A few weeks back I spoke at the Microbiome 2.0 Symposium, part of the Personalized Lifestyle Medicine Institute’s Mastering the Implementation of Personalized Lifestyle Medicine series. This was one of the first live events that I have attended since March of 2020! I was tasked with teaching on a variety of topics, but my first lecture focused on the gut-immune interface. As part of this lecture, I included a few slides designed to remind the clinician audience how the immune system interprets self from non-self, or more specifically, harmful vs. non-harmful encounters.
This, of course, included a little of what we were all taught in school: that the immune system is easily divided into the innate immune system and the adaptive immune system. I also included information about how various internal and external antigens are presented to immune cells (via MHC class I and II etc.) and how this helps the adaptive immune system (i.e., B and T cells) to select which antibodies or T cells will respond to the threat. Now, before your eyes glaze over or you cringe attempting to remember what you learned from your immunology course(s) years ago, I am here to say they got a few things wrong. The simplistic way we have understood these two “systems” has been radically shifting and our nomenclature needs to catch up.
A few decades back, I did my PhD dissertation on the process by which naïve B and T cells rearrange their DNA to convert a finite number of gene segments into an almost limitless number of antigen binding sites (a process known as VDJ recombination). Once a B or T cell expresses a functional immunoglobulin or T-cell receptor gene (most don’t and are eliminated) the expressed protein binds to a very limited set of structures. This is why we say the adaptive immune system has great specificity.
However, these cells cannot “adapt” much at all. For instance, if a B-cell produces an antibody that recognized a self-antigen, this B-cell must be neutralized (it can’t adapt, it can’t be retrained). And even though B-cells can produce various types of antibodies (IgM, IgG, IgA, etc.), this process (known as class switching) is also a unidirectional process which can’t be reversed and is directed by signals from T-helper cells. But where do the T cells get their instructions and how do they know friend from foe or what type of response to trigger when a threat is detected? All of this requires the innate immune cells!
So, while the cells within the adaptive immune system produce high levels of specificity, they do this before encountering antigens and they are pre-programmed to respond to signals coming from the innate immune system. Ironically, the innate immune cells with their plethora of pattern recognition receptors (PRRs), most notably toll-like receptors (TLRs), allows them to create a highly adaptive response; especially in their communication with T cells and B cells as they direct the immune response.
In fact, TLRs on dendritic cells (the master innate immune cells at the gut interface) regulate nearly every aspect of antigen presentation, including how the antigen is processed, how the MHC proteins are expressed and the types of cytokines expressed to tell the T-helper cells how to respond.1 Using these PRRs to recognize a variety of antigen molecular patterns (e.g., cell wall, spike proteins, nucleic acid patterns and more), dendritic cells can adapt their response and help trigger the appropriate cells within the more rigid “adaptive” immune system.2,3 I was just minutes before getting on stage when the thought “the innate immune system is much more adaptive than the adaptive immune system” hit me!
Now that you have picked yourself off the floor from reading this revolutionary idea, what implications does this have? Well, our conference was called “Microbiome 2.0: New Updates and Practical Approaches in Treating the Gut-Immune Interface” for a reason. The gut-immune interface is the primary location the immune system learns to recognize friend vs. foe; and it must do so while interacting closely with all of these “non-self” organisms in the gut. It is the adaptive ability of the innate immune cells, with all their pattern recognition receptors, that trains and tweaks the immune response. And since our gut microbiota is constantly changing (adapting?) to the environment around us, their constantly changing interaction with the innate immune cells allows for a constantly adaptive immune response.
This process takes decades and progresses from early childhood; and is influenced greatly by the introduction of antibiotics and what is usually called the “hygiene hypothesis.”4,5 The role of lifestyle, diet, stress, access to sunlight and a host of other factors that influence the gut microbiota are critical in the process that creates a balanced response to a hostile world—a world that is hostile enough even with a properly trained immune system.
- Watts C, West MA, Zaru R. TLR signalling regulated antigen presentation in dendritic cells. Curr Opin Immunol. 2010 Feb;22(1):124-30.
- Dolasia K, Bisht MK, Pradhan G, Udgata A, Mukhopadhyay S. TLRs/NLRs: Shaping the landscape of host immunity. Int Rev Immunol. 2018 Jan 2;37(1):3-19.
- Corridoni D, Simmons A. Innate immune receptors for cross-presentation: The expanding role of NLRs. Mol Immunol. 2019 Sep;113:6-10.
- Shekhar S, Petersen FC. The Dark Side of Antibiotics: Adverse Effects on the Infant Immune Defense Against Infection. Front Pediatr. 2020 Oct 15;8:544460.
- Pfefferle PI, Keber CU, Cohen RM, Garn H. The Hygiene Hypothesis - Learning From but Not Living in the Past. Front Immunol. 2021 Mar 16;12:635935.
Thomas G. Guilliams, PhD
Thomas G. Guilliams, PhD (Tom) earned his doctorate in molecular immunology from the Medical College of Wisconsin in Milwaukee. For the past two decades, he has spent his time investigating the mechanisms and actions of lifestyle and nutrient-based therapies, and is an expert in the therapeutic uses of dietary supplements. Tom serves as an adjunct assistant professor at the University of Wisconsin School of Pharmacy and was the VP of Science for Ortho Molecular Products for 24 years (he now serves them as a consultant). Since 2014 he has been writing a series of teaching manuals (Road Maps) that outline and evaluate the evidence for the principles and protocols that are fundamental to the functional and integrative medical community. He is the founder and director of the Point Institute, an independent research and publishing organization that facilitates the distribution of his many publications. A frequent guest-speaker, Dr. Guilliams provides training to a variety of health care disciplines in the use of lifestyle and natural medicines. He lives in the woods outside of Stevens Point, Wisconsin with his wife and children.