The immune system is like a police force. It patrols everywhere, and if it finds a disturbance, it calls for back-up. In this way, it is different from other systems in that it has to be able to react in any part of the body. The immune system provides two levels of defense: innate and adaptive immunity. This discussion will begin with a brief description of the organs and tissues associated with the immune system and then focus on the cells that provide innate and adaptive immunity.

Organs and tissues

Organs and tissues important to the proper functioning of the immune system include the thymus and bone marrow, lymph nodes and vessels, spleen, and skin.

Bone marrow and thymus

If the immune system is a police force, the bone marrow is the police academy because this is where the different types of immune system cells are created. All cells of the immune system are created in the bone marrow from a common type of starting cell, called a stem cell. These stem cells later develop into specific cell types, including red blood cells, platelets (important for blood clotting), and white blood cells (important for immune responses). The cell generation and differentiation process occurs every day for as long as we live. As a result, in the same way that the red blood cells in our blood are replenished after an injury or blood donation, our immune system cells are constantly replenished.

Some of the stem cells will become a type of immune system cell called a lymphocyte. Two types of lymphocytes comprise the adaptive immune system — B cells and T cells. B cells mature in the bone marrow (hence the name “B cell”). Cells that eventually become T cells travel from the bone marrow to the thymus by way of our bloodstream where they mature (hence the name “T cell”). The thymus is located just above the heart behind the sternum, or breastbone.

Lymph nodes and vessels

Lymph nodes are tissues full of immune cells. These nodes are located strategically throughout the body. Some are better known than others. For example, many people are familiar with tonsils and adenoids in the neck, but may not be aware of Peyer’s patches, which are lymph nodes that line the intestine. Numerous unnamed lymph nodes also exist throughout the body; in fact, virtually every corner of our body has some group of lymph nodes associated with it. Lymph nodes tend to be most prevalent in areas near body openings, such as the digestive tract and the genital region, because this is where pathogens most often enter the body.

If the immune system is a police force, lymph nodes are their stations. Once a pathogen is detected, nearby lymph nodes, often referred to as draining lymph nodes, become hives of activity, where cell activation, chemical signaling, and expansion of the number of immune system cells occur. The result is that the nodes increase in size and the surrounding areas may become tender as the enlarged nodes take up more space than usual. “Swollen glands” in the neck are an example that most of us have experienced. But, the same thing can occur anywhere lymph nodes are activated.

Two vessel systems are critical to the immune function of lymph nodes:

• Blood vessels — Lymph, a fluid rich in immune system cells and signaling chemicals, travels from the blood into body tissues via capillaries. Lymphatic fluid collects pathogens and debris in the tissues. Then the lymphatic fluid containing immune cells enters draining lymph nodes where it is filtered. If pathogens are detected, immune system components are activated (see “adaptive immune system" section below for more about this).
• Lymphatic vessels — Once filtration is complete, lymph vessels carry this fluid toward the heart. Depending on where the filtered lymph arrives from, it enters either the thoracic duct on the left side of the heart, or a similar, but smaller duct on the right side of the heart. The thoracic duct collects lymph from the whole body except the right side of the chest and head. The lymph from these areas drains to the smaller duct. From here, the lymph and its immune cells are returned to the bloodstream for another trip through the body.

Spleen

The spleen is the largest internal organ of the immune system, and as such, it contains a large number of immune system cells. Indeed, about 25 percent of the blood that comes from the heart flows through the spleen on every beat. As blood circulates through the spleen, it is filtered to detect pathogens. As pathogens are detected, immune system cells are activated and increase in number to neutralize the pathogen. The spleen is particularly important in protecting people from bacterial infections, such as meningococcus and pneumococcus. So, while people can live without a spleen, it is important for them to be up to date on vaccines that protect against these infections because they are at greater risk of suffering from them.

Skin

Sometimes the skin is described as the largest organ of the immune system because it covers the entire body. People may not think about the skin as being part of this system, but the reality is that skin serves as an important physical barrier from many of the disease-causing agents that we come into contact with on a daily basis.

Innate immune system

The innate immune system is the first line of defense against pathogens. In our example, the innate immune system is like the cops that patrol local beats. They take care of most of the criminal activity that takes place in a community and generally keep the peace. Similarly, most of the time our innate immune system effectively wards off infections by keeping pathogens in check. This is accomplished in several ways.

Physical barriers

Our bodies physically ward off many potential pathogens. As mentioned above, our skin is an important protective barrier. But, most people don’t realize that the top layer of skin cells, known as the epithelium, is designed so that pathogens cannot easily get between the cells. These cellular intersections are called tight junctions. Our skin also tends to be dry and tough making it difficult for pathogens to gain entry.

Epithelial cells that line openings into our bodies, such as the nose and mouth as well as throughout the respiratory, digestive, and genital tracts, tend to have one or more additional protective features. First, the epithelial cells in these regions are coated with mucus, a thick, sticky solution that makes it difficult for pathogens to attach to them. Second, some of them also have microfibers, called cilia, which move the mucus and any pathogens in the mucus along the cell surface. Hairs in the nasal cavity work in a similar manner to trap pathogens in the air before they get into the lungs. Our bodies also use muscles to move air and liquids to keep pathogens from infecting us. Sneezing, watery eyes, vomiting and diarrhea are all examples of our innate immune system working to protect us.

Chemical barriers

Mucus not only provides a physical barrier, it also contains chemicals that help protect us from pathogens. Epithelial cells also secrete chemicals that prevent infection. This is true of epithelial cells on our skin and in our digestive, respiratory, and genital tracts. Our body also uses chemical factors, such as acid, to create harsh environments for some pathogens. For example, the stomach has an acidic pH that makes it difficult for many viruses to survive the journey through the digestive tract. Fever, although not a chemical barrier, also makes the environment more difficult for a pathogen to survive while simultaneously enhancing the immune system’s ability to be effective. Find out more about fevers in this video or on this Q&A.

Partnerships

Bacteria live in and on us. As humans evolved, so did the bacteria that live on us. As a result, they are able to survive on our skin or in our digestive tract without our immune systems acting to rid them. Known as commensal bacteria, these “residents” are not completely risk-free. For example, while Staphylococcus bacteria are generally harmless on our skin, if they enter our bodies, they can be troublesome. In some cases, the disturbance is minor, such as a pimple. In other cases, the result can be deadly, such as a bloodstream infection. So, even though our immune system doesn’t actively rid us of these bacteria, it does work to keep commensal bacteria in check.

You may be wondering, then, why does our immune system allow these bacteria to be around at all? Like with other things in life, the answer comes down to a risk-benefit ratio. When these bacteria are covering the surface of our skin or digestive tract, more harmful bacteria have less of an opportunity to do so. Additionally, commensal bacteria can help create conditions in the local environment that keep infectious agents from causing problems. For example, commensal bacteria may release chemicals that are toxic to other types of bacteria. Evidence for the importance of these bacteria can be seen after taking oral antibiotics. You may have loose stools or intestinal cramping for a few days. This is because antibiotics, such as penicillin, can kill many different types of bacteria — good and bad. Until the commensal (or good) bacteria repopulate, your innate immune system is left to fend off bacteria that wouldn’t otherwise have been a problem.

Non-specific cellular responses

A final way that the innate immune system works is through immune system cells. These cells are not specific in their search for invaders. The most important cells associated with innate immune responses are:

• Neutrophils — These are the most numerous type of innate immune responder cells. Their primary job is to destroy pathogens. Neutrophils circulate in the blood, but enter different parts of the body where an invader has been identified. When a neutrophil finds a pathogen, it surrounds and ingests it — a process called phagocytosis. Neutrophils only survive a few days.
• Macrophages — These long-lived cells are present in virtually all tissues of the body where they use phagocytosis to trap invaders found in the tissue. While the phagocytic activity of macrophages is an important part of innate immunity, these cells are even more important for their role in activating other parts of the immune system.
  
  Macrophages that have ingested a pathogen secrete chemical signals, called cytokines, which help recruit other immune cells to the area — this leads to inflammation. Inflammation is important for a few reasons. First, it establishes an environment in which cells traveling in the blood can move into the affected tissue. Second, it allows for clotting factors to become activated in an effort to contain the infection, and third, it promotes tissue repair. Pain, redness and swelling at the site of a wound are indicative of the inflammatory response induced by macrophages.
• Dendritic cells — These cells have long tentacles and also phagocytose pathogens in tissues. However, the main purpose of dendritic cells is not to destroy pathogens (like neutrophils) or to alert the immune system to cause inflammation (like macrophages). Instead, dendritic cells serve to bridge the innate and adaptive immune responses. How dendritic cells do this will be described in more detail in the “adaptive immune system” below.
• Natural killer cells (NK cells) — These cells work to keep viral infections from getting too severe while the adaptive immune system is generating a targeted response (see “adaptive immune system” section below). Unlike neutrophils, macrophages, and dendritic cells — all of which employ phagocytosis — NK cells attach to an infected cell and release chemicals into it to kill it. Natural killer cells are also known for their ability to fight tumor cells.

Watch this short video showing how the innate immune system works.

Adaptive immune system

When pathogens get past the non-specific mechanisms of protection afforded by the innate immune system, the adaptive immune system takes over. In our police force example, consider the components of adaptive immunity to be the “special forces.”

The “special forces” of the adaptive immune response have two important jobs:

• Stop the current infection
• Generate immunologic memory

Memory cells monitor the body to stop or lessen the impact of future infections by the same pathogen. If a second infection occurs at all, it is typically shorter in duration and less severe than a first encounter.  Vaccines allow us to leverage the advantages of immunologic memory without the risks involved with a first encounter. Sticking to our police force example, vaccines are like the practice drills that officers complete in an effort to be ready for an actual event.

Calling in the “special forces”

The adaptive immune response is driven by the activities of cells called antigen-presenting cells (APCs). Three cell types can serve as APCs — dendritic cells, macrophages and B cells. Of these, dendritic cells are the most common and powerful APC type. They are considered to be the bridge between the innate and adaptive immune responses.

Dendritic cells are produced in bone marrow and migrate through the blood to tissues where they monitor for pathogens. When they encounter a pathogen, they phagocytose it, break it into pieces, and put the pieces on their surface as a “signal” to other immune system components. As this happens, the dendritic cell migrates from the tissue to the nearest lymph node where these surface signals, called antigens, help to activate T cells. Dendritic cells can process and present most types of pathogens, such as viruses, bacteria, fungi and parasites.

Whereas antigen presentation is the primary function of dendritic cells, macrophages and B cells are capable APCs, but this is not their primary function. Macrophages, as described in the innate immune system section, primarily destroy pathogens, signal the innate immune response, and cause inflammation. When they function as APCs, it is typically to present antigens from pathogens they have ingested that have evolved so that they are not killed by typical innate immune responses. B cells are an essential part of the adaptive immune response (see “Preparing for battle” section below), but they sometimes serve as APCs to activate responses against toxins or smaller antigens, like proteins. Similar to dendritic cells, macrophages and B cells, acting as APCs, must travel to the draining lymph node to activate the adaptive immune response.

Preparing for battle

When antigen is presented in draining lymph nodes, the adaptive immune response starts in earnest. In our police force example, the antigen presentation results in an “all hands on deck” response. These responses are fascinating in that they are primarily guided by small proteins and “matching” markers on cell surfaces. The small proteins are called cytokines, and when they bind to a cell’s surface, the cell acts accordingly. The actions are wide-reaching, but can include growing, changing, reproducing, or interacting with other cells. More than 50 kinds of cytokines have been identified. For a particular cytokine to bind to a cell surface, the cell must have a “matching” marker, called a receptor. Different types of cells have different receptors, and, therefore, can be more or less affected by particular cytokines. Additionally, some cytokines cause more than one action, and multiple cytokines can cause similar actions. This seeming “overlap” is important because it positions our immune system to avert infections in multiple ways. It also allows for people born with immune deficiencies to survive. For more about this aspect of the immune system, see the section titled “What Happens when the Immune System Does Not Function Properly.”

In addition to the cytokines and APCs, two primary cell types are central to the efforts of the adaptive immune response — T cells and B cells.

T cells

These cells are important in moderating the adaptive immune response. You can think of them like the police chiefs and sergeants making sure the appropriate numbers of staff are responding to a situation. Three types of T cells each have distinct roles:

• Helper T cells oversee cytokine signaling to activate B cells and increase the efficiency of other immune cells, such as macrophages.
• Cytotoxic T cells are important in viral infections in that they kill cells that have been infected by viruses.
• Regulatory T cells regulate the immune response. They signal for increased activity early in an infection, and conversely, signal for a decrease in the response as the infection is brought under control.

B cells

Once activated, B cells start to reproduce, quickly increasing in number. In our example, B cells are the troops of officers that descend on the crime scene. And, like the weapons troopers carry, B cells are also armed. The sole purpose of most B cells is to secrete large quantities of antibodies. B cells that secrete antibodies are also known as plasma cells.

Antibodies secreted by B cells are a crucial weapon of the adaptive immune response. They are specific for the pathogen that is attacking, so they can bind to and neutralize it. Five different classes of antibodies, also known as immunoglobulins (Ig), exist in people: IgG, IgM, IgA, IgE, and IgD. Each has unique characteristics and roles.

• IgG is the most abundant and is found in blood and tissues. Four different subcategories of IgG have been identified. Typical adults have more than 70 grams (or 17 teaspoons) of IgG circulating in their bloodstream every day to monitor for pathogens. IgG also circulates in the spaces between tissues. This is also the type of antibody that is shared across the placenta during pregnancy.
• IgM also circulates in the blood. IgM is one of the earliest antibody types to appear during an infection. While these antibodies are specific for the pathogen, they are less effective than IgG antibodies that appear later during an infection. Because IgM appears as a pentamer, meaning 5 IgM molecules traveling together, it does not leave the blood and enter tissues like IgG. The grouping of these molecules makes up for the lower effectiveness compared with IgG. Think of this like five citizens keeping a suspect from leaving the scene of a crime versus one police officer with a weapon. The five citizens can surround the criminal making it more difficult to escape, but when a single officer arrives with police resources, the possibility of escaping is even less.
• IgA is found in the blood, but its most important role is protecting mucosal surfaces. For this reason, IgA antibodies tend to be found at higher levels in the digestive and respiratory tracts. IgA is also commonly found in breast milk.
• IgE antibodies are found just below the skin and along blood vessels. They are most effective at combatting infections caused by parasites. This type of antibody is most commonly associated with allergic reactions.
• IgD is less well understood, but it may have roles in protecting against respiratory infections and preventing our immune system from attacking our own cells and tissues, known as “self” antigens. IgD is found in the respiratory tract and at low levels in the blood.

Watch this short video about how antibodies work.

After success, preparing for the future

Most of the cells that are activated during an infection die during or shortly afterward. However, a small subset of both B and T cells remain indefinitely. They are called memory cells. These memory cells recognize specific antigens. For example, most of us have memory B and T cells that monitor our body for influenza. Whether our first encounter with influenza was an infection or the result of vaccination, our immune system went through the process of becoming activated and responding to the assault. This first response is called the primary immune response. The memory cells that remain after a primary infection serve as guards watching for influenza to appear again. If it does, these cells will quickly activate allowing the immune system to produce a faster and more efficient immune response to this second (or third or fourth, etc.) attack.

Immunologic responses driven by memory cells are called secondary responses. In our police example, think of memory responses as experienced officers. Those officers with more experience are likely to anticipate what is happening allowing them to respond more quickly, confidently and efficiently. In the same way, memory cells allow the adaptive immune system to ramp up its attack more quickly. This preparedness decreases the response time by several days. The results can be realized in a few ways. Some people may not have any symptoms and not even realize they were exposed the second time. Some people will have symptoms, but they will not have as severe of symptoms. They are likely to be sick for fewer days as well.

Watch this short video about how the adaptive immune system works.

References

• Chen K and Cerutti A. The Function and Regulation of Immunoglobulin D. Current Opin Immunol 2011; 23(3): 345-52. doi:10.1016/j.coi.2011.01.006
• Murphy K. Janeway’s Immunobiology, 8^th Edition. 2012.
• The Lymphatic System. Accessed at http://www.lymphnotes.com/article.php/id/151/.