Natural Killer Cells
Natural killer cells are part of the innate immune response that recognize abnormal MHC I molecules on infected/tumor cells and kill them.
Describe the role of natural killer cells in the immune response
- Natural killer (NK) cells are lymphocytes (a subclass of white blood cells) that recognize infected or tumorogenic cells and kill them.
- Unlike the related T cells, NK cells do not recognize fragments of the infecting particle, but rather the incorrect display of major histocompatibility complex ( MHC ) I molecules.
- NK cells are always active, but will not perform their killing function on cells with intact MHC I molecules.
- When NK cells detect an infected or tumor cell, they secrete granules that contain perforin, creating a pore in the target cell; granzymes then pass through these pores, degrading cellular proteins, causing cells to undergo apoptosis.
- lymphocyte: a type of white blood cell or leukocyte that is divided into two principal groups and a null group: B-cells, T-cells, and natural killer (NK) cells
- major histocompatibility complex: a protein present on the extracellular surface of the cell that displays portions of the proteins that are degraded inside the cell
- T cell: a lymphocyte, from the thymus, that can recognize specific antigens and can activate or deactivate other immune cells
Natural killer cells
Lymphocytes are leukocytes (white blood cells) that are histologically identifiable by their large, darkly-staining nuclei; they are small cells with very little cytoplasm. After a pathogen enters the body, infected cells are identified and destroyed by natural killer (NK) cells, which are a type of lymphocyte that can kill cells infected with viruses or tumor cells (abnormal cells that uncontrollably divide and invade other tissue). While NK cells are part of the innate immune response, they are best understood relative to their counterparts in the adaptive immune response,T cells, which are also classified as lymphocytes.
T cells are lymphocytes that mature in the thymus gland and identify intracellular infections, especially from viruses, by the altered expression of major histocompatibility class (MHC) I molecules on the surface of infected cells. MHC I molecules are proteins on the surfaces of all nucleated cells which help the immune system distinguish between “self” and “non-self.” If the cell is infected, the MHC I molecules display fragments of proteins from the infectious agents to T-cells. Healthy cells do not display any proteins and will be ignored by the immune system, while the cells identified as “non-self” by foreign proteins will be attacked by the immune system.
An infected cell (or a tumor cell) is often incapable of synthesizing and displaying MHC I molecules appropriately. The metabolic resources of cells infected by some viruses produce proteins that interfere with MHC I processing and/or trafficking to the cell surface. The reduced MHC I on host cells varies from virus to virus and results from active inhibitors being produced by the viruses. This process can deplete host MHC I molecules on the cell surface, which prevents T-cells from recognizing them, but which NK cells detect as “unhealthy” or “abnormal” while searching for cellular MHC I molecules. As such, NK cells offer a complementary check for unhealthy cells, relative to T cells. Similarly, the dramatically-altered gene expression of tumor cells leads to expression of extremely- deformed or absent MHC I molecules that also signal “unhealthy” or “abnormal.”
NK cells are always active; an interaction with normal, intact MHC I molecules on a healthy cell disables the killing sequence, causing the NK cell to move on. After the NK cell detects an infected or tumor cell, its cytoplasm secretes granules comprised of perforin: a destructive protein that creates a pore in the target cell. Granzymes are released along with the perforin in the immunological synapse. A granzyme, a protease that digests cellular proteins, induces the target cell to undergo programmed cell death, or apoptosis. Phagocytic cells then digest the cell debris left behind. NK cells are constantly patrolling the body. They are an effective mechanism for controlling potential infections and preventing cancer progression.
Physical and Chemical Barriers
The innate immune response has physical and chemical barriers that exist as the first line of defense against infectious pathogens.
Describe physical and chemical barriers in the innate immune response
- The skin, or epithelial surface, serves as the primary barrier to microbial entry into the body; skin peeling, drying out, and the skin’s acidity all serve to dislodge or kill foreign pathogens.
- Orifices such as the eyes and mouth, which are not covered by skin, have other mechanisms by which they prevent entry; tears wash away microbes, while cilia in the nasal passages and respiratory tract push mucus (which traps pathogens) out of the body.
- Many chemical barriers also exist once pathogens make it past the outer physical barriers; the acidity of the stomach ensures that few organisms arriving with food survive the digestive system.
- cilium: a hairlike organelle projecting from a eukaryotic cell (such as unicellular organism or one cell of a multicelled organism), which serves either for locomotion by moving or as sensors
- microbicidal: functioning to reduce the infectivity of microbes
Physical and chemical barriers
The immune system comprises both innate and adaptive immune responses. Innate immunity occurs naturally due to genetic factors or physiology. It is not induced by infection or vaccination, but is constantly available to reduce the workload for the adaptive immune response. The adaptive immune response expands over time, storing information about past infections and mounting pathogen-specific defenses. Both the innate and adaptive levels of the immune response involve secreted proteins, receptor-mediated signaling, and intricate cell -to-cell communication. From an historical perspective, the innate immune system developed early in animal evolution, roughly a billion years ago, as an essential response to infection. In the innate immune response, any pathogenic threat triggers a consistent sequence of events that can identify the type of pathogen and either clear the infection independently or mobilize a highly-specialized adaptive immune response.
Before any immune factors are triggered, the skin (also known as the epithelial surface) functions as a continuous, impassable barrier to potentially-infectious pathogens. The skin is considered the first defense of the innate immune system; it is the first of the nonspecific barrier defenses. Pathogens are killed or inactivated on the skin by desiccation (drying out) and by the skin’s acidity. In addition, beneficial microorganisms that coexist on the skin compete with invading pathogens, preventing infection. Desquamation, or peeling skin, also serves to dislodge organisms that have adhered to the surface of the body and are awaiting entry. Regions of the body that are not protected by skin (such as the eyes and mucous membranes ) have alternative methods of defense. These include tears in the eyes; mucous membranes that provide partial protection despite having to allow absorption and secretion; mucus secretions that trap and rinse away pathogens; and cilia (singular cilium) in the nasal passages and respiratory tract that push the mucus with the pathogens out of the body. Furthermore, tears and mucus secretions contain microbicidal factors that prevent many infections from entering via these routes.
Despite these barriers, pathogens may enter the body through skin abrasions or punctures, or by collecting on mucosal surfaces in large numbers that overcome the mucus or cilia. Some pathogens have evolved specific mechanisms that allow them to overcome physical and chemical barriers.
Once inside, the body still has many other defenses, including chemical barriers. Some of these include the low pH of the stomach, which inhibits the growth of pathogens; blood proteins that bind and disrupt bacterial cell membranes; and the process of urination, which flushes pathogens from the urinary tract. The blood-brain barrier also protects the nervous system from pathogens that have already entered the blood stream, but would do significantly more damage if they entered the central nervous system.
The Complement System
Around 20 soluble proteins comprise the complement system, which helps destroy extracellular microorganisms that have invaded the body.
Explain how the complement system aids antibody response
- The complement system is so named because it is complementary to the antibody response of the adaptive immune system.
- The complement system proteins are produced continuously by the liver and macrophages, are abundant in the blood serum, and are capable of immediate response to infecting microorganisms.
- The complement system works by first having several proteins bind to a target; this binding event then begins a series of highly-specific and regulated sequences wherein successive proteins are activated by cleavage and/or structural changes of the preceding proteins.
- The complement system serves as a marker to indicate targets for phagocytic cells; complement proteins can also combine to form attack complexes capable of opening pores in microbial cell membranes.
- opsonization: the process by which a pathogen is marked for ingestion and destruction by a phagocyte
- complement system: an aspect of the innate immune system that supplements the actions of the antibodies and phagocytic cells in clearing out pathogens from an organism
The innate immune system serves as a first responder to pathogenic threats that bypass natural physical and chemical barriers of the body. Using a combination of cellular and molecular attacks, the innate immune system identifies the nature of a pathogen and responds with inflammation, phagocytosis (where a cell engulfs a foreign particle), cytokine release, destruction by NK cells, and/or a complement system. In this concept, we will discuss the complement system.
An array of approximately 20 types of soluble proteins, called a complement system, functions to destroy extracellular pathogens. Cells of the liver and macrophages synthesize complement proteins continuously. These proteins are abundant in the blood serum and are capable of responding immediately to infecting microorganisms. The complement system is so named because it is complementary to the antibody response of the adaptive immune system. Complement proteins bind to the surfaces of microorganisms and are particularly attracted to pathogens that are already bound by antibodies. Binding of complement proteins occurs in a specific and highly-regulated sequence, with each successive protein being activated by cleavage and/or structural changes induced upon binding of the preceding protein(s). After the first few complement proteins bind, a cascade of sequential binding events follows in which the pathogen rapidly becomes coated in complement proteins.
Complement proteins perform several functions. They serve as a marker to indicate the presence of a pathogen to phagocytic cells, such as macrophages and B cells, to enhance engulfment. This process is called opsonization. Certain complement proteins can combine to form attack complexes that open pores in microbial cell membranes. These structures destroy pathogens by causing their contents to leak. When innate mechanisms are insufficient to clear an infection, the adaptive immune response is informed and mobilized.
Upon pathogen entry to the body, the innate immune system uses several mechanisms to destroy the pathogen and any cells it has infected.
Describe the role of PAMPs and PRRs, interferons, and other cytokines in innate immunity
- Pathogens are recognized by a variety of immune cells, such as macrophages and dendritic cells, via pathogen-associated molecular patterns (PAMPs) on the pathogen surface, which interact with complementary pattern-recognition receptors (PRRs) on the immune cells’ surfaces.
- Upon binding of PRRs with PAMPs (pathogen recognition), immune cells release cytokines to tell other cells to start fighting back.
- One class of cytokines, interferons, warn nearby uninfected cells of impending infection, cause cells to start cleaving RNA and reduce protein synthesis, and signal nearby infected cells to undergo apoptosis.
- Another class of cytokines, called inerleukins, mediate interactions between white blood cells ( leukocytes ) and help bridge the innate and adaptive immune responses.
- Inflammation (hot, red, swollen, painful tissue associated with infection) is encouraged by cytokines that are produced immediately upon pathogen recognition; the increase in blood flow associated with inflammation allows more leukocytes (a type of innate immune cell) to reach the infected area.
- macrophage: a white blood cell that phagocytizes necrotic cell debris and foreign material, including viruses, bacteria, and tattoo ink; part of the innate immune system
- phagocytosis: the process where a cell incorporates a particle by extending pseudopodia and drawing the particle into a vacuole of its cytoplasm
- cytokine: any of various small regulatory proteins that regulate the cells of the immune system; they are released upon binding of PRRs to PAMPS
When a pathogen enters the body, cells in the blood and lymph detect the specific pathogen-associated molecular patterns (PAMPs) on the pathogen’s surface. PAMPs are carbohydrate, polypeptide, and nucleic acid “signatures” that are expressed by viruses, bacteria, and parasites, but which differ from molecules on host cells. These PAMPs allow the immune system to recognize “self” from “other” so as not to destroy the host.
The immune system has specific cells with receptors that recognize these PAMPs. A macrophage is a large, phagocytic cell that engulfs foreign particles and pathogens. Macrophages recognize PAMPs via complementary pattern recognition receptors (PRRs). PRRs are molecules on macrophages and dendritic cells which are in contact with the external environment and can thus recognize PAMPs when present. A monocyte, a type of leukocyte (white blood cell) that circulates in the blood and lymph, differentiates into macrophages after it moves into infected tissue. Dendritic cells bind molecular signatures of pathogens, promoting pathogen engulfment and destruction.
Once a pathogen is detected, the immune system must also track whether it is replicating intracellularly (inside the cell, as with most viruses and some bacteria) or extracellularly (outside of the cell, as with other bacteria, but not viruses). The innate immune system must respond accordingly by identifying the extracellular pathogen and/or by identifying host cells that have already been infected.
Cytokine release affect
The binding of PRRs with PAMPs triggers the release of cytokines, which signal that a pathogen is present and needs to be destroyed along with any infected cells. A cytokine is a chemical messenger that regulates cell differentiation (form and function), proliferation (production), and gene expression to affect immune responses. At least 40 types of cytokines exist in humans that differ in terms of the cell type that produces them, the cell type that responds to them, and the changes they produce.
One subclass of cytokines is the interleukin (IL), which mediates interactions between leukocytes (white blood cells). Interleukins are involved in bridging the innate and adaptive immune responses. In addition to being released from cells after PAMP recognition, cytokines are released by the infected cells which bind to nearby uninfected cells, inducing those cells to release cytokines, resulting in a cytokine burst.
A second class of cytokines is interferons, which are released by infected cells as a warning to nearby uninfected cells. A function an interferons is to inhibit viral replication, making them particularly effective against viruses. They also have other important functions, such as tumor surveillance. Interferons work by signaling neighboring uninfected cells to destroy RNA (often a very important biomolecule for viruses) and reduce protein synthesis; signaling neighboring infected cells to undergo apoptosis (programmed cell death); and activating immune cells.
Cytokines also send feedback to cells of the nervous system to bring about the overall symptoms of feeling sick, which include lethargy, muscle pain, and nausea. These effects may have evolved because the symptoms encourage the individual to rest, preventing them from spreading the infection to others. Cytokines also increase the core body temperature, causing a fever, which causes the liver to withhold iron from the blood. Without iron, certain pathogens (such as some bacteria) are unable to replicate; this is called nutritional immunity.
Phagocytosis and inflammation
The first cytokines to be produced are pro-inflammatory; that is, they encourage inflammation, or the localized redness, swelling (edema), heat, loss of function, and pain that result from the movement of leukocytes and fluid through increasingly-permeable capillaries to a site of infection. The population of leukocytes that arrives at an infection site depends on the nature of the infecting pathogen. Both macrophages and dendritic cells engulf pathogens and cellular debris through phagocytosis. A neutrophil is also a phagocytic leukocyte that engulfs and digests pathogens. Neutrophils, the most-abundant leukocytes of the immune system, have a nucleus with two to five lobes and contain organelles (lysosomes) that digest engulfed pathogens. An eosinophil is a leukocyte that works with other eosinophils to surround a parasite. It is involved in the allergic response and in protection against helminthes (parasitic worms).
Neutrophils and eosinophils are particularly important leukocytes that engulf large pathogens, such as bacteria and fungi. A mast cell is a leukocyte that produces inflammatory molecules, such as histamine, in response to large pathogens. A basophil is a leukocyte that, like a neutrophil, releases chemicals to stimulate the inflammatory response. Basophils are also involved in allergy and hypersensitivity responses and induce specific types of inflammatory responses. Eosinophils and basophils produce additional inflammatory mediators to recruit more leukocytes. A hypersensitive immune response to harmless antigens, such as in pollen, often involves the release of histamine by basophils and mast cells; this is why many anti-allergy medications are anti-histamines.