Terry M. Bella
Innate and Acquired Immunity
The human immune system is easily divided into two components, innate immunity and acquired immunity. More specifically the division is cell mediated and humoral immunity, innate and acquired respectively. Innate immunity, as the name implies, are immune functions that exist and function the same in every person. It is comprised of structural features, chemical secretions, and non-discrete white blood cells. Understanding innate immunity can help students to think about their body's activities from a perspective of the body protecting itself. Innate immunity is typified as a general response to invasive particles, molecules or other foreign material. Acquired immunity encompasses the facets of the immune system that are either received from the child's mother or developed through life. This is also referred to as adaptive immunity because it allows the body to constantly adapt to new invasions. This is an evolutionary advantage allowing humans to combat pathogens that pass the innate immune system. This component includes antibodies and cell-mediated defense pathways. Acquired immunity protects us from specific invaders, in particular, ones that have been previously encountered by either ourselves or our mothers. The body has a wonderfully complicated and efficient method of maintaining homeostasis and avoiding a disease state.
Innate Immunity
Innate immunity can be thought of as design elements common to all humans. This is the set of defense structures that passively defend the body as well as cells that actively respond automatically to anything that is nonself. Nonself refers to molecules, particles, cells, and even multicellular things that come into contact with the human body. The body has secretions and structures that limit the crossing of foreign matter of the epithelial cells that line the exterior of the body.
Innate Immunity: External Body Surfaces
External, in the case of the body, not only refers to the skin that you see but also includes the linings of organs that are exposed to the outer-body world. For example, the mouth, though it seems that something that passes into the mouth has passed into the body, it has not. The mouth is lined with a layer of cells called epithelial cells. This barrier of cells is a first line of separation between the outside world and the body. Epithelial tissue is the layer of tightly packed epithelial cells that form the barrier. This tight packing prevents pathogens from entering the body, along with other functions such as fluid retention and protection from mechanical injury.
Consider a fence around private property. It is a barrier, but not impenetrable. Furthermore it has to include a door for entry and exit.
Epithelial tissue, skin, is in constant contact with the outside world. Any instance of contact with material, whether it is a door knob, food, another person, puts the person in contact with bacteria, fungi, viruses, chemicals, and even parasites. Furthermore bacteria, and fungal spores, are in the air, water, and soil. Unless a person has just recently sterilized section of epithelium it is covered with bacteria. We live our lives in close association with bacteria but the epithelial lining keeps these single celled organisms out of the body. The epithelial lining does a remarkable job at being a physical barrier against minute invaders. Different types of epithelium line different parts of the body, but in general the tight junctions serve the function of innate immunity.
Epithelial tissues are strong enough to help prevent mechanical injury while still retaining major flexibility. Skin must be flexible enough to allow for muscular movement but strong enough to resist being punctured. Light abrasions do not compromise the epithelial layer thus presenting a point of entry to the body by foreign matter. At times abrasions will compromise the external tissue and the body has defenses for this situation that will be addressed later both within the realm of innate immunity and more thoroughly encompassed by acquired immunity.
Innate Immunity: Mucous Membrane and Secretions
The mucous membrane is found contiguous with epithelial tissues as well as below. These are specialized cells and glands that secret a fluid called mucus. Mucus secretion is integral to the prevention of colonization and possible infiltration by foreign organisms via destruction and/or removal. The mucus that is found in your respiratory tract traps foreign matter and then the ciliated epithelial cells help to sweep the secretion, with its trapped matter, up and out of the body. Tears provide a washing action to sweep would be invaders away, preventing colonization.
Consider a door mat at the entrance to a building. Designed to remove and trap debris, keeping it from entering the building.
Mucus as well as tears and saliva contain lysozyme. Lysozyme can destroy microbes, such as bacteria. Lysozyme's action is on the cell wall of bacteria, causing the rupture of the cell wall and subsequent death.
The stomach secretes a gastric juice. This is a mixture of enzymes, mucus, and hydrochloric acid, creating a barrier for microbes that are ingested in our food or mucus. This highly acidic environment solid barrier for all but the most specialized bacteria.
Secretions of sebaceous glands and sweat glands help to keep the skin coated with an acidic environment. Microorganisms are prevented from colonizing the skin thus keeping the tissue free of pathogenic bacterial growth. It must be noted that the skin is home to bacteria, but this bacteria, like most all bacteria is non-pathogenic. A skin swab will reveal the existence of countless symbiotic bacteria that live in harmony with us. Later I will discuss this intimate relationship between humans and symbiotic flora. The acidic environment helps to keep large colonies of bacteria from forming and posing a threat to the body.
Consider spilling something on your kitchen floor. If you leave it there it will attract bugs, trap dirt, or even stain the linoleum. You need to clean your floor frequently to avoid the accumulation of matter that may ultimately affect the integrity of the material.
Innate Immunity: Skin Shed
Lastly, concerning epithelial tissue, the process of constant regeneration of the epithelium helps to keep the body free of pathogens. As new epithelial cells are generated the old ones are shed. The epithelial lining of the body is constantly being turned over. This prevents bacteria from taking up long term residence as they, with their microenvironment, are discarded as new growth occurs. For example the rate of turnover for "the (epithelial) cells lining the small intestine is every 4 to 6 days for humans."
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Just like skin is shed, people change clothes. We must change our clothing frequently to avoid the build of smells and grime.
Innate Immunity: External Barrier Breach
In the event of the external barrier being compromised and breached by microbes or foreign matter there exist innate internal defenses. A system that relies on first the detection and recognition of nonself matter infiltration and the subsequent destruction and removal of said invaders. Leukocytes, a type of white blood cell, work in concert with the lymphocytes, another type of white blood cell, of the acquired immune system. Recall that the overarching theme is that of maintaining homeostasis. Internal innate defenses primarily incorporate phagocytosis of invading microbes and chemical pathways that elicit multicellular reactions such as inflammation that serve to remediate the problem quickly.
Innate Immunity: Inflammation
Inflammation of tissue, the swelling, redness, and heat associated with tissue comprise. This helps to protect the body from a diseased state. The redness results from the increased blood flow that has been encouraged by damaged cells. Damaged cells release a chemical messenger called histamine that initiates the inflammatory response. Mast cells help amplifying the response through the release of more histamine. Mast cells are found in connective tissue and epithelial tissue. Chemicals released by these cells will attract other immune cells to the area, thus helping to mediate the response. The more blood flow to the area caused by the dilation of blood vessels also results in more white blood cells to help mediate the invasion and return the body to a normal state. The increased blood flow also results in the swelling. The pain is felt because of the swelling and subsequent pressure that is created and sensed by local neurons. Pain and itchiness is also associated with direct action of mast cells. The increased temperature associated with inflammation is also a result of the increased blood flow.
Consider that when a fire breaks out, the firemen rush to area and drench it with water. This connection seems like a stretch, but the accumulation of firemen in one area along with the action of changing the environment to an extreme, temporarily, is the same idea. The necessary professionals are attracted to the problem area and as a result of mitigating a problem, the local environment changes temporarily.
Innate Immunity: Fever
Fever is an immune response that results in an increased body temperature. It is easily mistaken as being the cause of disease when in fact it is the result. It is a calculated compromise of the body to raise its temperature to increase metabolic activity to hasten the immune response. It also helps by surpassing a threshold temperature for some pathogens, a temperature maximum, wherein beyond which they cannot survive thus resulting in death. It is a compromise because the body also has a temperature threshold that if passed will result in tissue damage and subsequent problems. It is a temporary therapeutic response that is mediated by the hypothalamus in response to infection.
Imagine when a school has to go into lock down. Every person is alert and aware of the fact that an intruder if present. The whole building affected because the actions of one are a threat to the whole system.
Innate Immunity: Leukocytes
Circulating in the blood, in interstitial fluids, and the lymph systems are leukocytes. These defenders of the body range from large macrophages to comparably small granulocytes. These are cells that recognize microbes and foreign matter and are able to respond to protect the body from a diseased state. Unlike the white blood cells associated with acquired immunity, these defenders do not have memory and responding to signals from the humoral immune system or directly to cells that present themselves as nonself. As will be discussed later, the cell mediated responses do not act in isolation and are typically activated by signals from the humoral immune system lymphocytes. Furthermore, autoimmunity will be covered wherein some of these same players are overreacting to non-threatening foreign matter or in some cases inappropriately attacking self-cells that have been accidently determined to be foreign.
Leukocytes respond to signals generated by lymphocytes or markers on microbes that identify the microbe as being of foreign origin. You can equate this response as a sort of validation process wherein the leukocyte will respond to specific molecules that it "knows" are of bacterial origin or are signals generated by the immune system such as antibodies. The latter would be signals that result in a host of responses specific to the type of phagocyte. In contrast leukocytes screen self-cells and are able to recognize them as such and take no action. In the event that a self-cell is infected or comprised a leukocyte can identify it as such because of changes to surface level proteins of the infected cell and take the necessary action against the cell. Our cells are able to communicate with the immune system when they have been compromised and in the interest of maintaining homeostasis the cell can signal that it must be destroyed. Normally a cell will present parts of the proteins that it is manufacturing, in the case that a cell has been infected it will presenting proteins that are nonself, thus eliciting a response from the leukocyte. A major roll of leukocytes is to act in response to antibodies generated and released by B-lymphocytes of the humoral immune system. In the case of invasion by foreign matter, it is the macrophage, of the innate immune system that teaches the B-lymphocytes of the acquired immune system, what is nonself. This is done with antigen presentation. In subsequent attacks by the same foreign invader the humoral immune system can now recognize the invader as well, resulting in a quicker immune response. This complex interaction will be covered in subsequent sections and was discussed here to reinforce that cell mediated and humoral immunity work in concert to protect the body.
Leukocytes that will be covered in this unit are macrophages, granulocytes (neutrophils, eosinophils, and basophils), dendritic cells, and natural killer cells. The mode of action for these leukocytes is primarily phagocytosis. Antimicrobial proteins including interferons and the complement system will also be discussed. These proteins will attack pathogens directly as well as mitigate by impeding reproduction of the microbe.
The connection between leukocytes and varying levels of security guards will be made to illustrate the necessary differences of these white blood cells.
Innate Immunity: Leukocytes: Macrophages
Macrophages are large phagocytic cells that as the descriptor phagocytic implies, consume microbes and foreign invaders. They are found migrating throughout the body in the blood and interstitial spaces. They are also found in organs and within the lymphatic system. Dense populations of macrophages are found in lymph nodes and in the spleen. Both are filtering points for lymph and blood respectively. Microbes are trapped in these organs and consumed by the resident macrophages.
Though macrophages can immediately sequester and destroy invading microbes, it is their relationship and communication with lymphocytes that is most important. Macrophages are antigen presenting cells. Antigen is a general term for any molecule that is identified as foreign to the body. These are commonly proteins or polysaccharides that are specific to the invading microbe. An antigen can also be a toxin found in extracellular fluids. The antigen is essentially the identifier. Macrophages consume foreign matter and then present that matter on their surface in order to show it to T-lymphocytes, important white blood cells of the acquired immune system. This communication between the two systems is integral to the learning process of humoral immunity. Ultimately antibodies are created for each specific antigen and protect the body by "binding to antigens they find, the antibodies can neutralize them or precipitate (antigen) destruction by complement enzymes or by scavenging cells."
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Macrophages also release cytokines and chemokines that will initiate the inflammatory response. They do this in response to infection. This is another way that the macrophage is operating as a player within a bigger network or immune response cells and pathways. Macrophages can be activated by the release of proteins from infected cells, proteins such as interferon that will be discussed shortly.
You can equate the macrophage to a security guard. A security guard that knows who belongs and who does not and is big enough to sequester an intruder. This security guard will then alert the police about the intruder and share identifying information.
Innate Immunity: Leukocytes: Granulocytes
There are three granulocytes that we currently know of, neutrophils, eosinophils, and basophils. These are first responder cells and though part of innate immunity their action can be in response to antibody presence, antibodies are created by lymphocytes. Phagocytic action is the mode for some of them and they are known for consuming invaders until they die. The yellowy white fluid associated with an infection, pus, is primarily dead granulocytes.
These granulocytes are differentiated but share the common characteristic of being first responders in the event of infection. Neutrophils respond to chemoattractants released by bacteria, inflamed cells, or dead and dying cells. They utilize phagocytosis to neutralize affected cells. Eosinophils are associated with attack of multicellular invaders. Lastly basophils are associated with allergic responses and parasitic attacks.
These are the first responders to an accident. A good analogy is a paramedic, they respond quickly and deal with the situation the best they can.
Innate Immunity: Leukocytes: Dendritic Cells
Dendritic cells are phagocytic and will also present antigens. Antigen presentation is a primary function of these leukocytes, helping to strengthen the humoral immune response. They differ from macrophages in that they are capable of initiating attacks on pathogens. Wherein a macrophage will consume and present, a dendritic cell will go further and activate other phagocytes to remedy a problem. Dendritic cells are found all throughout the body and largely around epithelial barriers.
Think of an armed security guard. This is a defender that has weapons to defend the territory and the discretion to judge a threat and carry out the needed response. This guard will also recruit others to join in. This guard will communicate with the police as well.
Innate Immunity: Leukocytes: Natural Killers
Natural killer cells are uniquely developed to identify and kill virus infected cells. They are also known to attack cancer cells. There mode of action is to release a chemical attack that results in apoptosis of the infected cell. Apoptosis is cascade of pathways that is set in motion resulting the death of a cell, it is considered programmed cell death.
This is a specialized soldier guard that will neutralize threats according to a certain protocol. The type of protection needed to identify a domestic threat such as a terror cell that has set up residence.
Innate Immunity: Antimicrobial Proteins: Interferons
Interferon is considered an antimicrobial protein because its use by infected cells will trigger events that result in an immune response. Interferon can be thought of a distress signal that is released by a cell in response to viruses, bacteria, parasites, and even cancer cells. This warning can signal leukocytes to action as well as warn nearby cells to prepare and produce defense chemicals. Though interferons cannot directly mitigate a response against a pathogen, their role of warning the rest of the immune system and neighboring cells is pivotal in the maintenance of homeostasis.
Any properly defended building will have an alarm system with a series of sensors that can respond to abnormal activity and notify the guards.
Innate Immunity: Antimicrobial Proteins: Complement Cascade
The complement cascade or complement system involves about 25 to 30 proteins that participate in the immune response. They work by aiding in the destruction and removal of bacteria and antigens. They circulate within the blood in an inactive state and are activated by antibodies. Different cascades will result in the destruction of a bacterial invader through a chain reaction of events initiated by the activation of the first protein in the cascade. Other cascades result in the inflammatory response, while still others will increase the susceptibility of microbes to phagocytosis.
This is a low level, unarmed security guard that is relegated to doing rounds. This is an active guard that circulates the building for suspicious activity. This guard has radio or whistle to alert other guards of a disturbance.
Innate Immunity: Summary
What is defined as the human innate immune system ranges from structural facets of the body to tissue responses to bodily secretions to cell level action all the way down to antimicrobial protein action. This system does not stand alone and cannot defend the body from all attacks. Innate immunity is intertwined with acquired immunity yet is defined by immediate call to action in response to foreign material. As will be discussed, acquired immunity, though more targeted and effective, relies on presentation of antigens by the leukocytes and subsequent production of antibodies. These antibodies are produced onsite in response to new antigens as well as by memory cells from a previous encounter or via maternal acquisition. This is a loop though and antibody action within body stimulates many components of the innate immune system.
Acquired Immunity
Acquired immunity, as the name implies, encompasses the white blood cells, lymphocytes, which manage the defense against pathogens based through antigen recognition with antibodies. The information that is used is either presented to the lymphocytes by leukocytes or has been transferred to the person via maternal methods. In more understandable terms, acquired immunity is actively developed by exposure to pathogens or vaccinations. Falling under the definition of passive acquired immunity is immunity that develops because of transfer of lymphocytes or antibodies from a donor.
There are two general types of cells involved in this immune system, B-cells and T-cells. B-cells, or B-lymphocytes, are produced in the bone marrow and T-lymphocytes in the thymus. Their roles are remarkably different but inherently intertwined in the effective defense against disease.
Acquired Immunity: T-Lymphocytes
T-lymphocytes aid in the discovery of antigens and the subsequent presentation of them to B-lymphocytes. The B-lymphocytes create and release the antibodies. T-lymphocytes search for antigens. They find them being presented by leukocytes as well as infected cells. In the case of leukocyte presentation, the white blood cell has consumed a pathogen and then presented an antigen on its surface for the T-cell to discover. Furthermore, antigens can be found by T-cells when presented by diseased cells. For example, a cell that has been co-opted by a virus will be producing viral proteins. Fragments of those viral proteins will be presented by the cell and the T-cells will discover them. The presentation of the antigen is done with a special molecule called a major histocompatibility complex (MHC) protein. T-lymphocytes also aid in the destruction of pathogens. T-cells are further differentiated into two classes, helper T-cells and killer T-cells.
Acquired Immunity: T-Lymphocytes: Helper T-Cells
The helper T-cell is the type that communicates with leukocytes. Leukocytes share the antigen with the cells along with how to neutralize an attack from the pathogen. The binding of the T-cell receptor with an antigen that has been presented by another cell on and MHC complex serves to activate the T-cell into an effector cell. The effector cell multiplies and carries out two vital processes. One process is that the effector cells communicate information about the antigen to B-lymphocytes. This is information that leads to antigen specific antibody creation as well as about how the antigen is neutralized. In the case of an antigen that the body already recognizes, the effector cells are activating memory B-cells to produce the necessary antibodies. Secondly, the effector cells will signal killer T-cells, also known as cytotoxic cells, as well as macrophages. Helper T-cells are important both in the immediate response and mitigation of a pathogen as well as future responses by sharing antigen information with B-lymphocytes.
Acquired Immunity: T-Lymphocytes: Killer T-Cells
Killer T-cells also have receptors for antigens and are activated by antigen binding. When activated they are considered effector cells. Cytotoxic cells are effective at killing cells that have intracellular pathogens such as viruses, bacteria, or parasites. Intracellular action is beyond the reach of the antibody. Cytotoxic cells kill by inducing apoptosis in the infected cell. "Once bound to its target cell, a can employ at least two strategies to kill the target, both of which operate by inducing the target cell to kill itself by undergoing ."
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Acquired Immunity: B-Lymphocytes
B-cells are white blood cells that begin as naïve plasma cells. A single B-cell that has been generated by the bone marrow is considered naïve until it is activated by a helper T-cell that presents an antigen. The antibodies, immunoglobulin molecules, produced by the B-cell are specific to the antigen. Any given B-cell can only produce one type of antibody and because of possible variations in the structure of the antibody and specialized enzymes that can add DNA to the antibody coding section, the combinations are nearly infinite. This means that the human body has the potential to create antibodies for nearly any molecule. This can be good and bad as will be discussed later concerning autoimmune diseases. The antibodies themselves do not necessarily destroy pathogens but more help to make pathogens visible to the components of the innate immune system for destruction. The creation of memory B-cells results from the initial interaction of a naïve B-cell with an antigen.
Antibodies are the crucial component of the B-cell. Antibodies are receptor molecules. These molecules have antigen binding sites of near infinite variation. Any given B-cell will only produce one specific antibody. That being said, antibodies of different class are produced by the same B-cell. These all bind the same antigen but have different roles such as surface receptor for antigens; allergen binder to promote the allergic response; secreted antibodies that have differing functions in the extracellular space.
With primary introduction of an antigen the humoral response is slow. Once binding of antigen to antibody occurs the B-cell is activated and it will proliferate creating plasma cells as well as memory B-cells. When this antigen is presented again at a later date the immune system already has memory B-cells to be activated. Before the initial pathogen infection there is a limited number of B-cells specific to the antigen that the pathogen has. After this initial interaction there exist memory B-cell clones. With more cells present that can recognize a given pathogen a quicker response occurs. Once the immune system is taught about a pathogen it is prepared for any subsequent attacks by the pathogen.
The ability to teach the immune system which antibodies are important is fundamental to our ability use vaccines to protect ourselves from infection. It is not so much that getting a vaccination for measles prevents the body from encountering measles, but instead that when measles do enter the body the pathogen is recognized and the defense is already prepared. This prepping of the immune system is what keeps us free of those diseases that we have vaccines for.
Acquired Immunity: Summary
This was very brief description of the acquired immune system. It is typified by its ability to learn about new pathogens and tailor specific responses against them. The learning allows for an effective strategy of having the response ready and waiting for a possible attack. The acquired immune system does not work as an isolated entity, instead it is interwoven with innate immunity to protect the body from a disease state.
Consider how the police and other armed forces can work together to keep track of dangerous people. There is a lot of communication among the different forces and they respond to known threats as identified by previous encounters. The police and army are geared up and ready for known threats that have been encountered before or that they have been warned about.
The Lymphatic System
Immunity as a process to keep the body healthy and maintain homeostasis cannot be discussed without addressing the lymphatic system. The thymus, where T-cells are produced, is part of the lymphatic system. This is a network of tubes that permeate the body to collect extracellular fluids for filtering, sampling, replacement, and removal. The arterial capillaries of the circulatory system are permeable, allowing blood cells, water, and other small constituents pass out of the circulatory system into the extracellular space. Some of this fluid is recovered by venous capillaries. The remaining fluid is collected by lymph vessels to flow through the lymphatic system. Within this fluid are pathogens and antigens as well as cellular waste. Fluid, and its constituents, found in the lymph system is called lymph.
As lymph is passed through the lymph vessels it must pass through lymph nodes. Lymph nodes house lymphocytes and leukocytes giving these white blood cells a chance to screen the molecules, cells, and microbes that are in the lymph. Phagocytic activity is high in lymph nodes. T-lymphocytes are also conveniently located here in this advantageous location. T-cells that are activated can continue in the lymph vessels and enter into the circulatory system via the left and right subclavian veins or be transported to the organs and structures that the lymph system is associated with. The structures associated with the lymph system are the thymus, adenoids, tonsils, appendix, spleen, and Peyer's patches.
The lymphatic system can be equated to the sewer system and processing plants that a major city will have. This is a network of structures that are in place to handle the waste of the population.