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An Introduction to Immunology

Although he’s known for his writing and not for any kind of scientific discoveries, H.G. Wells makes an interesting scientific point at the end of his science fiction novel, The War of the Worlds. Throughout the story, the protagonist can only watch helplessly as Earth is attacked by Martians who intend to conquer the planet, only for them to meet their end at the hands of bacteria which they have never been exposed to, and therefore have no defences against.


In theory, the smallest of microorganisms also has the ability to cause a human body considerable damage (either by causing direct damage to cells and tissues, or by producing toxins). But unlike the alien invaders in The War of the Worlds, we have a powerful biological system on our side, which means that for the average person, a considerable portion of the harmful microorganisms (also known as pathogens) which infect us are either not even noticed or are, at most, a mild inconvenience. This powerful biological system is known as our immune system.


The immune system is a highly complex network of tissues and organs that protects us against illness caused by infections through responding to antigens. In short, any substance which does not belong in the body will activate our immune system if the system detects its presence. When the immune system is activated, it deploys various kinds of cells and proteins to get rid of pathogens without damaging the host (i.e. us!), and it also helps to protect us from future infections.


The diagram below shows all the parts of the body which are involved in the immune response.

Figure 1: A diagram of all the parts of the human body involved in the immune response. Image courtesy of OpenStax.


The study of the immune system is known as immunology. Although it is a relatively new field compared to other areas of science (with most immunology-related discoveries only having occurred in the last 250 years), an increasing amount of cutting-edge research is being devoted to it.


A growing understanding of immunology has completely revolutionised the face of modern medicine, allowing us to improve on existing treatments or to develop completely new ones. Disease prevention has also taken a great leap forward thanks to the invention of vaccines, whereas organ transplantation has become more successful through employment of strategies to reduce the rate of rejection by the immune system (since this is caused by the immune system recognising the new organ as a foreign object).


The function (and dysfunction) of the immune system can also be linked to many areas of disease, ranging from autoimmune disorders, where the immune system attacks healthy parts of the body due to misidentifying it as pathogenic, to cancer, in which the immune system has been shown to be able to inhibit the growth of cancerous cells. This feature is exploited in immunotherapy cancer treatment.

The widespread impact of immunology is what makes it really important to have a basic understanding of immunology as a whole. With that in mind, this article outlines some of the key principles of the field.


One crucial thing to note - the key cells of the immune system are white blood cells, which are derived from stem cells in the bone marrow and are constantly circulating in the blood, ready to respond to any potentially harmful foreign substance in the body they encounter.


Innate immunity

The immune system can be split into two categories: the innate immune system and the adaptive immune system.


The innate immune system acts as the human body’s first line of defence against pathogens. Since it is “older” than the adaptive immune system from an evolutionary perspective, it also acts as the primary immune defence system in simpler organisms such as invertebrates and even bacteria.


The best strategy for avoiding infection is to stop germs getting into the body in the first place, which is why the innate immune system has several anatomical barriers to prevent entry of pathogens. The most outwardly obvious one is the outermost layer of skin, but there are also mucous membranes - which are soft tissues lining the parts of the body exposed to the external environment, such as the mouth, nose, and throat. Meanwhile, some of the cells in mucous membranes secrete mucus, which is able to trap germs and stop them reaching internal organs. Besides that, there are also little hairs on some of the cells that line the airways. These are called cilia and they help to move pathogens out of the respiratory system with their “sweeping” movements.


In addition to physical barriers, there are a number of chemical barriers that are capable of killing external microorganisms. For example, the stomach contains extremely strong acid that not only digests food, but is also able to dissolve pathogens that make it into the digestive tract. Some other bodily fluids, such as tears and saliva, contain antimicrobial enzymes like lysozyme which are capable of breaking down germs.


Pathogen recognition and inflammation

If the anatomical barriers are not sufficient to keep a pathogen out of the body, then it’s up to the other components of the immune system to eliminate the pathogens.


The first step is for the immune system to recognise the pathogen as foreign. Some white blood cells are able to do this because they have special receptors (i.e. proteins that bind to specific molecules) on their surface called pattern recognition receptors (PRRs), which are capable of recognising certain molecular sequences that are only expressed on pathogens, known as pathogen-associated molecular patterns (or PAMPs).


In combination with this, and the recognition of stress signals that our cells send out in response to injury (known as damage-associated molecular patterns/DAMPs), the white blood cells are stimulated to release small proteins known as cytokines and chemokines, which act as signalling molecules and attract more immune cells to the site of infection.


One of the main biological responses of the innate immune system that this triggers is inflammation, which occurs in the event of tissue damage. Its purpose is to confine tissue damage to the site of injury and eradicate its cause.


The inflammatory response can be observed in everyday life. For instance, if you get stung by an insect, not only is there pain and swelling, but the area may also turn red and feel warm to the touch. These are the four classic signs of inflammation (with loss of function sometimes regarded as a fifth).


After these cytokine signals that promote inflammation are released, the area responds, and vasodilation occurs. Vasodilation is where some small blood vessels around the site of injury increase in width in response to the release of certain chemical mediators by local immune cells and damaged cells (such as histamine and nitric oxide). This results in increased blood flow to the wound or infected area.


The increase in blood flow and vascular permeability allows more immune cells to reach the area - and in particular, a group of cells known as phagocytes. Phagocytes are white blood cells which are capable of breaking down pathogens by ingesting them through a process known as phagocytosis. The main white blood cells involved in this are neutrophils and macrophages, but some other white blood cells are also capable of phagocytic activity.


Keeping track of what all the different kinds of innate immune cells do can get complicated, but the table below outlines the main functions of each type:

Figure 2: A table outlining all the kinds of white blood cells that are involved in innate immunity, their main functions and where they are located. Image courtesy of BC Open Textbooks.


After the inflammatory process occurs, the injured tissue can be repaired. But in some cases, inflammation is inappropriately prolonged (or chronic), which can lead to diseases such as rheumatoid arthritis.


The complement system

Another essential component of immunity is the complement cascade, which refers to a network of over 30 different kinds of soluble plasma proteins that circulate in the blood and work alongside the other components of immunity to enhance its response. Although it is mainly thought of as augmenting the innate immune response, it also has some involvement in the enhancement of adaptive immunity.


There are three main routes in which the complement cascade can take depending on how complement activation occurs, all of which have its own unique mechanisms. These pathways are known as the classical pathway, the alternative pathway, and the lectin pathway.

Figure 3: A simplified diagram of the various pathways and outcomes of the complement system. Diagram simplified from Figure 2 of Xu, H., & Chen, M. (2016).


As the diagram shows, all three pathways lead to the formation of an enzyme known as C3 convertase, which splits the protein known as C3 (or complement component 3) into two separate proteins, C3a and C3b. Following this, the complement cascade can proceed in different ways, leading to three possible events:

  1. C3b binds to and coats pathogens, which can then be recognised by immune cells, making the coated pathogens a target for phagocytosis (this is known as opsonisation).

  2. C3a and another complement component known as C5a stimulate the recruitment of immune cells, thereby promoting inflammation.

  3. The complement cascade continues, leading to the formation of a membrane attack complex (MAC), a structure which is able to kill pathogens directly by causing the cell membrane of the pathogen to break down (this is known as lysis).


Adaptive immunity

The other part of the immune system is the “adaptive” immune system, which comes into play at a later stage than the initial innate immune response. It is given this name because unlike the innate immune system, which generally responds in the same way to any kind of pathogen or foreign body, it “adapts” its response according to the type of germ which is attacking, and develops throughout life as we come into contact with more and more sources of infection.


The main types of white blood cells involved in adaptive immunity are lymphocytes, specifically B cells and T cells. They are named this way because B cells mature in the bone marrow, and T cells mature in the thymus (although they are still initially produced in the bone marrow like all white blood cells). B cells and T cells each have receptors on their cell surface that are specific for and can bind to a single antigen.


When B cells are activated, they are stimulated to produce antibodies. Antibodies (or immunoglobulins) are Y-shaped proteins which recognise antigens on the surface of pathogens and use a lock and key mechanism to bind.


They have three main functions:

  1. To directly bind to and inactivate pathogens via antibody-antigen binding

  2. To bind to pathogens so they can be targeted for phagocytosis (opsonisation)

  3. To activate the complement system via the classical pathway, leading to direct lysis of pathogens (via the MAC)


Figure 4: The structure of an antibody. Antibodies are composed of two heavy chains and two light chains, held together by a strong bond between sulfur atoms known as disulfide bonds. The constant region is consistent between antibody classes, while the variable region is different for each antibody. The Fab (fragment antigen binding) region binds to antigens, while the Fc (fragment of crystallisation) region is where Fc receptors on phagocytes or complement factors can bind to trigger opsonization, or to activate parts of the immune system (such as the complement system). Image courtesy of OpenStax.


T cells do not directly recognise antigens themselves because they have a slightly different structure to B cells. Instead, they interact with antigen-presenting cells (APCs) such as dendritic cells (not to be confused with dendrites).


APCs are cells which engulf and phagocytose pathogens before presenting pathogenic antigen fragments on their surface. These fragments are also bound to other cell surface proteins known as major histocompatibility (MHC) molecules, which the receptors on T cells can recognise.

Figure 5: A diagram outlining the various steps involved in antigen presentation to T cells. Image courtesy of OpenStax.


T lymphocytes can be split into cytotoxic T cells (or CD8+ cells) and helper T cells (or CD4+ cells), which have different roles in immunity. Helper T cells secrete cytokines that activate other immune cells such as macrophages and B cells. On the other hand, cytotoxic T cells, like NK cells in the innate immune response, destroy infected cells and tumour cells.

Figure 6: The steps of action of helper (CD4+) T cells and killer (CD8+) T cells. Image courtesy of Concepts of Biology.


A small portion of both B cells and T cells become “memory cells”, which are long lived lymphocytes that are not involved in the initial immune response but are specific for the antigens involved in the initial infection. If the same pathogen gets into your body again in the future, then these memory cells are ready to go and work to get rid of the infection much more quickly than the first time around.

Figure 7: A graph showing the general trend of antibody concentration after initial infection and after reinfection. This shows that on secondary exposure, the body is able to produce more antibodies in less time in order to tackle the pathogen. Image courtesy of OpenStax.


It’s possible to stimulate the production of these memory B cells and T cells artificially through exposure to small amounts of a weakened (or even dead) pathogen, which is the main idea behind vaccination.


Conclusion

In reality, immunology goes into far more detail than what is outlined above, and although the components outlined in the article are listed separately, the reality is that there is a lot of overlap and all the different mechanisms and cells involved in the immune system are greatly interlinked.


It can be a complicated topic, but is definitely one worth exploring. With that in mind, here are some useful resources if you’re interested in exploring immunology a little further:


Author: Emma McCarthy, MSc Health Data Science

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