An overview of the highly sophisticated immune system – Ian Craig

The modern view of immunology seems to revolve around a narrative of ‘killing the bugs’, but the reality is that our bugs outnumber our own cells by a large magnitude. So, according to Ian Craig, we should pay more attention to nourishing our highly complex immune system, meaning that it helps if we have some understanding of how it works! 

Because it has so many working parts, the immune system is perhaps the most complex piece of physiology you will ever try and understand. The aim of this article, therefore, is to give you a relatively brief overview of how the immune system actually works in regards to its component parts. 

We’ll start with a reference to the remarkable mind of Dr Alex Concorde; a British medical doctor and psychoneuroimmunologist who gives a highly eloquent, clear and concise explanation of the immune system. Interestingly, she considers the immune system to be a hologram of everything going on in our lives.  

The overall immune system can be divided into the innate and adaptive systems, two systems that work fluently and synergistically. The innate system is non-specific, but fast, whereas the adaptive system is highly specialised, but slow to get going. To give a working example of these systems, Dr Concorde has used the superb analogy of the operations of a police force. The ‘bobbies on the beat’ (the general patrolling police force) are the non-specialised police officers who are already on the ground, and who can get to the crime scene extremely quickly – if it is just some petty crime (in immune terms, low-risk microorganisms that are normally in our environment), the general police officers (innate immune system) can deal with the problem themselves. If, however, it is a highly unusual and large scale criminal event, such as the London Underground train terrorist bombings in 2005 (in immune terms, something like the novel Covid-19 virus), the bobbies on the beat will do as much as they can to secure the crime scene(s), but they also have the important job of sharing the situation with their more specialised units (the adaptive immune system). 

The specialist arm of the police force (e.g. terrorist squad) must acquire as much information about the new threat as possible, train up its officers on this novel threat, then dispatch officers who will attempt to intercept the criminals. This scenario can, in some cases, become complicated and prolonged, such as in the case of Covid-19 and other potentially serious (novel) infections that the body has never been exposed to before. Referencing the ‘germ’ versus ‘terrain’ theory (Needes, 1994), the terrain represents the immune system within our body (our police force in this analogy). If you have a highly efficient police force that is well paid (nourished) and trained, threats to your body should not progress very far. If, on the other hand, like in many third world countries, your police force is low in numbers, under-paid, and susceptible to bribes from the criminals, some sort of dis-eased state will follow in time.

The innate immune system

The innate immune is a complex and ancient first line system of host defence. As a concise overview of the innate immune system, please consider Figure 1 from the work of Gleeson et al., 2013. Before delving into the cellular components associated with the innate immune defence, it is appropriate to consider the physical barriers and chemical factors that are often overlooked. For example, stomach acid may not be an obvious part of our immune system, but the state of hypochlorhydria (low stomach acidity) immediately increases the vulnerability of our body to infection because a low pH is one of the early defence barriers to bugs (Filardo et al., 2022). Certain bacterial pathogens, such as Escherichia coli, Salmonella Typhimurium, and H. pylori are capable of circumventing the acidic conditions of the stomach by developing adaptive mechanisms that allow these bacteria to survive in acid environments (Filardo et al., 2022), but they need to be able to get into the body in the first place, so the state of hypochlorhydria may represent the beginnings of gastrointestinal (GI) and immune dysfunction. Microbes are sensitive to acid in general, and all physical surfaces and defence mechanisms are naturally slightly acidic, including our skin, ears, saliva during eating, and urine (Bono and Reygaert, 2019).

Figure 1 – Overview of the innate immune system, recreated with permission; Figure 2.1 from Gleeson, M., Bishop, N.C. and Walsh, N.P., Editors (2013). Exercise Immunology. Routledge.

Other physical barriers obviously include the skin (cuts and wounds are a potential route of entry), which also has its own colonies of friendly bacteria. Additionally, all mucosal membranes in the body are actually external barriers to our interior health, the largest of which is our GI tract, followed by our respiratory tract. What’s more, pancreatic enzymes and bile salts are also toxic to microbes, and the rhythmic action of peristalsis is required to remove potential pathogens from the gut. Taste and smell are also part of our defence force, which when combined with experience and intuition, allow us to avoid exposure to infected foods and substances. 

Soluble components include complement, lysozyme, cytokines, acute-phase proteins, lactoferrin, among others. Complement acts as a rapid and efficient immune surveillance mechanism to control infection and also to stimulate a T- and B-cell response (acquired system) and generation of antibodies (Daha, 2011). Lysozyme is a special enzyme found in tears, saliva, sweat, and other body fluids, which breaks down bacteria that attempt to enter our body through these passageways. Cytokines, which will be discussed in more detail later, are inflammatory mediators that play a role in the innate (and adaptive) immune response by means of direct mechanisms against the invading agent (e.g. inhibiting viral replication) or by activating a cellular response. Acute phase proteins are up-regulated by inflammatory cytokines, which mediates systemic effects such as fever, leukocytosis, increased cortisol and decreased thyroxine, plus a suppression in serum iron, and many others. Lactoferrin is present in breast milk, with its highest concentration in colostrum – it has antimicrobial, antiviral, and antibacterial properties. Lactoferrin also has the ability to bind free iron, which could otherwise be used for microbial proliferation. 

All blood cells originate from the bone marrow – stem cells are produced, which then differentiate into erythrocytes (red blood cells), platelets and leukocytes (white blood cells). There are three types of leukocytes: granulocytes (60–70% of total number), monocytes (10–15%) and lymphocytes (20–25%) (Jeukendrup and Gleeson, 2019). 

Granulocytes, part of the innate defence system, can be subdivided into neutrophils (the most abundant), eosinophils, basophils and mast cells. Neutrophils are phagocytes with degranulation capabilities, while eosinophils, basophils and mast cells destroy pathogens primarily by degranulation. 

Monocytes, also part of the innate immune system, after their production from stem cells, circulate in the bloodstream and spleen for about one to three days and then typically move into tissues throughout the body, where they differentiate into macrophages and dendritic cells. Monocytes and macrophages are often discussed interchangeably in the literature, but put simply; monocytes are macrophages in the blood and macrophages are monocytes in the tissues. They serve three main functions in the immune system; phagocytosis, antigen presentation to the adaptive immune system via the presentation of toll-like receptors (TLRs), and cytokine production, forming a fundamental basis of illness and injury response (Chiu and Bharat, 2016). 

There are three kinds of lymphocytes; natural killer cells (innate immunity), plus B-cells and T-cells (adaptive immunity), which will be discussed later. Natural killer (NK) cells are large granular lymphocytes that provide cytotoxic activity against virus-infected cells and forming tumours. They are unique in that they have the ability to detect and kill diseased cells without needing the cells to express antibodies or major histocompatibility complex (MHC) – this means a very rapid response time and a vital part of the innate immunity.

The adaptive immune system

As a concise overview of the adaptive immune system, please consider Figure 2 from the work of Gleeson et al., 2013. The cellular components of the adaptive immune system, the specialised police force described previously, are the B-cell and T-cell lymphocytes, which are derived from what are called multipotent hematopoietic stem cells in the bone marrow. This component of the immune defence, in contrast to the innate defence, is very slow because information needs to firstly be gathered about the new pathogen before these lymphocytes can be matured and put into action. In contrast, if the body has been exposed to that bug in the past, and ‘immunity’ gained, the next time the body is faced with the organism, the adaptive immunity is likely to respond so quickly that we’re not even aware of any infection. 

Figure 2 – Overview of the adaptive immune system, recreated with permission; Figure 2.6 from Gleeson, M., Bishop, N.C. and Walsh, N.P., Editors (2013). Exercise Immunology. Routledge.

B-cells are formed and matured in the bone marrow, hence the use of the letter ‘B’. Naive B-cells are circulated through the lymphatic system where they express membrane bound antibodies on their cell surface. When they encounter antigens that fit these antigen binding sites, they rapidly differentiate into memory or effector B-cells. Memory B-cells express the same membrane-bound antibody as the original naive B cell, whereas effector B-cells (also called plasma cells) secrete antibodies into the circulation at the lymph nodes, which can identify a wide range of antigenic organisms. Antibodies are also known as immunoglobulins, and this is the humoural aspect of the adaptive immune system. Five major immunoglobulin (antibody) classes have been identified: IgA, IgD, IgE, IgG and IgM, of which IgA is the most abundant. Immunoglobulins can’t kill antigenic cells directly, so they tag them ready for destruction by complement and cells of the innate immune system, plus they modulate inflammation by the signalling of cytokines.

T-cells are matured in the thymus, hence the use of the letter ‘T’, where they express T-cell receptors plus certain CD receptors depending on their differentiation (see below). Unlike B-cell antibodies, T-cell receptors only recognise antigens that are bound to MHC molecules, which are membrane-bound surface receptors on antigen-presenting cells (APCs), such as dendritic cells and macrophages.  

Very importantly, T-cells have to go through a selection process to ensure they can distinguish between self and non-self proteins in the body. They must be capable of binding only self-MHC molecules which are presenting a foreign (non-self) antigen, otherwise they are eliminated by apoptosis. Any dysfunction in this critical process may lead to an autoimmune condition, in which the body’s own cells become compromised. After selection, we end up with three types of mature T-cells: 

• T helper (Th) cells, which help with the activation of B-cells, Tc cells and other immune components.
• T cytotoxic (Tc) cells, which are responsible for removing pathogens and infected host cells.
• T regulatory cells, which help distinguish between self and non-self proteins. 

T helper cells need to be further differentiated. Th0 cells are naive Th cells that, depending on the antigen presented, will become Th1 or Th2 cells, which have been classified by the specific cytokines they secrete (Perkel, 2001). Th1 cells generate responses against intracellular pathogens such as viruses, certain bacteria and tumour cells – they primarily produce the pro-inflammatory cytokines interferon gamma (IFN𝛾) and interleukin 2 (IL-2). Th2 cells, which drives humoural immunity, generate responses against extracellular pathogens such as other types of bacteria – they primarily produce interleukins 4, 5, and 13, which are associated with the promotion of IgE and allergic responses, and interleukin-10, which has more of an anti-inflammatory response (Berger, 2000). The cytokine action of the Th1 and Th2 systems has been considered to be mutually inhibitive, meaning that they will stimulate production of that Th subset, and inhibit development of the other Th subset. This is a clever system, but it means that the immune system of certain people can become overactive on one side – for example, it is thought that cortisol may push the Th system towards Th2 dominance, and for this reason good diurnal rhythms (cortisol-melotonin relationship) are importance for Th balance. Many scientists believe that Th1 dominance is related to inflammatory and autoimmune conditions, whereas Th2 dominance is related more to allergies. 

However, if we stop right there in our understanding of the Th system, we might wonder why some people suffer from an allergic condition, such as eczema or asthma, and an autoimmune condition, such as inflammatory bowel disease or rheumatoid arthritis. Th17 cells, named for their production of IL-17, are now recognised as a third lineage of Th cells (Dong, 2006) because they are not dependent on the cytokines and transcription factors that mediate Th1 and Th2 cell development. The Th17 system can eliminate pathogens that are unaffected by Th1 and Th2, but because it is considered to be pro-inflammatory in nature, imbalanced production of these immune cells have been strongly implicated in autoimmune and inflammatory diseases (Weaver et al., 2013).

CD classification

The cluster of differentiation (CD) classification was introduced to immunology in 1982, allowing cells to be defined based on what molecules are present on their surface, which are often used to associate cells with certain immune functions. For example, all T-cells express CD3+, plus Th cells also express CD4+, whereas Tc cells express CD8+ molecules. Such nomenclature is part of advanced immunological study and therefore beyond the remit of this overview, but it has been mentioned to improve your understanding when you see mention of various CD types in the literature. 

Messaging of the immune system – cytokines

We will finish this classical overview of the immune system with a discussion of our third communication system within the body (alongside the nervous and endocrine networks of system integrations). Cytokines are peptides that are involved in within cell (autocrine), cell-to-cell (paracrine) and systemic (endocrine) messaging – they can be pro-inflammatory and/or anti-inflammatory in nature, and are involved in immune messaging, pain signalling (Zhang and An, 2007) and musculoskeletal function. Most athletes have two fears in their athletic life: injury and illness. You can see here that these two experiences have a larger crossover than we might otherwise think – both are mediated by an underlying pro-inflammatory cytokine response. In fact, we can extend further than injury and illness: it is now understood that inflammation forms the basis of many, if not ‘most’, states of health imbalance and disease. 

The predominant producers of cytokines are T helper cells and macrophages, although a broad range of other cells also possess this role (Zhang and An, 2007). Cytokines include: 

• Chemokines – attract cells to sites of infection/inflammation by chemotaxis 
• Interferons (IFNs) – produced as part of an inflammatory response to infection, and have an anti-viral role
• Interleukins (ILs) – have an important role in inflammatory/immune responses, and also regulate cell growth, differentiation, and motility. 
• Tumour necrosis factors (TNFs) – involved in immune/inflammatory responses, and also proliferation, differentiation and apoptosis

Pro-inflammatory cytokines are produced predominantly by activated macrophages and include IL-1β, IL-6 and TNF-α. Anti-inflammatory cytokines are immunoregulatory peptides that control the pro-inflammatory cytokine response. Major anti-inflammatory cytokines include interleukin (IL)-1 receptor antagonist, IL-4, IL-10, IL-11, and IL-13 (Zhang and An, 2007). However, as we’ll see, certain cytokines, most notably IL-6, can be pro- or anti-inflammatory in nature depending on the circumstances. 

Gut based immunity

We’ve often heard it said that at least 70 per cent of the immune system resides within and around the gut, but is there any truth to this statistic? According to Vighi et al (2008), gut-associated lymphoid tissue (GALT) is the prominent part of mucosal-associated lymphoid tissue (MALT) and represents almost 70 per cent of the entire immune system. What’s more, about 80 per cent of all plasma cells, which are IgA secreting, reside in our GALT. An important aspect of the GALT-based immune system is immune tolerance to food proteins in the diet (Vighi et al., 2008) – i.e. modulation of food allergies and sensitivities.

Unsurprisingly, as discussed extensively in Chapter 3 of Integrative Sport and Exercise Nutrition, our GALT and gut-based immunity is highly dependent on our microbiota. Our microbiota influences the balance between pro-inflammatory and regulatory responses and shapes our immune system (Cerf-Bensussan and Gaboriau-Routhiau, 2010). As described by Quigley et al. (2013): “Central to this beneficial interaction between the microbiota and host is the manner in which bacteria and most likely other microorganisms contained within the gut communicate with the host’s immune system and participate in a variety of metabolic processes of mutual benefit to the host and the microbe.” Specific to IgA, it has been understood for a long time that intestinal bifidobacteria induce the formation of IgA (Yasui et al., 1992), and more recent research recognises that a substantial fraction of the commensal microbiota is coated with IgA antibodies during homeostatic conditions (Bunker and Bendelac, 2019). What’s more, mice that were reared to be germ-free where shown to have impaired IgA production (Rafoo-Nahoum et al., 1996). 

IgA represents a small component of serum antibodies, but because of the abundance of IgA-secreting cells in mucosal membranes, it means that IgA comprises at least 70 per cent of all immunoglobulin in humans. Secretory IgA (sIgA), converted from IgA in the MALT/GALT, is continuously secreted into the lumen of the GI tract, and it prevents pathogenic organisms from binding to mucosal cells (Ash, 2010). Insufficient levels of sIgA, which as we’ve seen is dependent on commensal microbial populations, predisposes the mucosal lining to compromised immune tolerance.  

SIgA, in contrast to the other immunoglobulins, exerts an important role in both innate and adaptive immunity. It defends the mucosal membrane against pathogenic organisms, plus also manages the microbiota and maintains the integrity of the mucosal membrane (Johansen et al., 1999).  

Conclusions 

This article represents a brief overview of a body system that should realistically take a whole degree, or even career, to study in adequate detail. Even then, scientific discoveries move at such a fast rate that we’d be very quickly out of date with our studies! If anything, this article should go someway towards outlining some of the many moving parts of our immune system, and to hint at its complexity. As Dr Concorde mentioned, the immune system may be considered a hologram of everything going on in our lives, which also means that everything happening in our lives will have an impact on our immune system for better or worse. Read Chapter 5 in the textbook of Integrative Sport and Exercise Nutrition for a more expansive understanding of this viewpoint.