Immune Tolerance: Understanding the Basics

A healthy immune system eclipses the best military minds in strategy, organization, intelligence, and central command on the biological battlefield. 

Conveniently the Art of War can help us remember not just the immune system's military-like skill, but also its three fundamental strategies:  Avoidance, Resistance, and Tolerance. (And the classic book is good, too). 

When the immune system notices antigens from food, commensals, or the environment, resistance could be more harmful than simply letting them be. This is true to an even higher degree for self-proteins, which are already behind the barriers, and so we cannot avoid them. The best immune strategy in these cases is intentional non-responsiveness, AKA tolerance. 

Immune tolerance is active, highly regulated unresponsiveness of the immune system to self-antigens or against a particular antigen that can induce an immune response in the body. It is how the immune system issues stand-down orders, and our lives depend on tolerance functioning reasonably well.

Tolerance is critical because a truly “strong” immune system that pounces on everything is deadly.

Autoimmune diseases and allergies occur when immune tolerance dysfunctions. Babies with IPEX syndrome, a genetic disorder of extremely dysfunctional immune tolerance die in just a few years from systemic autoimmunity without aggressive intervention. Humans require a balanced immune system with a heavy dose of tolerance to survive, so you won’t hear immunologists promoting ways to indiscriminately “boost” or “strengthen” your immune system. 

Immune tolerance is generally divided into two major pathways: central tolerance and peripheral tolerance. 

Central tolerance is the immune system’s method of testing new adaptive immune cells to weed out those that are overzealous. For T cells, it happens in the thymus, and for B cells it happens in the bone marrow, as part of their development.

In successful central tolerance cells that recognize potential threats are deployed into circulation, dangerous cells that strongly react to self are retrained or killed, and some T cells that recognize self are trained to induce tolerance; these are called T Regulatory Cells (TRegs).

But central tolerance is not enough. 

There are far too many antigens for everything to be tested during central tolerance, and in mouse studies, we see central tolerance is imperfect, even in healthy mice. Thankfully, adaptive immune cells that passed their tests and enter circulation as naive cells can continue to learn to respond appropriately on the job through peripheral tolerance.

Peripheral tolerance refers to all the ways the immune system can prevent immune cells that recognize self, helpful, or benign antigens from causing harmful immune responses. Peripheral tolerance tactics include deleting cells, disarming cells (called anergy), issuing stand-down orders via TRegs (suppression), or training T cells to become TRegs themselves, now responsible for reducing resistance responses instead of promoting them.

Does immune tolerance matter if you have IBS or  GERD? 

Tolerance is paramount in the gut, where so many antigens from food and commensals exist. But it can be lost. Local intestinal immune reactions to dietary antigens may cause abdominal pain in those with IBS, although more research is needed--especially on how to most practically and accurately measure these responses. Importantly, lost or dysfunctional immune tolerance also plays a role in several conditions that may manifest in IBS-like symptoms, such as celiac disease, or GERD-like symptoms, such as eosinophilic esophagitis.

Here are six simple steps you can take (and might already be doing!) to promote appropriate immune tolerance.

1. Support your barriers. 
2. Eat a varied, balanced, and sufficient diet. That means not just sufficient fruits and vegetables, but also the basics: Calories, fats, carbohydrates, and protein. All forms of malnutrition could negatively affect immune function.
3. Optimize your vitamin and mineral levels with foods and if necessary, supplements recommended by your healthcare provider when they identify low levels. TRegs and other immune cells’ function depends on total nutrient sufficiency and a wide variety of vitamins and minerals, but especially vitamins A and D.
4. Monitor your vitamin and mineral levels on lab work with your healthcare provider to catch deficiencies, especially if you have had bariatric or intestinal surgery, or are following a restricted diet.  
5. Do not DIY an elimination or low FODMAP diet on your health journey. Work with your physician and RDN to help you do so strategically and sufficiently, with the appropriate testing to confirm diagnoses like EoE or Celiac disease at the right time, if necessary. Prebiotics, present in many high FODMAP foods, may affect commensal microorganisms that influence immune tolerance in the gut, although more human studies are needed to better understand. So while the low FODMAP diet can be very helpful to identify problematic carbohydrates, it is important to implement it correctly and use it for the shortest time possible. 
6. Speak with your dietitian or healthcare provider about whether probiotics or probiotic-rich foods are right for you. For those who suspect dysbiosis, it's important to speak with your healthcare provider about whether testing for and treating infections or SIBO might be important for you. The oral and gastrointestinal microbiota make up a large number of the antigens in the GI tract that influence immune tolerance in the gut. 

Stay tuned for close-ups on immune tolerance in the gastrointestinal tract and T Regulatory cells!

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