

The image below shows the antigen identification system in action. Plasma cells, macrophages, and DCs are all APCs. As you can see, in the healthy gut, Treg cells dominate:19

Wheat: The Master Criminal

Now we’ll talk about how wheat is essentially a “master criminal” able to flip our antigen identification system on its head. But unlike a virus, wheat doesn’t break the system to try to evade detection. Instead, it intentionally sets off the alarms and provokes the immune system to respond. Tragically, it’s also very good at getting immune cells to attack the wrong target.20

The Lock Picker

Part 2 of this series explains how wheat effectively opens the tight junctions of our gut allowing bacteria, large molecules, and gliadin from wheat itself to enter the body.21-24 But that’s not the only way wheat breaks in.

A protein in wheat called Wheat Germ Agglutinin (WGA) is very good at binding to the cells in our digestive tract and passing right through them into our bloodstream.13, 25, 26 WGA can also bind to other particles. So not only can it gain entry into circulation, but it can carry antigens from the gut with it.27, 28

The Police Provoker

We know the immune system doesn’t automatically respond to foreign antigens. It first needs a co-stimulation before calling in the big guns. The first thing the immune system needs is exposure to a large quantity of antigens. Wheat essentially flings open the doors of our intestinal barrier, allowing a huge flow of antigens from the gut into the body.

The second thing that gets APCs to provide the co-stimulation is inflammation. In Part 3 of this series, I explained how wheat tricks the body into believing it is under perpetual bacterial stress.29-33 This creates a constant inflammatory state that causes the once-suppressive DCs to flip and start activating the immune system.34, 35 Other APCs follow suite.30, 32, 36-39

In short, wheat ensures there’s a co-stimulation. Wheat also breaks oral tolerance.

WGA is able to enter the body bypassing all the mechanisms of oral tolerance.25, 28 So, the first time WGA and the food antigens bound to it are exposed to the immune system is in circulation, where the response is almost always inflammatory.

Worse, in multiple studies of wheat’s effect on mice and humans, wheat reduced levels of Treg (the immune suppressors) in favor of a type of T Cell called Th17.29, 34, 40 We’ll explore this shift in greater detail in Part 5; all you need to know for now is Th17 is a loose cannon who shoots first, asks questions later.41-43

The Red Herring

The above process is the definition of an autoimmune disease. It is a condition where the immune system identifies self-antigens as foreign and attacks its own body.44 One popular theory of how autoimmune disease comes about is the viral mimicry theory. A virus enters the body that mimics self-antigens.14 In the process of fighting the virus, the immune system ends up identifying the mimicked self-antigens as foreign.6, 7, 45

For this to happen, the body has to be in an inflamed state. That way APCs provide the co-stimulation required and they also suppress Treg cells which would otherwise prevent a reaction to self. This is why the theorists looked at viruses. Not only would they mimic self-antigens, they’d also create the necessary inflammation.7, 45

However, we’ve just seen that wheat does an equally good job of providing the co-stimulation and shutting down Treg cells. And wheat may provide the mimicry as well, so forget the virus.20, 44, 46-48

Of the over 100 autoimmune conditions identified, the trigger has been discovered for only a handful. One of those is celiac disease. In this condition, gliadin from wheat binds a protein in the body called tissue transglutaminase (tTG). The immune system reacts to tTG-gliadin antigens causing it to attack the digestive tract.39, 49, 50

Gliadin may also cross-react with neural components of the brain and contribute to conditions like multiple sclerosis, gluten ataxia, and autism.46, 47, 51 Similarly, WGA is able to bind to many different cells once inside the body.20, 26, 31 While responding to WGA, the immune system will sometimes also react to its binding tissues.20, 52

Fortunately, while wheat can dysregulate the immune system in all of us, not everyone who eats it develops an autoimmune disease. In the final part of this series we’ll talk about how genetic susceptibility is required for disease.


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Trevor Connor, M.S.

Dr. Loren Cordain’s final graduate student, Trevor Connor, M.S., brings more than a decade of nutrition and physiology expertise to spearhead the new Paleo Diet team.

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