Internal defense mechanisms
Inflammation
If pathogens manage to breach the barriers protecting the body, one of the first active responses of the innate immune system kicks in. This response is inflammation. The main function of inflammation is to establish a physical barrier against the spread of infection. It also eliminates the initial cause of cell injury, clears out dead cells and tissues damaged from the original insult, and initiates tissue repair.
Inflammation is often a response to infection by pathogens, but there are other possible causes, including physical trauma, such as a cut or a blow, burns, frostbite, and exposure to toxins. The signs and symptoms of inflammation include localized redness, swelling, warmth, pain, and frequently some loss of function. These symptoms are caused by increased blood flow into infected tissue, and a number of other processes, illustrated in Figure 10.2.
Figure 10.2: White blood cells (leukocytes) release chemicals to stimulate the inflammatory response following a cut in the skin. For instance, the break in the skin caused by a paper cut could provide an easy way for bacteria to enter the human body.
Inflammation is triggered by chemicals such as cytokines and histamines, which are released by injured or infected cells, or by immune system cells such as macrophages that are already present in tissues. These chemicals cause capillaries to dilate and become leaky, increasing blood flow to the infected area and allowing blood to enter the tissues. Pathogen-destroying leukocytes and tissue-repairing proteins migrate into tissue spaces from the bloodstream to attack pathogens and repair their damage.
Various kinds of leukocytes are attracted to the area of inflammation. The types of leukocytes that arrive at an inflamed site depend on the nature of the injury or infecting pathogen. For example, a neutrophil is an early arriving white blood cell that engulfs and digests pathogens. Macrophages follow neutrophils and take over the phagocytosis function and are involved in the resolution of an inflamed site, cleaning up cell debris and pathogens.
A cytokine is a chemical messenger that regulates cell differentiation (form and function), proliferation (production), and gene expression to produce a variety of immune responses. Approximately 40 types of cytokines exist in humans. Cytokines promote chemotaxis, which is migration to the site of infection by pathogen-destroying leukocytes. In addition to being released from white blood cells after pathogen recognition, cytokines are also released by the infected cells and bind to nearby uninfected cells, inducing those cells to release cytokines. This positive feedback loop results in a burst of cytokine production. Some cytokines have anti-viral effects. They may shut down protein synthesis in host cells, which viruses need in order to survive and replicate. Cytokines send feedback to cells of the nervous system to bring about the overall symptoms of feeling sick, which include lethargy, muscle pain, and nausea. Cytokines also increase the core body temperature, causing a fever. The elevated temperatures of a fever inhibit the growth of pathogens and speed up cellular repair processes. For these reasons, suppression of fevers should be limited to those that are dangerously high.
One class of early-acting cytokines is the interferons, which are released by infected cells as a warning to nearby uninfected cells. An interferon is a small protein that signals a viral infection to other cells. The interferons stimulate uninfected cells to produce compounds that interfere with viral replication. Interferons also activate macrophages and other cells.
Phagocytosis
Phagocytosis is an important feature of innate immunity that is performed by cells classified as phagocytes. Phagocytes are leukocytes that kill pathogens by phagocytosis and they include neutrophils, macrophages, and dendritic cells.
The phagocytosis process is shown in Figure 10.3. In the process of phagocytosis, phagocytes engulf and digest pathogens or other harmful particles. Phagocytes generally patrol the body searching for pathogens, but they can also be called to specific locations by the release of cytokines when inflammation occurs. Some phagocytes reside permanently in certain tissues. When a pathogen such as a bacterium is encountered by a phagocyte, the phagocyte extends a portion of its plasma membrane, wrapping the membrane around the pathogen until it is enveloped. Once inside the phagocyte, the pathogen becomes enclosed within an intracellular vesicle called phagosome. The phagosome then fuses with another vesicle called lysosome, forming a phagolysosome. Digestive enzymes and acids from the lysosome kill and digest the pathogen in the phagolysosome. The final step of phagocytosis is excretion of soluble debris from the destroyed pathogen through exocytosis.
Figure 10.3: Phagocytosis is a multi-step process in which a pathogen is engulfed and digested by immune cells called phagocytes.
Complement system
The complement system is a complex biochemical mechanism named for its ability to “complement” the killing of pathogens by specific proteins called antibodies, which are produced as part of an adaptive immune response. The complement system is so named because it is complementary to the innate and adaptive immune system.
The complement system consists of more than two dozen proteins normally found in the blood and synthesized in the liver. Liver cells and macrophages synthesize inactive forms of complement proteins continuously; these proteins are abundant in the blood serum and are capable of responding immediately to infecting microorganisms. The complement proteins usually circulate as non-functional precursor molecules until activated. Then, they bind to the surfaces of microorganisms and are particularly attracted to pathogens that are already “tagged” by the adaptive immune system. When they attach to the pathogen (or “tag” the pathogen), the antibodies change shape providing a binding site for one of the complement proteins. As shown in Figure 10.4, when the first protein in the complement series is activated, typically by the binding of an antibody to an antigen on a pathogen, it sets in motion a domino effect. A cascade of binding in a specific sequence of proteins follows, in which the pathogen rapidly becomes coated in complement proteins. This precise chain of steps is known as the complement cascade. The end product is a cylinder that punctures a hole in the pathogen’s cell membrane. The hole allows fluids and molecules to flow in and out of the cell, which swells and bursts.
Complement proteins perform several functions, one of which is to serve as a marker to indicate the presence of a pathogen to phagocytic cells and enhance engulfment. Certain complement proteins can combine to open pores in microbial cell membranes and cause lysis (bursting) of the cells.
Figure 10.4: The complement system is a cascade of proteins that complements the killing of pathogen cells by antibodies.
Natural killer cells
A lymphocyte is a leukocyte that contains a large nucleus (Figure 10.5). Most lymphocytes are associated with the adaptive immune response, but infected cells are identified and destroyed by natural killer cells, the only lymphocytes of the innate immune system. A natural killer (NK) cell is a lymphocyte that can kill cells infected with viruses or cancerous cells.
NK cells identify intracellular infections, especially from viruses, by the altered expression of Major Histocompatibility Class I (MHC I) molecules on the surface of infected cells. MHC I molecules are proteins on the surfaces of all nucleated cells that provide a sample of the cell’s internal environment at any given time. Unhealthy cells, whether infected or cancerous, display an altered MHC I complement on their cell surfaces.
After a NK cell detects an infected or tumor cell, it induces programmed cell death or apoptosis. Phagocytic cells then come along and digest the cell debris left behind. NK cells are constantly patrolling the body and are an effective mechanism for controlling potential infections and preventing cancer progression.
Figure 10.5: Lymphocytes, such as NK cells, are characterized by their large nuclei that actively absorb Wright stain and therefore appear dark colored under a microscope (credit: scale-bar data from Matt Russell).
Innate immune evasion
Many pathogens have evolved mechanisms that allow them to evade human hosts’ innate immune systems. Some of these mechanisms include:
- Invading host cells to replicate so they are “hidden” from the immune system. The bacterium that causes tuberculosis uses this mechanism.
- Forming a protective capsule around themselves to avoid being destroyed by immune system cells. This defense occurs in bacteria, such as Salmonella species.
- Mimicking host cells so the immune system does not recognize them as foreign. Some species of Staphylococcus bacteria use this mechanism.
- Directly killing phagocytes. This ability evolved in several species of bacteria, including the species that causes anthrax.
- Producing molecules that prevent the formation of interferons, which are immune chemicals that fight viruses. Some influenza viruses have this capability.
- Forming complex biofilms that provide protection from the cells and proteins of the immune system. This characterizes some species of bacteria and fungi.
References:
- Fowler, Samantha, et al. Concepts of Biology. OpenStax College, Rice University, 2013. Download for free at: https://openstax.org/details/books/concepts-biology.
- Miller, Christine, Human Biology, 2020. Terms of use: This work is licensed under a Creative Commons Attribution NonCommercial. The original version can be found here.