Everything You Wanted to Know About Oral Tolerance and the Autoimmune Protocol

In my first article, Is Baking Soda and Effective Treatment for Autoimmune Disease?, I directly addressed concerns with a research study that contained some methodologic and reporting flaws that was then taken out of context in many medical news outlets. We discussed together some tips to recognize concerning headlines in medical news media and ways you can be your own critical detective.

While I will not be directly addressing a specific research study in this piece, I want to start this article by reinforcing my primary intention of writing any articles in the first place.

I want to give you the tools to think critically and curiously about medical science and to provide you with conceptual frameworks in which to think about new or novel ideas.

Essentially, trying to teach ourselves (because I am learning too!) how to fish in the medical science pond instead of just handing out fish. Does that make sense?

On to our Topic: Tolerance (or “Oral Tolerance”)

This concept is something that has generated a lot of debate over the past few years, and more recently, it (or the loss of it) has been attributed to many disease states including autoimmunity. Many individuals have published blogs expressing concern that elimination diets and specifically the Autoimmune Protocol can lead to a loss of tolerance (“oral”) and lead to more food sensitivities, both in quantity and in severity.

I have also started to see these messages infiltrate into the broader AIP and autoimmune communities, leading to significant fear and trepidation over pursuing a self-directed nutrient dense elimination and reintroduction protocol.

This is a misunderstanding of the concept of tolerance and the overall complexity of our immune system. This article will explain why.

CLICK TO EXPAND // Read more of my thoughts on fear-based writing and discouraging empowered behavior change

  1. Whether or not elimination diets such as AIP affect tolerance, positively or negatively, fear based writing is not acceptable, period. Fear based medicine, and anything for that matter is unsustainable and does not promote relational peace.
  2. Insinuating or directly stating that individuals should or must pursue expensive testing, protocols or clinical services in order to completely heal from conditions is not acceptable. Education and support are first and paramount. I personally take a value based approach to healthcare and believe very strongly in starting first with empowerment and supporting people in making positive behavior change.

What is tolerance, as it applies to a dietary protocol like AIP?

Tolerance can best be described as a state of non-responsiveness of one’s immune system to “self” tissues. The process of “developing” tolerance within one’s immune system is rather complex and occurs both in specialized immune organs (think your bone marrow and spleen) as well as in other areas throughout the body (think your gut).

“Oral” tolerance, as it has been most recently portrayed, is actually only one part of our immune system’s “education” and functioning, and fundamentally only describes a very specific process that involves the immune system’s response to ingested foreign elements (like food) and not actually the immune system response to one’s own tissues.

In order to fully grasp the complexity of tolerance more broadly, we must begin to appreciate the processes behind which our immune system is able to recognize and not respond to “self” tissue and the processed behind its ability to recognize and respond appropriately to foreign elements.

Since most of the discussions of tolerance within this community thus far have focused on “oral” tolerance, or the immune system’s reaction to ingested foreign elements, I think it is important to include a thorough discussion of some of the other processes at play with regards to the immune system’s recognition and lack of response to self tissue, an arguably more important topic when it comes to the development or treatment of autoimmune disease.

Like I said above, tolerance is a physiologic state of less or non-responsiveness to “self” tissues. This is a continuous process performed by the immune system. It can be considered for functional purposes to occur independently of the recognition of foreign antigens, “non-self”.

Tolerance can be subdivided in many ways or processes. I like to think of it based on location.

  • Central tolerance occurs in primary immune organs: the thymus and bone marrow and ensures the production and maturation of immune cells (B and T cells) that do not respond inappropriately to “self”.
  • Peripheral tolerance occurs in the peripheral immune tissues such as the spleen, lymph nodes, gut associated lymphoid tissue (GALT), etc. This process is quite complex and occurs via numerous mechanisms. One of the emerging mechanisms and areas of research regarding peripheral tolerance involves immune cells called T regulatory cells or Tregs for short. (We will talk about these important immune cells later in the post!)

The recognition of “self” depends on the function of a protein complex: the MHC-I complex present on all cells (except red blood cells). This protein complex functions in a continuous manner showing the immune system different recycled proteins taken from inside our cells. Usually these recycled proteins represent self, but sometimes they can actually represent a virus or even cancerous cell. (Read below to learn how this actually occurs in the body!)

CLICK TO EXPAND // Read more in-depth science about tolerance

Central Tolerance

Central Tolerance is the process of self recognition in primary lymphoid (immune) tissue. This occurs in the thymus gland, by the removal of autoreactive (inappropriately recognizing “self”), T cells (a common type of immune cell) and in the bone marrow, by the appropriate maturation of B cells (another common type of immune cell).

The mechanism by which T cells mature and become tolerant to “self” in the thymus is rather fascinating. Through the control of the Autoimmune Regulator (AIRE) the thymus is able to express “self” proteins from ALL of our organs and tissues. Essentially this allows “baby” new T cells to “practice” recognizing and not react to self tissues in the thymus. If they recognize and respond to self in the thymus than they are removed -- this means they are not allowed to go into circulation. Sounds pretty awesome doesn’t it?

How do we know this is important?

People with inactivating mutations of the AIRE manifesting numerous types of autoimmune conditions, many around endocrine organs. Pretty important huh?

Going back to our friends the B cells, these immune cells are primarily responsible for recognizing antigens (“self” and “non-self”) as well as making antibodies. We will explore this more in another section, but I simply want to point out that they too go through an incredibly complex maturation process in the bone marrow to ensure that they too, do not inappropriately respond to self tissue and have the capacity to respond and adapt to foreign elements.

Peripheral Tolerance

As compared to central tolerance, where we were focused on creating cells that do not respond inappropriately to self in the thymus and bone marrow, peripheral tolerance is the process of self recognition in the periphery tissues including the spleen, lymph nodes, gut associated lymphoid tissue, etc. There are many mechanisms by which peripheral tolerance occurs in the body, I have provided a summary of some of the most important below.

1) Anergy Induction of Autoreactive T Cell

Very similar to the thymus mechanism. Anergy is special state of “non-reactivity”. The immune cell doesn’t die, but will no longer be a “reactive” cell. This is protective for obvious reasons, and also energy efficient.

The process behind this is also rather cool. In order for T cells to communicate they often require two signals! Think of it as requiring two handshakes instead of just one. One handshake is the interaction of the cell with the antigen (e.g. protein fragment), the other is what is often referred to as a co-stimulatory signal. If the T cell only gets the antigen-specific signal without the co-stimulatory signal, it will go into a state of anergy and not respond. If it just gets the co-stimulatory signal without the antigen, it will have no effect, no anergy, and no response.

2) T Regulatory Cells

These cells have recently become a hot topic within immunology and have been studied for their role in educating the immune system to properly respond to “self” and “non-self”. They are often the cells suppressing an inappropriate immune response. Sounds pretty important doesn’t it? It’s perhaps the main reason why people are studying ways to increase and improve their functioning to treat and prevent immune mediated disease.

T reg cells function to suppress immune responses in two main ways:

  1. Direct suppression (destruction) of the effector cells, the immune cells that are carrying out the immune response.
  2. Indirectly modifying the supporting antigen presenting cells (APCs), basically helping them do a better job at presenting antigens (both self and foreign) and communicating with the effector cells, the cells carrying out the immune response.

You can also categorize and separate T reg cells into two broad categories. First, natural T reg cells that are made centrally in the thymus, and second, induced T reg cells which happen in the periphery. This follows the same concepts of central and peripheral tolerance. Location is important!

And guess where the most common site of induced T reg cell formation is?

Mucosal surfaces: Think the GUT!

Now I will not go into an exhaustive discussion here, but there are many reasons and mechanisms to suggest why AIP can support the induction of positive T reg cell function. Many of these center around the effects of its inclusion of certain nutrients including vitamin A, vitamin D, omega 3 fatty acids, probiotics (think fermented foods and supplements) as well as molecules called short chain fatty acids (SCFAs for short), that are made by gut bacteria from the prebiotic fibers (think fruits and veggies) that we consume. (Here's an article about Th1 and Th2 by Mickey Trescott for further reading).

3) Local regulation in mucosal tissue

Think cavity lining cells, cells lining internal organs (gut, nose, internal organs, vaginal tract), etc. I think it is important to make a point here that we should start to think of our inhabitant gut microbiota as one with our own and actually the recognition of “self” antigens could be broadly thought to also include certain of our bacterial counterparts. Mechanistically, we begin to see that gut dysbiosis can actually result from an immune reaction (in the context of an inflammatory response) to “self” or normal commensal bacteria.

Interesting way to think about it, isn’t it?

How does the immune system actually recognize self?

Now you may be asking: How do the immune cells (B and T cells) recognize “self”? While it is a rather elegant and complex process, I like to think of it metaphorically as each cell having a name tag on its surface, however, this name tag is not permanent, and you don’t want it to be.

Why would you not want a permanent name tag? Another good question. While the majority of the time your cells are healthy and normal, sometimes things can go wrong. One good example: a cell gets infected by a virus. A virus interestingly is what we call an obligate organism. It is not really alive. It requires energy and cellular machinery to replicate. The way it does this, in simple terms? It enters your cells and incorporates its genetic material (DNA or RNA) into your genome. SO, the next time your cell needs to replicate, it starts to make viral proteins too. Wow. The virus is assembled inside the cell and can exit either by ripping the cell apart, not the best way to go undetected by the immune system or by budding off and taking a little of the cell’s membrane with it, a pretty good way of staying under the radar I would say. Now do you start to see why we wouldn’t want a permanent name tag?

What is so amazing is the complex, known technically as the MHC-I complex, is a protein complex present on all cells, except red blood cells, and is constantly presenting on its cell surface (to our immune cells- T cells) processed fragments of internal proteins. While these “fragments” are usually our own proteins that are being recycled- generating NO immune response, this can change to viral proteins or even cancerous proteins and we need to know that!

What is even more amazing is that there is incredible genetic variability between individuals that causes significant variation in the peptide binding site or “groove”. What does this mean? Our immune response, recognition of “self” or “non-self” depends not just on the antigen presented but on you -- the structure of your binding site (think Cinderella and the glass slipper)!

How does the development of autoimmunity relate to tolerance?

I will be the first to admit that this is a dynamic field, with many emerging theories seeking to explain the root reasons behind the development of autoimmunity. It is complex and multifactorial but one of the more promising theories involves the interplay of genetics, environmental exposures (ex. what we ingest) and the health of one’s gut.

The gut plays many important roles, but one of the most critical when it comes to tolerance and/or the development of autoimmunity is its job in maintaining a selectively permeable barrier between external and internal environments. This allows the immune cells of the gut to selectively sample foreign elements in the external environment (perhaps food particles, bacteria, etc) and educate other immune cells as to how they should respond.

When this selectively permeable barrier is breached, foreign elements can enter a new context and force the immune system to respond. In some this can lead to an exaggerated immune response that inadvertently damages our own tissue (also known as the bystander effect). This breach can also lead to overall increase in immune cell activity that makes it more likely for immune cells (in the process of responding to foreign elements) to inadvertently respond to similarly appearing “self” tissue — a breakdown of tolerance also known as molecular mimicry.

Failure to appropriately recognize “self” is a primary reason for the development of autoimmune conditions. Molecular mimicry refers to the inappropriate recognition and response to “self” after the presentation of a foreign antigen resembling “self” tissue. It is primarily an issue of improper self recognition. It is not a primary issue of choosing to respond or not respond to a foreign antigen.

Removing foreign antigens (viruses, bacteria, food particles, “fake-food components,” environmental toxins, etc) that are known or likely to contribute to the breakdown of the selectively permeable intestinal barrier and lead to an exaggerated immune/inflammatory response or the breakdown of the recognition of “self” through molecular mimicry appears both mechanistically, in animal and human studies, in anecdotal clinical evidence and early clinical human research to promote improved tolerance or recognition of “self”, and improved disease markers in many autoimmune conditions.

The context of antigen presentation is of utmost importance when considering the development of immune tolerance. Foreign antigens with similar structure to “self” are much more likely when presented in the context of acute or chronic inflammation to provoke an exaggerated or aberrant immune response that can lead to the disruption of self tissue or autoimmunity.

How does the immune system recognize foreign elements (aka, ingested food, bacteria, etc)?

Foreign element or antigen recognition is carried out by only a few types of immune cells in the body. These types of immune cells are known as antigen presenting cells or APCs. Utilizing specialized proteins and enzymes, these cells are able to sample elements taken from the external environment (think inside the gut or blood stream) and present them to other cells in the body ultimately asking the questions: 1) Is this a foreign element? 2) Should I mount an immune response against it?

We are coming to understand that these cells are critical to maintaining a balanced immune response and are often “malfunctioning” when it comes to the development or progression of autoimmunity or even certain infectious diseases.

CLICK TO EXPAND // More in-depth science on the mechanism behind foreign element or antigen recognition

The three main type of antigen presenting cells in the body are:

  1. Macrophage (“Big Engulffers”)
  2. B Cells
  3. Dendritic Cells

Just as we saw when it came to recognizing internal structures/proteins using the MHC-I nametag on all cells, these APC’s have another “nametag.” It is referred to as MHC-II, a twin to MHC-I.

Now the MHC-I “nametag” is a little different than the “MHC-II” nametag. Rather than present processed internal proteins, usually “self”, but sometimes virus or cancerous proteins, MHC-II is responsible for displaying external proteins or antigens- things taken up from the external environment.

APC’s and their MHC-II complex are tasked with presenting antigens taken up from the external environment. They communicate with effector T cells (CD-4) that then help to coordinate the immune response.

So what happens after the APC finds a foreign object and displays it on the MHC-II to the immune system? Really good question. This could be an entire blog or lecture series on its own, and I do not have enough time to go into detail about this process so I will summarize this very briefly.

The communicating effector (helper) T-cells can either coordinate a response that is primarily cellular - by recruiting more immune cells to help with the perceived insult or they can coordinate and recruit antibodies that are made from B-cells. In general, things (cell infected by a virus) that can be engulfed or killed effectively by cells will be responded to with a cellular response. Things that are large, cannot be engulfed or approached well by cells will be responded to with an antibody response. Think of the antibody attack as a bunch of little 5 year olds grabbing onto an adult, one of them alone can’t do it, so we get 4 or 5 to latch on to him to bring him down. I know silly analogy, but it works!

How do adverse food reactions relate to tolerance?

  1. Adverse food reactions, food intolerances and non IgE mediated food allergies represent a spectrum of clinical manifestations with a variety of underlying physiologic mechanisms. Having an adverse food reaction does not necessarily mean you have antibodies to that food or that your reaction to that food is mediated by the creation of antibodies in the first place.
  2. The temporary removal of whole food or whole food components is very unlikely to contribute to either a) the development or progression of autoimmune conditions, or b) development or worsening of clinically meaningful adverse food reactions, intolerances or non IgE mediated food allergies.

I think it is important to acknowledge that food reactions are real and different for every individual. It is also important to recognize two people with similar physical reactions or symptoms may actually each have very different physiologic responses happening at the level of the immune system.

For many people experiencing adverse reactions after the consumption of certain foods (perhaps after a period of dietary elimination), this is not necessarily a sign of an antibody response or permanent immune reaction to that food, it is actually a sign that the immune response in general is still too exaggerated or out of balance. It could be a sign that the selectively permeable intestinal barrier is not so selective and still leaky. Imagine if you are in the throws of an immune response with more immune cells than one would normally expect with a balanced immune system sitting ready to respond along the intestinal lining? Wouldn’t you think you would be more likely to respond negatively to foreign elements regardless of what it really was?

I completely acknowledge that this is anthropomorphising and generalizing a mechanism, but I simply want to make the point that what is actually happening within the immune system when it comes to adverse food reactions can vary from individual to individual and we cannot with 100% certainty know based simply on the outward physical symptoms.

The strong reactions to certain foods may simply tell us that we need more time to balance the immune response, restore the intestinal barrier, re-balance the gut microbiota, replete nutritional deficiencies, take time to calm down an overactive nervous system, and the list could go on and on.

CLICK TO EXPAND // A summary of why all the mechanisms and science behind autoimmunity are so important

You may be asking, “Why is he spending all this time talking about different mechanisms of tolerance? I thought all the focus and concern was on oral tolerance?”

It truly wasn’t meant to be a science rabbit hole for no reason.

I did it because I wanted to illustrate the key points of complexity and context. Tolerance you see is primarily involved with recognizing “self”. It is a continuous process that is complex -- it is not just about having intestinal permeability and “reacting” to foreign antigens. Breakdowns in tolerance or “self” recognition can occur for Genetic (rare reasons), issues with T reg cell function and the presentation of “self” antigen in the wrong context (location or setting).

Foreign antigens resembling self tissue presented in the context of an inflammatory response or in a state of gut dysbiosis are much more likely to lead to issues with self recognition and autoimmunity than if presented in a state of homeostasis, with a balanced gut microbiome, without pathologic intestinal permeability or significant inflammation.

Foreign antigens in the wrong context, should be responded too. Self antigens should not. You see this isn’t really an issue about improperly responding to foreign antigens, it really is an issue about root causes of chronic inflammation, disturbances to the gut and gut microbiome and confusing “self” for foreign after responding, one could argue, rather appropriately to the foreign particle.

I hope this line of thinking leads you to see that perhaps where we should start with treatments to address autoimmunity and allergy revolve around removing sources of chronic inflammation, restoring normal contextual immune environments, removing potential immune triggers that could lead to an exaggerated immune response or even induce molecular mimicry, and overall helping the immune system restore homeostatic flexibility and better recognize “self” (nutrient dense diets and restoring gut health are a wonderful place to start!)

Why is the term “oral tolerance” misleading?

This leads me to what you may have all been waiting for, an elaboration of the concept “oral tolerance”. As you saw already, I defined tolerance as recognition of “self”, so I will say first off that I do not like to use the term “oral tolerance” because it is misleading.

As I hope you have seen through my articulation of the immune system, what people really mean when they refer to “oral” tolerance, is a physiologically appropriate response to ingested foreign antigens. It is not referring the the immune system’s recognition or a response to “self”. The immune system is constantly interacting with the external foreign world (skin, nose, gut, blood stream, subcutaneous tissue, vaccines?) and being tasked to appropriately respond, and as we have already talked about before, there are a number of key factors that influence how the body still respond to these foreign elements.

CLICK TO EXPAND // Read more about the factors that your own immune system’s response to foreign antigens is dependent on

  1. Genetic variability of the MHC-I and MHC-II complexes (for MHC-II that’s where we see the DQ-2, DR-4 come into play -- many of you all have probably heard of this before).
  2. Context is another huge factor. If the immune system encounters something it is used to seeing in the gut, but now it is in the blood, it will likely respond in a different manner. Sources of chronic inflammation including gut dysbiosis, metabolic and blood sugar imbalances, damage to blood vessels, inadequate sleep, inadequate recovery from exercise, just to name a few change the context and environment of the immune system, thus, making it more likely that it will respond in an inappropriate fashion.
  3. Timing of antigen presentation is also critical as we begin to see that neonatal and early life exposures to certain foreign elements can predispose those children to either the development of allergic disease or to having minimal to no risk of reactivity. There appears to be a critical and somewhat irreversible window of exposure and development of the immune system in infants, such that, if an adult is exposed to the same spectrum of foreign elements later in life, they will not respond in the same way. Context and timing matter!

And if that wasn’t enough, it is beginning to appear that the gut microbiota may play an incredible role in determining how “our” immune system responds to foreign elements. Studies are beginning to show that modulation or perturbations in the gut microbiome are associated with allergic disease such as atopic dermatitis and IgE food allergies such as peanuts.

We are beginning to understand that proper, early colonization of the GI tract and the health/diversity of the gut microbiota is vitally important to the development of adverse food reactions or intolerances as well as immunologically identified food allergies and clinical autoimmune disease. Clinical research is beginning to illustrate how modulation of the gut microbiome can prevent or help reverse allergic disease.

Why the term “oral tolerance” is a red herring

There is NO science that I can find to support that the temporary removal of whole food such that is done with the Autoimmune Protocol diet is detrimental to an organism or decreases the organism’s resilience to foreign elements.

When we look back evolutionarily and think about context once more, we can begin to realize that what we should be concerned about when it comes to generating appropriate immune responses is not temporarily removing whole foods (like the Autoimmune Protocol), it’s introducing incredibly novel chemicals and non food stuffs into our internal environment. Structurally and chemically speaking, there is much more novelty between Cheetos and Pop Tarts than there is in Granny Smith apples and oranges, and which do you think our immune system has been exposed to over thousands of years?

Focus on the treatment, prevention or reversal of autoimmune disease given our current understanding of the disease process and contributing root causes should include:

  1. Temporary removal of potentially immunogenic stimuli or foods with strict limitations on novel foreign stimuli.
  2. Removal of root sources of chronic inflammation.
  3. Restoration of a balanced gut ecosystem through lifestyle habits and additional measures that may include prebiotic fiber, probiotics, herbal or prescription antimicrobials or in extreme cases fecal microbiota transplant.
  4. The promotion of the optimal maturation of the early immune system by supplying infants with breast milk, whole foods, and minimizing toxic exposures including antibiotics and pharmaceuticals that could disrupt the gut ecosystem.
  5. Promotion of homeostatic flexibility within the immune system, (aka balance between cellular and antibody responses as well as adequate T regulatory cell function).
  6. Promotion of healthy social relationships and reflective practices, minimizing the burden of health, relational, financial and work stress and promoting compassionate interactions that foster connection and love.

Final Remarks

Hopefully you are starting to see now how complex the immune system is, and to simply think about one area such as “oral tolerance” as it relates to overall health or autoimmune disease is myopic and potentially harmful.

I will not stand for fear based and pseudoscientific writing and wish to present knowledge in an accessible and relevant format.

I hope you have found this article both fun to read and enlightening for your health journey. Please let me know if you have any thoughts, questions or comments or the topic, for as I said before, I am learning just like you!

About Rob Abbott, M.D.

Rob Abbott, M.D. is Autoimmune Wellness's resident Medical Advisor. He is a family medicine resident at the Virginia Commonwealth University, Shenandoah Valley Family Medicine Residency Program in Front Royal, Virginia and is a graduate of the University of Virginia (U.Va.) School of Medicine where he served as a student ambassador for the U.Va. School of Nursing’s Compassionate Care Initiative, promoting resilience, compassion and self-care. Rob has completed training with the Institute for Functional Medicine, is a Kresser Institute ADAPT Level 1 trained clinician, and is an AIP Certified Coach. He is also the medical director of the newly formed Charlottesville Center for Functional Medicine. Rob approaches medicine from an evolutionary and functional perspective and practices what he calls “spiritually focused and evolutionarily informed functional medicine.” In his free time, Rob enjoys creative expression through writing, sharing blogs, poetry and podcasts through his website amedicinalmind.com.

3 comments

  • Thank you so much for this explanation, clear and to the point. I’ve had chronic psoriasis 50 years, thyroid issues 35 years, asthma 30 years (epilepsy as far as I know not autoimmune). I followed AIP and reintroduced everything except dairy and gluten. My life has been transformed on a try and see basis. Some insight into the science is great.

  • Sandra says

    Thank you Dr Abbot for the informed article on “oral tolerance” and AIP. I have been doing AIP for 3 months now and have had concerns about becoming less tolerant to eliminated foods. And am a 53 yr olds woman with past history if thyroid cancer total thyrodectomy, RA and recently diagnosed with onset of systematic scleroderma. I am working with a function medicine dr who advised me to supplement with collagen protein. But I found that my symptoms of raynauds was getting worse. I researched the disease in-depth and discovered that with SSc I have an over production of collagen that is damaging my connective tissue. So I made the conclusion that I should not be taking supplemental collagen. Am I correct in assuming this?

  • Zana says

    Thank you Dr Abbott. This was a well written, easy to follow explanation which I much needed in my journey through AIP.
    The more detailed scientific explanations were just perfect for my level of understanding. Please keep articles like this coming.

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