How Does the Immune System Work? Part 1: An Exploration of the Functions, Responses, and Processes of the Innate Immune System

How Does the Immune System Work? Part 1: An Exploration of the Functions, Responses, and Processes of the Innate Immune System

Key Learning Objectives

Learn about the immune system and its layered defenses

Understand the role of the innate immune system

Discover the cells of innate immunity and their functions

Find out what happens to immunity as we age


Introduction to the Immune System

The immune system is the collection of cells, tissues, and molecules that work together to recognize the healthy cells that make up the body, and protect us against the unfamiliar or damaged. 

The immune system monitors our body continuously searching for certain categories of things that may threaten our health: infectious microbes, viruses, fungi, and parasites (i.e., germs or pathogens); toxic cellular products; and damaged or diseased cells, including senescent or tumor cells. [1–3]  

The immune system is often described as having three layers of defenses. The first layer consists of physical and chemical barriers in skin and the nose, lungs, bladder, stomach and intestines. The next layer is nonspecific immune defense mechanisms. These are the parts of the immune response we are born with and that activate immediately or within hours of a new threat. The third layer of defense is specific resistance, which takes time to develop after exposure to a new threat, and occurs as the immune system learns, adapts, and remembers. The first two layers are part of innate immunity. The third layer is adaptive immunity. 

The innate immune system is our first line of defense against possible threats; it blocks invasion by pathogens or, when they do invade, it mounts early responses that control and eliminate infections, clean up damaged cells, and repair tissues. Innate immunity can be thought of as the immune defenses we are born with. 

The adaptive immune system is responsible for the more complex and optimized immune responses that develop when innate immunity is insufficient to manage a threat. It is the specific immunity we acquire over time as the immune system is challenged with new antigens and learns to deal with them.

We will learn about these two divisions of the immune system over a miniseries of two articles. We’ll leave adaptive immunity for part two and, for now, we’ll focus on innate immunity.

One of the primary jobs of the immune system is to recognize “self” and protect against “non-self.” It does this by having layers of defenses.

What Is the Innate Immune System?

The innate immune system is the front line of the immunity arsenal. Its primary function is to prevent, control, or quickly eliminate a mounting infection. Innate immunity is maintained by physical and chemical barriers, soluble effector molecules in the blood and extracellular fluids, immune cells, and chemical messengers in the blood and tissues. [1–3] 

The physical and chemical barriers of our body work in the prevention front of innate immunity, acting to block the entry of pathogens into our body, flush them away, or destroy them before they enter. They are built by the cells that line the outer surfaces and cavities of organs and blood vessels and by the antimicrobial chemicals they produce. Those cells are called epithelial cells and they form epithelial barriers in the skin, gastrointestinal tract, respiratory tract, and genitourinary tract. Skin, mucous membranes, urination, defecation, and vomiting are examples of physical barriers. Chemical barriers include saliva, stomach acid, and skin secretions.

Unfortunately, these physical and chemical barriers aren't always enough to keep pathogens out, which is why we need additional layers of defense. Therefore, the innate immune system has an army of sentinels that patrol our blood and tissues searching for foreign, damaged, or infected cells, and that devise quick immune responses when they find a potential threat. These sentinels are the effector cells of the innate immune system: dendritic cells, natural killer (NK) cells, macrophages, neutrophils, mast cells, basophiles, eosinophiles, as well as many types of tissue specific cells (tissue-specific macrophages, for example). Innate immune cells detect and eliminate the pathogens that have managed to breach epithelial barriers, and, if needed, they initiate additional immune responses. 

The innate immune system is able to recognize pathogens through a number of molecules that identify them, called pathogen-associated molecular patterns (PAMPs). Likewise, immune cells recognize damaged and dying cells in our tissues through molecules they produce called damage-associated molecular patterns (DAMPs). PAMPs and DAMPs are recognized by a set of cellular receptors expressed by cells of the innate immune system called pattern recognition receptors (PRRs). PAMP or DAMP binding to PRPs activates immune cells and promotes immune responses.

The innate immune system is the first line of immunological defense: it blocks invasion by pathogens and mounts early responses that control and eliminate infections and damaged cells.

Cells of the Innate Immune System

Immune cells recognize molecular patterns and antigens (antigens are molecules—peptides, sugars, lipids, or nucleic acid fragments—that can trigger an immune response) on pathogens and damaged cells and mount a response that aims at eliminating these possible causes of disease. 

White blood cells, also known as leukocytes, are the main cells of the immune system (both the innate and the adaptive). White blood cells derive from a common cellular precursor found in the bone marrow called hematopoietic stem cells (as do the red blood cells that transport oxygen and the platelets that trigger blood clotting). The bone marrow is also where many immune cells mature. There are also some innate immune cells that populate tissues during embryonic development and are maintained throughout life as independent, self-renewing, tissue-resident populations. [1–3]

Once mature, immune cells circulate in the bloodstream, reside within peripheral tissues, or circulate in a specialized system of vessels called the lymphatic system. The lymphatic system drains extracellular fluid and immune cells from tissues and transports them as lymph. Lymph is filtered by small organs called lymph nodes, where immune cells are concentrated and sample the lymph looking for signs of infection. Lymph is eventually emptied back into the blood flow. 

White blood cells are created in bone marrow from hematopoietic stem cells. There are five main types of immune cells: neutrophils, monocytes, eosinophils, basophils and lymphocytes.

Neutrophils 

Neutrophils are the most abundant population of circulating white blood cells and the principal cell type in acute inflammatory reactions. They can be thought of as the first responders, because they arrive quickly at the site of infection or damage, begin to deal with the problem, and recruit other immune cells to help.

Neutrophils are recruited to sites of infection, trauma, and inflammation to destroy pathogens. They do it through a process called phagocytosis and are therefore classified as phagocytes. This word comes from the Greek phagein, which means "to eat", and -cyte, the suffix for "cell". So, neutrophils are literally cells that eat other cells. 

Neutrophils ingest microbes and then digest and destroy them in specialized intracellular structures called phagolysosomes through the actions of reactive oxygen and nitrogen species and enzymes. 

Macrophages 

Monocytes are the largest type of leukocyte. They can differentiate into macrophages (discussed in this section) and a different cell type called dendritic cells (discussed further below). 

Macrophages are also phagocytes. Similar to neutrophils, they migrate to tissues where they clean up cellular debris, foreign substances, and pathogens. Macrophages can remain in tissues for long periods of time.

There are also tissue macrophages that do not derive from monocytes, but that instead reside in those tissues from birth. An example is a type of cell of the nervous system called microglia, the macrophages of the central nervous system.

Macrophages acquire different functions depending on the stimuli that activate them. Classical activation yields inflammatory macrophages (M1) that are efficient at killing pathogens, whereas alternative activation yields anti-inflammatory macrophages (M2) that are efficient at promoting tissue remodeling and repair. 

The main function of M1 macrophages is to ingest and kill pathogens and dead cells—cells in tissues that die due to toxins, trauma or interrupted blood supply (necrosis) and cells that die by programmed cell death (apoptosis) as part of physiological development, growth, and renewal of tissues. M1 macrophages also ingest neutrophils that die after accumulating at sites of infection, as part of the cleaning up process. 

Macrophages activated by pathogens secrete signaling molecules that act on endothelial cells lining blood vessels to enhance the recruitment and migration of immune cells from the blood into tissue sites of infection or damage, thereby amplifying immune responses against microbes. Macrophages also serve as antigen-presenting cells (APCs) that display fragments of protein antigens to activate lymphocytes, the cells of the adaptive immune system.

Neutrophils and macrophages are specialists in phagocytosis, the biological process where immune cells ingest cellular debris, foreign substances, and pathogens.

Figure 1: Cells of the innate immune system: neutrophils, monocytes, and macrophages. Adapted from: Innate Immune Response by Charles Molnar and Jane Gair. Licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Figure 1: Cells of the innate immune system: neutrophils, monocytes, and macrophages.
Adapted from: Innate Immune Response by Charles Molnar and Jane Gair. Licensed under a
Creative Commons Attribution 4.0 International License (CC BY 4.0).


Mast Cells, Basophils, and Eosinophils

Mast cells, basophils, and eosinophils are primarily involved in responses to parasite infections and in allergic reactions. They all carry cytoplasmic granules filled with potent antimicrobial and inflammatory molecules that are released upon their activation, including histamine, a well-known mediator of allergic reactions. 

Mast cells are present in the skin and mucosal epithelia where they function as tissue sentinels. Mast cells are coated with a type of antibody called IgE, which is specialized in the immune defense against parasites and allergens. They can be activated by antigen binding to IgE. Upon activation, mast cells release their cytoplasmic granules containing histamine and other inflammatory mediators to promote the changes in the blood vessels that cause inflammation and recruit other immune cells.

Basophils circulate in the blood. They are normally not present in tissues, but may be recruited to some inflammatory sites. Like mast cells, basophils can be activated by antigen binding to IgE. 

Eosinophils also circulate in the blood, from where they may be recruited into tissues. Some eosinophils are normally present in mucosal linings of the respiratory, gastrointestinal, and genitourinary tracts; their numbers can increase by recruitment from the blood in the setting of inflammation. Their granules contain enzymes that are harmful to the cell walls of parasites. 

Mast Cells, basophils, and eosinophils help protect us against germs, but they are a 'double-edged sword,' because they are also the immune cells involved with causing allergic reactions.

Figure 2: Cells of the innate immune system: mast Cells, basophils, and eosinophils. Adapted from: Innate Immune Response by Charles Molnar and Jane Gair. Licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Figure 2: Cells of the innate immune system: mast cells, basophils, and eosinophils. 
Adapted from: Innate Immune Response by Charles Molnar and Jane Gair. Licensed under a
Creative Commons Attribution 4.0 International License (CC BY 4.0).


Dendritic Cells

Dendritic cells (DCs) are found in the blood and tissues. They are an important part of innate immune defenses in tissues that interact with the external environment, such as the skin and the inner lining of the nose, lungs, stomach, and intestines.

Dendritic cells recognize microbial molecules through PRRs and respond by secreting signaling molecules that recruit and activate other immune cells at the infection sites. Dendritic cells also capture microbial protein antigens and display them to cells of the adaptive immune system (which are called lymphocytes) to initiate adaptive immune responses, thereby acting as antigen-presenting cells (APCs). Therefore, they act as sentinels of infection that prompt innate immune responses and that link them to the development of adaptive immune responses. 

There are two types of dendritic cells. One type is called conventional or classical dendritic cells (cDC). cDCs are the major type of DC and are specialized in capturing microbial protein antigens in tissues and in presenting them to cells of the adaptive immune system to activate them. 

The other, more rare type, of dendritic cells are called plasmacytoid dendritic cells (pDC). pDCs are the body’s major producers of the potent antiviral signaling molecules called type I interferons (IFNs) which play a key role in immune defenses against viruses. They also capture antigens from microbes in the blood and present them to adaptive immune system cells.

Dendritic cells are specialized antigen-presenting cells that initiate and orchestrate complex immune responses. They play a role in both the initial innate immune system response and the generation of adaptive immunity.

 

Figure 3: Cells of the innate immune system: dendritic cells. Adapted from: Innate Immune Response by Charles Molnar and Jane Gair. Licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Figure 3: Cells of the innate immune system: dendritic cells. Adapted from: Innate Immune Response by Charles Molnar and Jane Gair. Licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Natural Killer Cells

Natural killer (NK) cells are a subset of innate lymphoid cells (ILCs), a group of cells of the innate immune system that originate from the same precursor as lymphocytes of the adaptive immune system. As their name indicates, the main function of NK cells is to kill infected or dysfunctional cells. Their function is similar to that of a subset of lymphocytes called cytotoxic T cells; they are the cytotoxic or cell-killing specialists of the innate immune system. 

NK cells are early responders to viral infection and intracellular bacteria. They are also an important part of innate immune defenses against dysfunctional cells (e.g., senescent cells, tumor cells). 

NK cells circulate in the blood and are concentrated in tissues of the immune system. They are activated by recognition of activating ligands on the infected or dysfunctional cells. When NK cells detect these cells, they release cytotoxic protein granules adjacently to the target cells. These granules contain perforin, a pore-forming protein that facilitates the entry of other granule proteins, called granzymes, into target cells. Granzymes are proteolytic enzymes (i.e., enzymes that degrade proteins) that initiate signaling events that cause the death of the target cells. 

Natural killer (NK) cells play a critical role in identifying and eliminating physiologically stressed cells, such as senescent cells, tumor cells and virus-infected cells.


Figure 4: Cells of the innate immune system: natural killer (NK) cells. Adapted from: Innate Immune Response by Charles Molnar and Jane Gair. Licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Figure 4: Cells of the innate immune system: natural killer (NK) cells. 
Adapted from: Innate Immune Response by Charles Molnar and Jane Gair. Licensed under a
Creative Commons Attribution 4.0 International License (CC BY 4.0).


Cytokines and Inflammatory Responses

The main response of the innate immune system to infections and tissue injury is to stimulate inflammation. Inflammation is the process by which white blood cells, and substances they produce, are brought into sites of infection and are activated to destroy and eliminate the infectious agents. The acute inflammatory response is characterized by the recruitment and accumulation of immune cells, blood proteins, and fluid derived from the blood at the tissue site of infection or injury. The main regulators of inflammatory processes are a type of signaling molecules called cytokines. [1–3]

Cytokine is the name of a family of small proteins secreted by cells as means of communication and interaction. Cytokines may act on the same cells that secreted them (autocrine action), on neighboring cells (paracrine action), or even on distant cells (endocrine action). There are many different cytokines that are produced during immune responses; cytokines are often produced in a cascade, with one cytokine stimulating the production of additional cytokines, thereby quickly amplifying their signaling. Different cytokines can act synergistically or antagonistically.  

Proinflammatory cytokines secreted by resident sentinel cells in tissues—macrophages, DCs, mast cells, and endothelial cells—in response to pathogens or cell damage can trigger inflammatory reactions. Cytokines act not only to induce inflammation, but also to promote other immune responses, such as phagocytosis by macrophages and neutrophils, NK cell activity, inhibition of viral replication, and adaptive immune responses. There are also anti-inflammatory cytokines, which help to balance immune responses and to prevent a protective reaction from becoming excessive and damaging. 

Cytokines are small signaling molecules secreted by cells that mediate cellular communication, regulate inflammatory reactions, and modulate immune cell responses. They are needed to have a balanced immune response.

Immune Cells Are Aided by Effector Molecules

In the blood and extracellular fluids, there are also several types of molecules that recognize microbes and support immune responses as part of our early defense mechanisms. They stimulate the elimination of microbes by enhancing the recruitment and activity of immune cells, they coordinate inflammatory responses that bring more immune cells to sites of infections, and they assist in the elimination of pathogens. [1–3] 

The complement system is part of that defense mechanism. The complement system consists of blood and membrane proteins that interact in an orchestrated manner to kill invading microbes. 

The complement system can be activated by multiple pathways, but all converge in the cleavage of a complement protein called C3 to generate biologically active products that stimulate inflammation and enhance antibody responses. A product of C3 called C3b attaches to microbial cell surfaces or to antibodies bound to antigens and coats them (a process called opsonization), thereby targeting them for elimination by phagocytosis. 

The C3b fragment can also activate the cleavage of another complement protein called C5, which in addition to promoting inflammation, initiates the formation of a structure called membrane attack complex (MAC). In this process, a cascade of other complement molecules come together to create pores in the membranes of microbial targets. They form channels that allow free movement of water and minerals, leading to swelling and rupture of the cells (cytolysis), ultimately resulting in the death of the microbes. 

The  complement system is the part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells.

Regional Immune Systems

The skin, the gastrointestinal tract, and the respiratory tract are the major interfaces of our body with the outside world. Consequently, they are also the main points of entry of pathogens into our body. Therefore, all these systems (as well as the genitourinary tract) are lined by epithelial barriers that contain their own specialized local immune systems with their own immune cells and lymph nodes. These cutaneous and mucosal immune systems work in coordinated ways to provide specialized immune responses against the pathogens that enter at those barriers. Importantly, they are also essential for a healthy relationship with non-pathogenic microbes (i.e., good bacteria and germs) that inhabit our skin and the lumens of our mucosal organs and with which we have a symbiotic relationship. [1–3]

Gastrointestinal Immune System

The gastrointestinal (GI) immune system is probably the most important regional immune system because it must cope with the largest population of microbes in our body: the trillions of symbiotic bacteria that make up the gut microbiota. These microbes are beneficial as long as they stay within the gut lumen, meaning that the GI immune system must simultaneously prevent the invasion of these microbes into our body and tolerate their presence within the gut. It must do so while also identifying and responding to any pathogenic organisms that may show up.

Immunity in the GI tract is maintained by the intestinal epithelial barrier, which physically blocks microbial invasion, by a chemical barrier made up of mucosal secretions and antimicrobial molecules, and by innate immune effector cells that reside or circulate within the GI mucosa. For example, dendritic cells within the GI wall extend processes through epithelial lining cells to sample and capture luminal antigens. A type of cells in the epithelial lining called M cells also sample lumen antigens and transport them to antigen-presenting cells in the mucosa. 

Cells of the adaptive immune system (lymphocytes called T cells and B cells, see part two) are also present in the intestinal wall. B cells, which produce antibodies, secrete a specific type of antibody called IgA into the gut lumen. IgA antibodies can quickly neutralize potentially invading pathogens in the gut. Immune responses to symbiotic organisms and food antigens in the lumen of the intestinal tract are minimized by selective expression of pattern recognition receptors on epithelial lining cells and by the generation of regulatory T cells that suppress adaptive immune responses (we’ll learn more about immunological tolerance in part two of this series). 


Figure 5 - The intestinal epithelial barrier. Adapted from Liu Q, et al. Microb Cell Fact 19, 23 (2020). https://doi.org/10.1186/s12934-020-1289-4. Licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Figure 5 - The intestinal epithelial barrier. 
Adapted from Liu Q, et al. Microb Cell Fact 19, 23 (2020). https://doi.org/10.1186/s12934-020-1289-4. 
Licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


If you want to learn more about the interaction between the immune system and gut microbes, check out our article on how the gut microbiota influences our immune system.

Other Regional Immune Systems 

The skin also houses a large community of harmless microbes. Similarly to the gut’s immune system, the cutaneous immune system must defend us against invasion by microbes while also suppressing responses against symbiotic microbes. The epidermis creates a physical barrier against microbial invasion, and epidermal cells (keratinocytes) provide a chemical barrier through the secretion of antimicrobial molecules and inflammatory mediators. The dermis contains mast cells, macrophages, and dendritic cells that respond to microbes and injury and mediate inflammatory responses. Skin dendritic cells mediate innate immune responses and transport antigens that enter through the skin to lymph nodes, where they trigger adaptive immune responses. 

Mucosal immunity in the respiratory system defends against airborne pathogens. First line immunity in the respiratory tract depends on the epithelial lining, which produces mucus and, through the vibration of hairlike structures (called cilia) on the cell surface, moves the mucus with entrapped microbes out of the lungs. Antimicrobial proteins, surfactant proteins, and alveolar macrophages provide additional defenses. Immunosuppressive cells and cytokines in the respiratory tract help prevent harmful responses to non-pathogenic organisms or other inhaled antigens.

Regional immune systems in the gastrointestinal tract, skin, and respiratory tract provide specialized immune responses in these points of entry of pathogens into our body.

The Importance of a Healthy Innate Immune System

One of the factors that take a big toll on immunity is aging. Aging is associated with a number of changes that affect every component of the immune system. These age-related changes are known as “immunosenescence” and they contribute significantly to an increase in the susceptibility to infections as we age. [4,5] 

Age-related changes in the immune system are complex, but, in general, they involve a combination of changes in the cells of the immune system, in the tissues where they reside, and in the circulating factors and signaling molecules that support the activity and homeostasis of the immune system. 

Age-related changes in the innate immune system include reductions in PRR signaling and in the phagocytic function of neutrophils; defective responses to PAMPs and reduced phagocytic capacity and efficacy of macrophages; reduced activity (cytokine secretion and cytotoxicity) of NK cells; reduced uptake of antigens and/or microbes by dendritic cells and consequent diminished ability to present antigens to lymphocytes. The migratory capacity of cells is also affected, as well as their secretory activity; the production and activity of signaling molecules is thus also affected, which contributes to a decreased efficacy in the communication and cross-activation of immune cells. Together, these changes lead to a reduced ability to block and fight infections.

Immunosenescence is a natural and inescapable process, but like all the other natural aging processes, there are environmental and lifestyle factors that accelerate its progression. Therefore, interventions that may support healthy aging may also support our immune system’s health, and consequently, contribute to an extension of our healthspan. [4,5]

One of the hallmarks of immunosenescence, the age-related remodeling of the immune system, is a decreased ability to respond to new threats.


References

[1] A.K. Abbas, A.H.H. Lichtman, S. Pillai, Cellular and Molecular Immunology E-Book, Elsevier Health Sciences, 2017.
[2] K.M. Murphy, C. Weaver, Janeway’s Immunobiology: Ninth International Student Edition, W.W. Norton & Company, 2016.
[3] J. Punt, S. Stranford, P. Jones, J. Owen, Kuby Immunology, Macmillan Learning, 2018.
[4] J. Nikolich-Žugich, The twilight of immunity: emerging concepts in aging of the immune system, Nat. Immunol. 19 (2018) 10–19. https://doi.org/10.1038/s41590-017-0006-x.
[5] E. Montecino-Rodriguez, B. Berent-Maoz, K. Dorshkind, Causes, consequences, and reversal of immune system aging, J. Clin. Invest. 123 (2013) 958–965. https://doi.org/10.1172/JCI64096.

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