Liz is a licensed veterinary medical technologist with an interest in zoonotic diseases, comparative medicine, and One Health.
The Immune System
Immunology is the study of the immune system and its associated functions. Immunity is how the body attempts to prevent disease. The immune system is broken down into two main parts: innate immunity and adaptive immunity. In innate immunity, the individual is "just born with it;" it is non-changing and non-specific. Its primary function is to keep potential pathogens outside of the body. Innate immunity is further broken down into first and second line defenders. Examples of first line defenders include barriers, such as the skin and mucous membranes. Examples of second line defenders include inflammatory responses, macrophages, granulocytes, the compliment system, and cell signaling molecules. Adaptive immunity is considered the third line defender. In contrast to innate immunity, adaptive immunity matures after birth, is constantly changing throughout the lifespan, and is specific. Adaptive immunity can be further broken down into humeral immunity (B-cells) and cellular immunity (T-cytotoxic cells).
The Barriers of the Immune System
The best ways to avoid illness are to avoid coming into contact with pathogens in the first place or to keep them outside of the body. This is the function of the barriers. The barriers consist of the skin, and mucous membranes, and associated structures. These are continuous organs, and anything on the surface of these tissues is considered exterior to the body; for example, the contents of the stomach are actually considered external to the stomach because they are separated by the mucous membranes that line the inside of the stomach.
The skin is composed of multiple elastic, keratinized layers of cells. Skin cells are continually dividing and pushing cells outwards, with multiple layers of dead cells at the surface that continually flake off and carry away microorganisms. The skin is essentially waterproof in association with hair follicles, pores, sweat glands, and sebaceous glands that secrete oils. The skin is surprisingly arid with very low moisture on the surface that is enhanced by sweat glands that produce salt, which eliminates water availability to microorganisms and therefore aids to control their population.
The mucous membranes include the eyes, the oral cavity, the nasal cavity, the esophagus, lungs, the stomach, intestines, and the urogenital tract. These structures are thin, flexible, and some are multilayered. For example, the esophagus has multiple layers for protection, but the lungs are not multilayered in order to allow for gas transmission (oxygen and carbon dioxide exchange). The existence of layers is to prevent a breach in the system when one or two layers of cells are scrapped off. With multiple layers of cells in place (such as the esophagus), minimal damage is done upon removal of one layer. In cases where only one layer of cells exists (the lungs), removal of the only layer leads to a breach in the system and is considered very serious.
Lacrima is a fluid produced by the lacrimal glands around the eyes and serves to continually flush the eyes. Both lacrima and saliva contain the chemical lysozyme, a digestive enzyme that breaks down peptidoglycan, which reduces the presence of gram negative organisms by breaking down their protective peptidoglycan coatings. Saliva, lacrima, and the captured bacteria are sent to the stomach after use. The stomach contains gastric acid, which is efficient in killing microorganisms, leaving the following small intestine virtually (but not entirely) sterile.
We continually breathe in particles that carry microorganisms. However, because of the mucociliary escalator within the nasal/oral cavities, very little debris makes to the delicate, single epithelial layer of the lungs. The mucous membranes of the trachea and bronchioles have ciliated epithelium and goblet cells that produce mucous that trap debris and microorganisms. After inhaling contaminants, the particles get caught in the mucous, where the cilia continuously move it upwards until it is either coughed up or swallowed and broken down by the stomach.
Inflammation and Cellular Functions
The inflammatory response is a process that recruits immune cells to an injury or wound site. Signs of inflammation include redness, swelling, heat, and pain. The process starts immediately after injury with mast cells that release histamine and other signaling molecules that cause vasodilation, which is the expansion and increased permeability of the blood vessels. The expansion of the vessels increases blood flow to that area of interest, hence the observable redness and sometimes bleeding. The increased vessel permeability allows more plasma to enter the tissues and become interstitial fluid, causing edema (swelling). This allows the immune cells to move from the bloodstream into the tissues more readily. With increased blood flow and increased metabolic activity, there will be an increase in heat (or a localized "fever") at the site. Pain is primarily a secondary effect of swelling, due to the increased interstitial fluid putting pressure on the local nerve endings. Lymph vessels secondarily absorb the edema and return it to the blood stream, but in the process, the fluid and the cells that it contains pass through the lymph nodes. The primary purpose of the lymph nodes are to introduce antigen to the lymphocytes. The cells moving to the site of inflammation are neutrophils, basophils, eosinophils, macrophages, and dendritic cells.
The neutrophils’ primary function is to capture and break down organisms. They are filled with lysozymes and capture organisms via phagocytosis (or "cell eating"). They ingest the organism and fuse the granules with the vacuole containing the organism, killing it. When all the granules within a cell are used, the cell dies. They can also release granules into the surrounding tissues in an attempt to kill more organisms. If grayish pus is observed, dead neutrophils are predominantly present.
Eosinophils are primarily involved in allergic reactions, sometimes releasing histamines. Basophils produce histamine and, like eosinophils, are usually involved in killing parasites. Macrophages wander the body and behave similarly to neutrophils by going into tissues and trapping organisms. They cannot capture as many organisms as neutrophils, but they are much longer lived and remain active in the immune process for a much longer time. Dendritic cells function to capture the invading organisms, then take them to the lymph nodes to initiate the adaptive immune response.
Dendritic cells are “professional antigen-presenting cells” and actually stimulate the adaptive immune response. They are part of the group of cells termed antigen-preventing cells (APCs). They migrate to the site of a breach and engulf a microorganism, then plant an antigen from the organism on their surface. These are called epitopes. Here, the antigens can be examined by other cells, specifically B-cells. From there, they then migrate to the lymph nodes.
Ideally, infection stops at the site of inflammation: however, that does not always occur as microorganisms can move into the bloodstream. This is where cell signaling molecules come into play. Bacteria can be recognized by pattern receptors, which recognize complex repeating patterns such as peptidoglycan. This allows Gram positive cells to be easily recognized.
The Compliment System and Fever
The compliment system is a cascade system, where one step causes the next step to occur. This system is a series of proteins that circulate in the blood and the fluid that bathes the tissues. It can be activated by three different pathways; alternative, lectin, and classical. The alternative pathway is triggered when C3b binds to foreign cell surfaces. This binding allows other complement proteins to then attach, eventually forming the C3 convertase. Activation via the lectin pathway involves pattern recognition molecules called mannose-binding lectins. Once a mannose-binding lectin attaches to a surface, it interacts with other complement systems to form a C3 convertase. Activation by the classical pathway requires antibodies and involves the same components involved with the lectin pathway to form a C3 convertase.
There are three possible outcomes of the compliment system: stimulation of the inflammatory response, lysis of foreign cells, and opsonization. When lysing foreign cells, proteins create porins (holes) in the cell membrane of bacteria cells so that the internal contents of the cell leak out and the cell dies. Opsonization is essentially a protein flagging system, signaling macrophages to come and phagocytize whatever the proteins are attached to.
Sometimes, microorganisms enter the bloodstream and release molecules that are pyrogenic. This stimulates the hypothalamus (the body’s “thermostat”), causing fever. The idea here is that by increasing body temperature, the growth rate of bacteria will be reduced. There are two problems with this system, however, one being that human neurons are highly sensitive to temperature increases; if fever remains too high (103- 104 degrees F) for a long period of time, seizures and potentially neural death can occur. The other problem is that fever generally does not reach body temperatures high enough to significantly diminish bacterial growth.
Adaptive Immunity and Antibodies
Adaptive immunity can be broken down into humeral immunity (B-cells) and cellular immunity (T-cytotoxic cells). B cells are released immature, and every B-cell has a B-cell receptor. Immature B-cells test the antigens presented by the dendritic cells that they encounter, looking for a match to their receptor. If a match occurs and there is no T-helper cell, then the B-cell cell will undergo apoptosis and die, a process known as clonal deletion. The purpose here is to prevent the B-cell from maturing and producing self-antigen, causing autoimmunity. However, if a T-helper cell is present, the T- cell will confirm the match and signal the naïve B-cell to mature. In the process, the T-helper cell refines the match between the antigen and its B-cell receptor, helping it to become more specific. The B-cell then undergoes colonel expansion and makes one of two possible copies of itself: B-memory cells and plasma cells. Memory cells keep their receptor with the more refined endings and are more specific to secondary immune responses. Plasma cells do not have a receptor, and instead make Y-shaped copies of the B-cell receptor and releases them. When the receptors are no longer attached to the cell, they are called antibodies.
There are five classes of antibodies: IgM, IgG, IgA, IgE, and IgD. IgM eventually converts to IgG, and mainly undergoes cross-linking because it has ten binding sites. IgG is the predominant antibody circulating in the bloodstream and is also the longest lasting. IgA is found in mucus and other similar secretions. It forms dimers and is highly involved in upper respiratory infection prevention in infants that are breast fed. IgE commonly circulates in the bloodstream and is primarily involved in allergic reactions. Little is known about the function of IgD other than its involvement in the development and maturation of the antibody response.
Understanding antibodies is very important when discussing immunizations. Immunizations, or vaccines, are an attempt to stimulate the production of antibodies prior to actually meeting any antigens; they induce the primary immune response. When a vaccinated individual is later exposed to a pathogen with the same antigen as introduced by the vaccine, the reaction immediately becomes a secondary immune response.
Secondary, Humoral, and Cellular Immunity
The secondary immune response is more effective than the primary response because the memory cells recognize the antigen and immediately divide into effector cells. However, the memory cells associated with secondary immunity are not immortal; after about ten years or so, all the memory cells associated with a specific antigen have mostly all died off. If a specific pathogen occasionally makes it into the blood circulation, the individual is periodically re-exposed and continues to get periodic secondary responses. In this way, new memory cells to this specific antigen are continuously created, keeping the individual’s immunity ongoing. However, if an individual is not re-exposed to a pathogen for a long period of time, the secondary immune system will eventually become immunologically naïve to the specific pathogen again. This explains why it is recommended to get booster vaccines periodically, especially in cases such as tetanus.
There are six outcomes of antibody-antigen binding: neutralization, opsonization, complement system activation, cross-linking, immobilization and prevention of adherence, and antibody-dependent cellular cytotoxicity (ADCC). In neutralization, toxins or viruses are coated with antibodies and prevented from attaching to cells. IgG opsonizes antigens, making it easier for phagocytes to engulf them. Antigen –antibody complexes can trigger the classical pathway of complement system activation. The binding of antibodies to flagella and pili interferes with microbe motility and the ability to attach to cell surfaces, both capabilities that are often necessary for a pathogen to infect a host. In cross-linking, two arms of a Y-shaped antibody can bind separate but identical antigens, linking them all together. The effect is the formation of large antigen-antibody complexes, allowing for large amounts of antigens to be consumed by phagocytic cells at one time. ADCC creates “targets” on cells to be destroyed by natural killer (NK) cells. NK cells are another type of lymphocyte; unlike B-cells and T-cells, however, they lack specificity in their mechanisms of antibody recognition.
There is one major problem with humoral immunity. Antibodies circulate in the blood stream, capturing and attacking pathogens that are circulating there. However, not all pathogens are found in the blood stream. Pathogens such as viruses break into the body cells, whereas antibodies are incapable of actually entering the cells; if a virus goes into a cell, antibodies are rendered useless here. Humoral immunity acts only against pathogens that are extracellular. This is where there cellular immunity becomes important.
Cellular immunity is the function of T-cytotoxic cells. Essentially, T-cells kill infected host cells to interrupt the intracellular viral replication process. Much like B-cells, they are in immature and in circulation searching for a match to their T-cell receptor. The difference is that immature T-cells search for matches with their epitope with a MHCII molecule. When viruses infect a cell, portions of their proteins are left on the surface of the cell, basically serving as an indication that the cell is infected. If a match is found, the T-cell will replicate and go through colonel expansion. This includes producing more T-cytotoxic cells and some T- memory cells, but not antibodies. Once the T-cell has matured, it then searches for cells that are presenting a MHCI molecule containing the T-cells epitope. When the cell finds this pathogen on another cell, it releases cytokines to induce apoptosis in the other cell. This is an advantage in that it is an attempt to interrupt the replication of intracellular pathogens; if a cell that viruses are entering dies before viral replication is complete, then the virus is unable to spread to other cells. This also occurs with bacterial intracellular pathogens. If an immature T-cell finds its match in a MHCI molecule before finding it in a MHCII molecule, the naïve cell it will undergo colonel deletion and die in order to prevent autoimmunity.
MHCs are specific to an individual, their difference being the different structures they are found on. When undergoing organ transplants, surgeons try and “match” individuals. What they are actually matching are the MHC molecules and potential surface antigens, attempting to get them as close as possible in an attempt to prevent rejection. If the body recognizes transplanted tissue as foreign, it will attack that tissue and attempt to destroy it.
Types of Immunity, Immunological Testing, and Vaccines
In immunology, several variations of immunity are recognized. In active immunity, one has developed a current, functioning immune response to a pathogen. In passive immunity, one has the antibodies for a specific pathogen, but they were produced by another organism. With natural immunity, the individual must first become sick in order to produce the proper antibodies and acquire immunity. In artificial immunity, the body was essentially “tricked” into building up antibodies; this is the case with vaccinations. Natural active immunity is not necessarily desirable because the individual had to become sick first in order to attain it. In artificial active immunity, the individual was vaccinated, causing the body to produce antibodies in response. Artificial passive immunity results from immunization; antibodies that were made by an individual are administered to other individuals via vaccines. In natural passive immunity, a pregnant individual becomes sick or is vaccinated and her body then produces antibodies and passes them to her offspring via the placenta or milk, giving temporary immunity to the infant as well.
Immunological tests take antibodies against a pathogen or molecule and test for their presence. Antibody-antigen reactions are used for agglutination reactions (such as blood typing) and identification of specific microbes. Agglutination assays determine what antigens are present in a sample. For example, you go to the doctor with a sore throat and they perform a throat swab to test for streptococcus. This is a type of enzyme-linked immunosorbent assay (ELISA) test, which is also used in a similar way to determine pregnancy (by detecting the presence of hCG, which is only produced during pregnancy). Fluorescent antibody (FA) tests use fluorescent microscopy to locate fluorescently labeled antibodies bound to antigens fixed to a microscope slide. Several different fluorescent dyes, including fluorescein and rhodamine, can be used to label antibodies.
All of the aforementioned information is applied to vaccines. A vaccine is a preparation of a pathogen or its products, used to induce active immunity. The goal of a vaccine is herd immunity, which is a level of immunity in the population that prevents transmission of a pathogen amongst individuals within the group. The few individuals who are susceptible are typically so widely dispersed that if they acquired the disease, it would not be easily transmitted to others.
Vaccines fall within two basic groups: attenuated (live) and inactivated (killed). This refers to the state of the pathogen upon administration of the vaccine. Attenuated organisms have often been weakened to the point that the symptoms they cause are subclinical (go unnoticed) or very mild. A good example would be varicella (chicken pox) vaccines. These vaccines often produce a better immune response without the need for boosters. They are often safe, however, they can occassionally induce rare diseases (such as polio) in some individuals.
In inactivated vaccines, the whole agent, a subunit, or the product (toxin) has been treated with a substance such as formaldehyde to inactivate the disease-causing agent without damaging the antigens. In this way, the individual can still produce antibodies and develop an immune response without developing disease. These vaccines are typically safer than live vaccines, but often require periodic booster vaccines and require an adjuvant, or a chemical that encourages the development of the immune response in conjunction with the pathogen. Conjugate vaccines pair two pathogens and are given to an individual that is likely to form a strong reaction to one pathogen and a weak reaction to the other.
Immune System Problems
The immune system is an amazing structure, however, it does not always function correctly. There are three main categories of immune problems: hypersensitivity, autoimmunity, and immunodeficiency. Hypersensitivities occur when the immune system responds to a foreign antigen in an excessive, inappropriate fashion. There are four types of hypersensitivities. Type I hypersensitivities are the IgE mediated, common allergies. This is an immune response to a non-pathogenic antigen by which the immune system elicits the inflammatory response; the immune system is essentially “over-reacting.” The most common type of this reaction is seasonal allergies and the associated upper respiratory symptoms. If this reaction occurs in the blood stream, however, it can lead to a systemic reaction that can result in shock, or anaphylaxis. An example would be the anaphylactic reaction that occurs in a person who is allergic to bee stings. Typical treatment for severe type I hypersensitivities is desensitization, which is basically exposing the individual to the specified antigen with increasing amounts in an attempt to force the immune system from moving to an IGE response to a IgG response, which does not stimulate the powerful immune response.
Type II hypersensitivities are known as cytotoxic hypersensitivities. These occur in individuals whose antigens are foreign to the individual, but are found within the species. This results in the production of antibodies not against the self, but against other antigens from the same species. An example is a blood transfusion reaction; if you give someone who has type O blood type A or B blood, the reaction that occurs in their bloodstream causes mass death of the presented red blood cells. This makes blood typing before transfusions important. This reaction also occurs as hemolytic disease of the newborn (Erythroblastosis fetalis); this is when maternal antibodies cross the placenta to attack the Rh factor found on the fetal blood. This only occurs in an Rh- mother with an Rh+ fetus. The mother comes in contact with fetal blood during birth and starts producing antibodies. The first pregnancy is safe from this reaction, but each Rh+ child thereafter would be exposed to the antibodies, which destroys the infant’s red blood cells, leading to anemia or death at birth. An antibody (rhogan) is given to the mother before and after birth to prevent this immune response.
Type III hypersensitivities are immune complex mediated. These are essentially antibody-antigen interactions in which these complexes have been deposited in the tissues, particularly joints, which leads to chronic, ongoing inflammation. It is this localized inflammation that continually damages tissues, such as with rheumatoid arthritis.
Type IV hypersensitivities are delayed cell-mediated hypersensitivities. In this case, instead of antibodies being the mechanism for hypersensitivity, it is T-cells. These reactions take longer because the T-cells have to move to the target site and begin the response. Instead of an immediate reaction like with a bee sting, there is a delayed reaction, often a contact dermatitis. Examples include poison ivy, poison oak, and sumac reactions. Another, more severe example is skin graft rejections. In the medical field, we usually make use of this cell-mediated delay via the tuberculosis skin test.
Autoimmune disease occurs as an immune reaction to self-antigen; the body essentially attacks itself. It is not considered a hypersensitivity because the immune system is reacting against the body’s own tissues. Examples include type I diabetes, Grave’s disease, and systemic lupus. Type I diabetes (juvenile diabetes) kills the beta cells of pancreas. Grave's disease causes destruction of the thyroid tissues. Systemic lupus causes antibody production against the nuclear portions of the body’s own cells.
Immune deficiencies are essentially a general lack of immunity; the body is unable to initiate a sufficient immune response. Deficiencies can be either primary or secondary. Primary means that the deficiency is genetic, or a result of a condition in the individual. Secondary means that an event happened to cause the deficiency, either as a result of surgery or AIDS secondary to HIV infection. Human Immunodeficiency Virus infects T-helper cells and initiates cellular immunity, gradually wiping out the humeral immune response. With untreated HIV, the body initially displays a flu like syndrome known as antiretroviral syndrome. Over time, the body develops secondary immune deficiencies, making the body susceptible to a variety of opportunistic infections that the immune system fails to suppress. Without treatment, this condition sometimes ends in death from a secondary illness, oftentimes one as simple as the common cold. For more information on immune system disorders, refer to Basic Immunology: Functions and Disorders of the Immune System 5th Edition.
- Microbiology/Immunology college courses reference notes
- Personal knowledge/experience gained through related veterinary work
- Proofreading/fact checking performed by microbiologist colleague
© 2018 Liz Hardin