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
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’s 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 processes 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 a cancerous cell. (Read below to learn how this actually occurs in the body!)
CLICK TO EXPAND // Read more in-depth science about tolerance
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 an 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
How do adverse food reactions relate to tolerance?
- 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.
- 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
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?) 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 responds 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
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:
- Temporary removal of potentially immunogenic stimuli or foods with strict limitations on novel foreign stimuli.
- Removal of root sources of chronic inflammation.
- 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.
- 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.
- Promotion of homeostatic flexibility within the immune system, (aka balance between cellular and antibody responses as well as adequate T regulatory cell function).
- 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.
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!