Dendritic cells are the ultimate teachers of the immune system, and they make learning about friends and foes relevant for the soldier cells. It may seem simple enough to distinguish between self and strangers. Actually, it is a very intricate process, that generally works well. This is essential for autoimmunity and allergy risk.
Fascinating dendritic cells and why they are the ultimate teachers
Antigens are structures that are able to elicit an immune response. They can be fragments of complex molecules like proteins for example. Dendritic cells have the ability to extract these structures from complex substances (i.e., ingest the microbe, break it down and keep the relevant antigenic part). Why would dendritic cells do that? This is because they are part of the innate immune system and they work as antigen presenting cells (APCs). That means they teach the adaptive immune cells to recognise and fight invaders that contain those antigenic structures. Dendritic cells teach by presenting antigens on their surface. Dendritic cells are not the only antigen-presenting cells, but they are the most efficient (they are ‘professional’ APCs).
The Greek work ‘dendros’ means tree. So, you can imagine the dendritic cells as tree-like structures because they have branching projections. This shape helps dendritic cells to reliably feel what is in the environment and to get into contact with many soldier (adaptive) cells simultaneously.
Where can we find dendritic cells?
Dendritic cells migrate from the bone marrow to different tissues in the body where they act as sentinels. They normally stay in their new homes and do their environment monitoring job. However, they are able to leave those tissues and migrate into immune organs such as lymph nodes, when chemical signals associated with inflammation are present (1). Inflammation represents immune activation, and this is the consequence of danger signals. So, when there is a ‘war’ going on (an intruder is present), dendritic cells go back to headquarters and report on what they have found in the peripheral tissues where they reside. In the lymph nodes is where soldier-cells are instructed and presented with a sample of the intruder, so they can specifically recognise and attack it. This presentation by dendritic cells also occurs in the tissue where the ‘invasion’ occurred.
Thus, dendritic cells, an important player in the innate immune system, are also at the interface with the adaptive immune system. We can now appreciate their role in immune dysregulation like allergies or autoimmunity. The latter are adaptive immunity ‘malfunctions’ because the targeted attack is learnt and specific (i.e., antibodies against a specific self tissue structure, or against a harmless substance from the external environment like pollen or foods). However, to establish this immune response, the soldier cells need to learn that the specific self or environmental antigen is an ‘enemy’. And where do they learn from? The antigen presenting cells – and especially the professional ones, a.k.a. dendritic cells (2). This process is important both in autoimmunity development, and also in autoimmune flares. We’ll see below the practical importance of knowing this.
Antigen presentation
The immune system is akin to an army. Thus, intelligence (or information) is essential to the fulfilment of the defence function. Can you imagine an army where mere soldiers take it upon themselves to decide who is the enemy? Or can you imagine attack orders based on information from random sources? Neither of these scenarios is likely. Just like that, the body carefully regulates immune function. Adaptive immune cells that directly attack intruders or that produce antibodies against intruders, need to follow orders. They need instruction first. Enter dendritic cells, the ultimate teachers of the immune system.
First, the dendritic cell extracts the antigen from bacteria, viruses, damaged cells or other foreign structures. Then, it takes the antigen to its surface where it presents it on a ‘silver tray’ to adaptive immune cells. The silver tray’s name is the major histocompatibility complex (MHC) and is essential for the elicitation of the immune response. Hence, the teacher with the tray is essential (yes, that’s the dendritic cell!). MHC molecules come in two different types. Each type can have different structures among individuals. The difference in MHC molecules in different individuals is one of the contributors to the variation in autoimmunity risk in the population (3).
In conclusion, adaptive immune cells learn about antigenic structures when they find them on the surface of APCs like dendritic cells, in conjunction with MHC molecules. Furthermore, the adaptive cell can learn to either attack or tolerate the structure on the tray. They do that by perceiving secondary signals on the surface of the dendritic cell. An extra factor influencing the immune response triggered in adaptive cells, is the chemical environment where and when the antigen presentation occurs (which inflammatory mediators the dendritic cell itself produces and releases) (4).
The crucial secondary signals for the ultimate teachers, dendritic cells
As suggested, dendritic cells, these ultimate immune teachers, will present whatever they find in their environment. Some of this process will be akin to pleasant introductions: ‘Here is our friend or family member; let’s make sure we don’t hurt them!’. That equals immune tolerance. Other situations will be like police publishing a ‘wanted’ poster for a criminal. If the dendritic cell perceives signals in the environment that what it can find are offender structures, then, in turn, it will convey the danger signal to the adaptive immune cells at the time of antigen presentation (publish the criminal poster). Thus, the extra signals dendritic cells produce when they present antigenic structures, will tell to the rest of the immune cells if what is presented is an enemy (4).
So, what are the environmental structures that signal danger to the dendritic cells? These can either be microbial (pathogen) structures, or damaged self structures (5). The former are structural patterns that are never normally present in human tissues, so are foreign by definition. The latter can be, for example, substances that are normally only found inside cells. So if they are detected outside cells, then obviously something is killing the body’s cells and their content is spilled out. There is another process of programmed and controlled cell death, which is normal. Unlike in infections, the sequence of events in programmed cell death doesn’t lead to spilling out intracellular structures.
If dendritic cell receptors detect these pathogen or damage patterns inside the body, then there is obviously an attack to react to. Thus, this detection and the subsequent reaction are very important for self defence. However, this process can cause problems in certain circumstances.
How can a process designed for defence, become deleterious?
Imagine the infection scenario. Pathogen detected, cells destroyed by the infection. Dendritic cells perceive the danger. Dendritic cells act as the ultimate teachers and go and activate adaptive immune cells to fight against the antigens they present them with. That is normal and is exactly what the body needs to mount a strong response against the invading microbes.
However, local dendritic cells will also gobble up and extract antigens from the host tissues destroyed at the place of injury and they will also present these to adaptive immune cells (2). However, this time it won’t be the friendly introduction that would normally apply to self tissues. This time, the dendritic cells are primed for war, and they convey danger signals to protect the body.
Guess what may happen if self antigens are presented as enemies? This may initiate autoimmune processes. It may also cause autoimmune flares where the auto-reactive cells (those that produce the destruction in autoimmune inflammation) had been quiet and now are reactivated.
Further considerations on reactions to environmental factors
A similar process of innocent bystander targeting can happen at the interface with the external environment. For example, the gut lining is exposed daily to numerous foreign substances – mainly foods and their contaminants. So, it is subject to close surveillance by the immune system. An immense number of immune cells reside under the intestinal lining, continuously scanning for intruders into the internal environment. Moreover, local dendritic cells extend their projections between intact intestinal cells towards inside the digestive tube where food processing happens (6). If there is excessive intestinal permeability, these food antigens can also get into the internal environment where dendritic cells engulf them.
What happens if there are pathogenic microbes in the gut, or if microbes reside in portions of the intestine where they shouldn’t be present (i.e., in the small intestine, where food is in the process of being broken down for absorption – small intestinal bacterial overgrowth, or SIBO)? You may have guessed: the dendritic cells that sample the intestinal content will process food particles, and if primed for danger by the local microbes, they will, in turn, instruct immune cells to react to foods. Immune reactions to foods are born.
What can one do about these risks?
There are many ways in which the immune system fights intruders. Some are adaptive mechanisms, meaning the immune cells learn exactly how the specific intruder they are fighting against, looks like. Others are innate defences, when intruders are detected and directly engaged without a precise identification. Whilst the targeted adaptive mechanisms can be more efficient than innate ones, so far we have discussed some of the risks that may come with adaptive immunity. In cases of autoimmunity, an adequate innate response would be desirable. This would contribute to early elimination of infections and it would also clear up self cell debris to avoid risky antigen presentation (7).
Another strategy would be to promote those immune cells associated with tolerance (8) (i.e., not fighting diverse antigens, but tolerate them). This is essential in the discrimination between self and non-self, food tolerance etc. The immune mechanisms are very complex, and many pathways contribute to the end result of immune stimulation. Furthermore, several internal and external factors may determine the predominant type and subtype of immune cells. Fine tuning interventions would require professional input. However, as a starting point, just focusing on practical applications, some simple suggestions are provided below.
Also, a very logical measure would be to avoid infections altogether. This may translate to many diverse measures. Pertinent to the above discussion, we might want to ensure a healthy intestinal flora (9) (microbes that normally reside in the gut) and to avoid colonisation of those portions of the digestive tract that should be largely microbe-free (mitigate SIBO).
Practical applications – how can we manipulate the outcome of dendritic cells’ ultimate teacher function
To achieve the above objectives, some of the measures we might consider are (and this is not an exhaustive list):
- A healthy, diverse diet, with plenty of colourful, fibre-rich plant foods; this should promote a healthy intestinal flora. Not all foods are healthy for everyone, but this is a further refinement.
- Ensuring adequate production of stomach acid which will sterilise the foods that reach the small intestine. This may translate to adequate levels of zinc in the body (10). To address this, we use testing and adjusting the diet composition or even using supplements. Or, it may involve more sophisticated investigations and corrections.
- Normal secretion of bile from the liver will also kill unwanted microbes, alongside other relevant functions including in gut motility. There are many ways to assess this and correct any dysfunction. However, a very simple measure is to ensure adequate water intake.
- Ensuring good motility of the intestine so that microbes do not proliferate excessively in the small intestine (11). This may involve stress management and eating meals in a state of relaxation, as well as adequate fasting for a few hours between meals, alongside other specific interventions based on tests.
- Testing vitamin D levels and supplementing if needed to achieve optimal levels. Vitamin D is important for a robust innate immune function and for immune tolerance, among other functions (12).
- In the same vein of promoting tolerance-inducing cells, a very simple measure is avoiding excess salt (13).
In conclusion
The immune function is essential to health. Whilst it is very complex, there are ways to manipulate it for the benefit of each person.
Dendritic cells are the ultimate teachers of the immune system. They are at the interface between innate and adaptive immune responses, and their function is relevant in autoimmunity and allergy.
Complex diet and lifestyle interventions are important immune modulators and can bring significant benefits for people with autoimmunity and allergy risks. Beyond very basic healthy lifestyle measures that can be easily applied, these interventions, however, should be targeted and guided by a trained doctor.
At The Allergy-Immunology Doctor, we invest a vast amount of time to perform comprehensive assessments. We use cutting-edge laboratory testing where deemed necessary. And, we leverage our expertise and skills to design the most effective interventions to optimise immune function (thus health in general!) taking advantage of conventional approaches and also of the extensive Functional Medicine toolkit.
If you would like to find out more about ways in which we can help you with your health concerns, you may want to book a free discovery call:
References:
1. Flores-Romo L. In vivo maturation and migration of dendritic cells. Immunology. 2001 Mar;102(3):255–62.
2. Worbs T, Hammerschmidt SI, Förster R. Dendritic cell migration in health and disease. Nat Rev Immunol. 2017 Jan 1;17(1):30–48.
3. Fernando MMA, Stevens CR, Walsh EC, De Jager PL, Goyette P, Plenge RM, et al. Defining the Role of the MHC in Autoimmunity: A Review and Pooled Analysis. Fisher EMC, editor. PLoS Genet. 2008 Apr 25;4(4):e1000024.
4. Fucikova J, Palova-Jelinkova L, Bartunkova J, Spisek R. Induction of Tolerance and Immunity by Dendritic Cells: Mechanisms and Clinical Applications. Front Immunol. 2019 Oct 29;10:2393.
5. Dalod M, Chelbi R, Malissen B, Lawrence T. Dendritic cell maturation: functional specialization through signaling specificity and transcriptional programming. EMBO J. 2014 May 16;33(10):1104–16.
6. Schulz O, Jaensson E, Persson EK, Liu X, Worbs T, Agace WW, et al. Intestinal CD103+, but not CX3CR1+, antigen sampling cells migrate in lymph and serve classical dendritic cell functions. J Exp Med. 2009 Dec 21;206(13):3101–14.
7. Lleo A, Selmi C, Invernizzi P, Podda M, Gershwin ME. The consequences of apoptosis in autoimmunity. J Autoimmun. 2008 Nov;31(3):257–62.
8. Tan D, Yin W, Guan F, Zeng W, Lee P, Candotti F, et al. B cell-T cell interplay in immune regulation: A focus on follicular regulatory T and regulatory B cell functions. Front Cell Dev Biol. 2022 Sep 23;10:991840.
9. Kinashi Y, Hase K. Partners in Leaky Gut Syndrome: Intestinal Dysbiosis and Autoimmunity. Front Immunol. 2021 Apr 22;12:673708.
10. Liu J, Kohler JE, Blass AL, Moncaster JA, Mocofanescu A, Marcus MA, et al. Demand for Zn2+ in Acid-Secreting Gastric Mucosa and Its Requirement for Intracellular Ca2+. Sestak K, editor. PLoS ONE. 2011 Jun 15;6(6):e19638.
11. Avelar Rodriguez D, Ryan PM, Toro Monjaraz EM, Ramirez Mayans JA, Quigley EM. Small Intestinal Bacterial Overgrowth in Children: A State-Of-The-Art Review. Front Pediatr. 2019 Sep 4;7:363.
12. Cyprian F, Lefkou E, Varoudi K, Girardi G. Immunomodulatory Effects of Vitamin D in Pregnancy and Beyond. Front Immunol. 2019 Nov 22;10:2739.
13. Hernandez AL, Kitz A, Wu C, Lowther DE, Rodriguez DM, Vudattu N, et al. Sodium chloride inhibits the suppressive function of FOXP3+ regulatory T cells. J Clin Invest. 2015 Oct 20;125(11):4212–22.
