The Immune System: Defending Your Body Is A Full-Time Job
Crash Course Immunology — Part 1 of Cancer Immunotherapy Series
Note: This is just part 1 of my article series on cancer immunotherapy and covers basic immunology concepts that you might need to know to better understand the remaining articles on specific methodologies for cancer immunology.
This article does assume that you have some understanding of topics like transcription, translation, mitosis and meiosis, the chromosomal theory of inheritance, and cell biology. If you aren’t familiar with these, I’ve linked some resources for different topics throughout the article as they come up, so feel free to read those, understand the topic, and then come back to continue reading the article!
Let’s Start From The Top
You might not realize it, but keeping you alive is a full-time job for your cells. Every second, billions of reactions need to take place at the exact right moment and the exact right way to maintain the life many of us take for granted. To make this happen, your cells are constantly taking up nutrients from the food you eat and turning them into billions of different molecules that all fit together in exactly the right way to maintain homeostasis (the optimal state for your body).
And this makes your body prime real estate for invaders like bacteria, viruses, parasites, and more. Unfortunately for you, these invasions often lead to extremely damaging effects on your body, even causing death.
To protect against such invaders, your body has an arsenal of well-planned defences that all work together to detect and eliminate any invaders. All-together, these defences are referred to as your immune system.
The immune system includes many different interacting parts, with several levels of defence including your skin, and various types of cells. Excluding your first line of defence (ex. your skin), many of the cells in the immune system are collectively referred to as white blood cells, or leukocytes (leuko- = white, -cyte = cell). The source of these cells is a crucial process known as hematopoiesis.
Hematopoiesis
Most white blood cells are formed in the bone marrow, through a process known as hematopoiesis (hemato- = blood, -poiesis = formation). These cells (along with red blood cells and platelets, which are also produced in the bone marrow) descend from a single type of cell called a multipotent hematopoietic stem cell (HSC). Stem cells are types of cells that aren’t specialized in their function, but instead give rise to immature precursor cells of a specific type, which then mature into specialized or differentiated cells like specific leukocytes. The HSCs give rise to two forms of stem cells: myeloid stem cells and lymphoid stem cells. Lymphoid stem cells then give rise to lymphocytes (T-cells and B-cells) as well as natural killer cells, whereas myeloid stem cells give rise to myelogenous cells like macrophages, dendritic cells, and eosinophils, as well as red blood cells & platelets.
These cells all serve different purposes in the immune system, based on which of the two divisions of the system they fall under: innate or adaptive.
Innate Immunity
The innate immune system, also called the nonspecific immune system, is incapable of targeting specific invaders and is always active and on the lookout for invaders. It usually acts near entry points to the body to attack invaders as soon as possible, before they can wreak havoc on the body. As a result, the innate immune system is quite fast-acting, responding almost immediately to microbes and damage. Further, multiple exposures to the same pathogen will generate almost the same innate immune response every time.
First Class of Innate Immunity
The first class of defences in this system are the physical and chemical barriers. This includes the skin, which acts as a physical barrier between the external environment and the internal environment of the body, preventing many pathogens from entering. For other entries to the body, like the nasal passageway, the cells lining the entry often have methods to block the entry of pathogens. For example, your respiratory passage is lined with cells that release mucus (cells that release mucus are called goblet cells) and display small hair-like projections called cilia to trap any pathogens (like dust, bacteria, or viruses) that might enter your body with the air.
Furthermore, epithelial cells at the skin and other surfaces exposed to the external environment also release various antimicrobial molecules that kill off the microbes, forming the chemical barriers to invasion.
Another nonspecific noncellular defence is the complement system, which consists of small proteins circulating in the blood that attack bacteria. These proteins punch holes in the membranes of bacteria, causing cell lysis. This falls under innate immunity because it’s not modified in any way to target a specific organism over another.
Lastly, cells that may have been already infected with viruses may produce proteins called interferons, acting as a sort of distress and warning signal to surrounding cells. These proteins can cause cells to reduce the production of proteins, which would affect viral protein production should these cells already be infected. The cells also make their membranes less permeable, making it more difficult for viruses to enter and infect these cells. Lastly, cells also begin upregulating Major Histocompatibility Complex (MHC) Class I and II molecules (more about what these are near the end of the article), increasing the likelihood of activating an adaptive immune response. Interferons are responsible for many of the symptoms we experience when we have a viral infection like the flu, including fever, tiredness, and soreness.
Second Class of Innate Immunity
The second class of defences is a group of various cells that non-specifically attack any microbes that enter the body. These cells include phagocytic cells like neutrophils and macrophages, dendritic cells (DCs), mast cells, and natural killer cells (NK cells), among others. Here’s a quick summary of the function of each of these cells:
Phagocytic Cells
Phagocytes ingest and destroy microbes and remove damaged tissues.² Neutrophils, the most abundant type of circulating white blood cells, and contain various enzymes like lysozyme (antimicrobial enzyme), and other microbicidal (destroy microbes) substances. These cells also contain receptors, called Pattern-Recognition Receptors (PRRs), that recognize molecules particularly found in pathogens. When these receptors are activated, they trigger a range of biochemical events to trigger phagocytosis, which basically involves the neutrophil engulfing the pathogen and then using various enzymes to break it down. This is demonstrated in the GIF below, which shows a neutrophil (the big moving mass) chasing after a bacterium (appears as two small circles), before it engulfs the bacterium and then digests it (not shown in GIF).
Macrophages, like neutrophils, also phagocytize microbes and kill them using the various enzymes found inside organelles called lysosomes. However, unlike neutrophils, macrophages are also involved in clearing up dead cells of your own in the tissues that they roam around. Many cells, upon death, release inflammatory signals into the surroundings, which can be harmful if the death of the cell is natural, and so inflammation is not needed. Macrophages destroy such cells before they can release their signals, thus preventing inflammation in normal conditions. An interesting property that macrophages also possess is the ability to display the proteins of a microbe after digesting them, which can be presented to helper T-cells to activate the adaptive immune system (more on this later).
Dendritic Cells
Dendritic cells (DCs) are considered the ‘sentinels’ of the immune system, responsible for activating the adaptive immune responses. When these cells come into contact with microbes and invaders (also recognized using PRRs), they can uptake the invaders and process them to produce small peptides that they display on their surface. As helper T-cells interact with DCs, they may recognize some of the peptides displayed on the DCs as antigens and activate an adaptive immune response to attack invaders displaying those antigens. In this way, DCs (along with macrophages) connect the innate and adaptive immune systems together.
Mast Cells
Mast cells are long-lived immune cells often found at the boundaries between tissues and their external environment. When activated by a variety of different antigens, mast cells respond by releasing many chemicals called inflammatory mediators, like histamine and cytokines, all of which play a role in the local inflammatory response designed to isolate foreign pathogens and strengthen our defences against them.
Natural Killer Cells
Natural Killer (NK) cells are largely responsible for killing virally infected cells, & preventing cancer tumorigenesis. These cells are constantly patrolling the body and interacting with cells, searching for abnormalities. They possess a host of different receptors on their surface which act as either stimulators or repressors of NK cell activity. Most cells of your body use surface proteins called MHC Class I (MHC-I) to display some of their own antigens to T-cells, telling the immune system not to attack them. However, some virally infected cells and cancers, to avoid activating T-cells with their abnormal antigens, repress the expression of the MHC-I proteins. NK cells, which have a receptor that normally binds to MHC-I and represses NK cell activity, are no longer repressed upon encountering these infected/cancerous cells and kill them off.
Adaptive Immunity
The adaptive immune system is capable of mounting highly specific attacks based on the identity of the pathogens, as opposed to the more generalized attacks of the innate immune system. But, this system does take some time to develop and respond to the antigen (up to 1–2 weeks), making it much slower than the innate immune system. Lastly, repeated exposure to the same pathogen results in stronger responses following the first attack, due to the system’s ability to develop a memory of pathogens (more on this later).
There are two main types of adaptive immunity: humoral immunity, mainly coordinated by B-cells in the body fluids (hence it is called humoral, meaning “pertaining to the fluids of the body”), and cell-mediated immunity, coordinated by T-cells.
Humoral Adaptive Immunity
Antibodies
The humoral immune system involves the production of molecules called antibodies (also called immunoglobulins), which you might’ve heard of before. If not, antibodies are essentially Y-shaped proteins, either dissolved in the blood (hence the name humoral) or extending off of B-cells (aka B-lymphocytes), that bind to a specific antigen. The fork at the end of the Y consists of a light chain and a heavy chain (named according to their length), the ends of which have highly specific sequences designed to bind to a specific complementary sequence. These sequences are called variable regions since their sequence differs based on the antigen that the antibody is looking for.
Variable regions are encoded by segments of the genome known as the V (variable), D (diversity), and J (joining) sequences. These sequences consist of various subsections, which each encode a different sequence. During a recombination event (called V(D)J recombination) early in B-cell maturation, the cell makes a genetic change where it randomly chooses one subsection from each of the three regions and combines them in the DNA.
As a result, the sequence of a B-cell’s antibody variable regions will depend on the specific V, D, and J segments that were chosen in the DNA. With the help of this process, your body can produce 3 × 10¹¹ different combinations (and thus different antibodies) from V(D)J recombination alone (though many of these antibodies are avoided since they recognize antigens produced by your own body). Because this is a genetic change, which is permanent, it also means that each B-cell can only produce one antibody with the specific VDJ sequence that binds to only one antigen. Thus, your body has to produce tons of B-cells to represent the millions of different antigens that it might encounter.
B cells are formed from multipotent lymphoid stem cells (LSCs), which give rise to B-cell progenitors, which then mature in the bone marrow. This maturation process involves positive selection processes where their effectiveness at binding to its specific antigen is tested, and negative selection, where B-cells that recognize self-antigens (antigens produced by your own body) are eliminated.
Activating the Humoral Immune Response
Once one of the surface antibodies on a B cell binds the corresponding antigen, it sets off a cascade of chemical events to prime the B cell for an attack. However, just to be safe and protect from autoimmune attacks, the body has a safety mechanism in play that stops the B cell from immediately launching an attack on the antigen. In order to launch an attack, the B-cell must first display segments of the antigen on its surface using MHC-II proteins. Next, the B-cell travels to the lymph nodes, the immune system’s hubs, and finds a T-cell that recognizes the displayed segments. If this occurs, the B-cell is given the go-ahead to launch an all-out attack against the pathogen that displays the antigen.
The activated B-cell now enters a process called clonal expansion, which serves to massively increase the population of B-cells present to recognize said antigen. The activated B-cell begins dividing rapidly, and in just a few hours, has given rise to millions of B-cells all targeting the same antigen. Further, during this process, random mutations can take place in the VDJ segments encoding the variable segment of the antibodies. Some of these cause the antibodies to be better at recognizing and binding the antigen, while others reduce their accuracy and effectiveness. So, during the cloning process, the ability of the B-cell to bind the antigen determines if it clones itself or not: those better primed at attacking the antigen replicate rapidly, while those worse at doing so are selectively eliminated.
Some of the cells formed from clonal expansion transform into a subset of B-cells called plasma cells, which make large amounts of the antibody. There are several different types of antibodies/immunoglobulins, all of which play a slightly different role in the immune attack.
Immunoglobulin A (IgA), accounts for 15% of all immunoglobulins and is the main class of antibody found in body secretions like tears, saliva, and respiratory secretions. They serve as the primary defence against microorganisms attacking exposed mucosal surfaces, like those in your respiratory and digestive systems.
Immunoglobulin G (IgG) is the main immunoglobulin found in blood, accounting for 70–75% of all antibodies. These antibodies are responsible for defending newborns against infections.
Immunoglobulin M (IgM) is the first type of immunoglobulin that actually takes part directly in the immune response by causing agglutination (clumping) of bacteria, where the clumps are then easier to target by the immune system and prevents the bacteria from being able to wreak havoc. IgMs also cause bacteriolysis or rupturing of the bacterial membrane causing them to die.
Immunoglobulin D (IgD) is a rare immunoglobulin type found on the surfaces of B-cells themselves, and are involved in actually regulating the production of the antibodies by these cells (either stimulating or suppressing).
Immunoglobulin E (IgE) is also a relatively rare type of antibody in the blood in normal circumstances, but levels increase with allergic reactions or infection by parasites. They also are found on the surfaces of mast cells and other types of white blood cells in the blood, where recognition of the allergen by IgEs causes the release of inflammatory mediators like histamine, generating an immune response. In this way, IgEs are often involved in allergic reactions.
A few of the cells from clonal expansion don’t transform into plasma cells, but instead, convert into a type called memory B-lymphocytes. These cells stick around in your blood for decades, in case the invader attacks the body again. If this happens, the memory B-cells are already ready to attack them, and take very little time to launch a strong immune response. This is why secondary immune responses are often much stronger and faster than during the first, original infection.
Cell-Mediated Adaptive Immunity
This form of immunity is coordinated by another lymphocyte subtype known as T-cells. These cells are formed in the bone marrow but then migrate to the thymus gland, where they mature (i.e. develop their specificity to their specific antigens). The exact method that T-cells regulate adaptive immunity, however, is quite distinct from B-cells.
Major Histocompatibility Complexes
Let’s finally talk about the MHC molecules that we referenced a few times previously. MHC molecules can be thought of as little displays on the surface of a cell showing the different proteins either present inside of it, or in the environment. There are two main classes of MHC molecules, expressed on different cells and recognized by different types of T-cells.
The first, MHC class I (MHC-I), is found on the surfaces of all nucleated cells in the body. These present the proteins being produced inside the cells they belong to. The pathway to do so involves (at a high level):
- The breakdown of some cellular proteins by an organelle called a proteasome,
- Translocation of the peptides produced into the endoplasmic reticulum,
- Production and folding of MHC-I molecules by bound ribosomes on the endoplasmic reticulum,
- Binding of the MHC-I molecule to the peptide, and
- Transport of the MHC-I-peptide complex to the cell surface via the Golgi body and vesicles.
MHC-I is recognized by a class of T-cells known as cytotoxic T-cells or CD8+ T-cells. These cells detect if an MHC-I molecule is expressing abnormal proteins that signal infection, cancer, or some other reason that poses a significant risk to the body. If a specific cytotoxic T-cell recognizes its particular antigen on an MHC-I molecule on a cell, it is then ready to attack. At the same time, receptors called CD8 receptors also must bind to a region of the MHC-I molecule itself, which serves as the signal that unleashes the T-cell to kill off the infected/cancerous cell. To do so, the cytotoxic T-cells release various molecules designed to kill the cells and prevent the infections from spreading. Since cytotoxic T-cells recognize antigens presented on normal somatic cells, they need to traverse your tissues to find infected cells.
The second class of MHC molecules, MHC-II, are only expressed on antigen-presenting cells (APCs), which are a subset of white blood cells (include dendritic cells, B-cells, macrophages, etc.) that present antigens that they find in the extracellular environment. The pathway to do so involves:
- An antigen-presenting cell recognizes the antigen in the extracellular space,
- The cell endocytoses the antigen, breaks down the antigen into small peptides,
- The peptides make their way to the endoplasmic reticulum, where they bind to MHC-II, and
- MHC-II is transported to the cell membrane where it presents the antigen.
MHC-II molecules are recognized by helper, or CD4+, T-cells. When these cells recognize an antigen presented by APCs, and their CD4 receptors bind to the MHC-II molecules, they react in a few different ways, most of which involve activating other aspects of the immune system, like B-cells.
Regulatory T-cells
One last subtype of T-cells is regulatory T-cells, which, like the name suggests, regulate the immune response. These cells generally function to prevent autoimmune responses and identification of self-antigens, as well as modulating the intensity of the immune response and stopping the immune response once the invader has been eliminated.
How Can We Use This?
Phew… that was a lot of information, and I’ve barely even scratched the surface of the field of immunology. But, you might be thinking, why is all this important? Well, let’s just think about the ongoing pandemic. The more we understand how our immune systems work, the better we would be at directing it to attack bacteria and viruses (like SARS-CoV-2).
But, the field of immunology also has tons of potential in helping you with so many diseases of the body, including cancer. The thing is, your body already has defences against cancer, and that is exactly what keeps most people from developing cancer right in their childhood. But, in some people, the cancerous cells in their body slowly evolve to evade these natural defences, allowing them to develop into tumours.
So, my passion for a few months now has been investigating cancer immunotherapy, which focuses on unleashing the immune system to recognize these tumours as targets and attacking them. I’m personally investigating immunotherapy to target cancer stem cells, a subtype of cancer cells, in order to prevent cancer recurrence. Still looking into this, but will be making an article and video on this as soon as I have enough details figured out. In the meantime, I am going to be publishing a series on cancer immunotherapy (this is article #1 in that series, as you might’ve noticed in the subtitle), to discuss all the exciting research going on and medicine being made. So, if you’re interested, make sure you follow me here on Medium to read the next one when it drops (which will hopefully be really soon).
But that’s all for me for now! If you’re interested in finding out more about what I’m passionate about and what I’m working on, check out my website and follow me on Twitter. Also, to keep up with my growth and progress, make sure you subscribe to my newsletter here. See you next article!
If you’re interested in reading more about immunology-related topics, check out my article on the vaccine development process and why they take so long to make and my article on everything you need to know about the coronavirus.
