Anatomy/Immune System

The immune system is a focus topic of the event Anatomy. It comes into rotation for the 2014 season. The immune system is composed of cells, tissues, and organs that work together to defend the body against attacks by “foreign” invaders.

Overview
The immune system protects the body from disease and potentially harmful foreign invaders called pathogens. 5 types of pathogens include bacteria, viruses, fungi, protozoa, and helminths, or worms. The first 3 are often referred to as microorganisms, and the later 2 are also known as parasites. The process through which pathogens cause disease is called pathogenesis.

The immune system defends against pathogens two ways: preventing foreign organisms from entering the body and destroying harmful organisms that do enter the body. It detects pathogens and differentiates between potentially harmful agents and the body's own healthy tissues. When the immune system cannot differentiate harmful foreign invaders and its own cells, it is an autoimmune disease. It creates an immune response to itself.

The Immune System
There are 3 levels of the immune system. The first two are nonspecific (or innate), meaning they defend against all kinds of pathogens. The third is specific (or adaptive, or acquired), because it identifies and targets certain pathogens.

First Line of Defense
The first line of defense is made up primarily the skin, mucous membranes, and their secretions. They protect against external pathogens from entering the body. Here are some examples.
 * The skin is a physical barrier made of dead cells. It secretes oily and acidic secretions from sweat glands, which inhibit bacterial growth.
 * Sebum (unsaturated fatty acids) provides a protective film on the skin and inhibits growth
 * Secretions from mucous membranes (saliva, tears, sweat, etc.) contain antimicrobial proteins such as lysozyme, which breaks down bacterial cell walls.
 * Vibrissae (nose hair) filters microbes, dust, and pollutants within air.
 * Cilia that line the lungs traps and moves foreign substances out from the lungs towards the throat with a sweeping motion.
 * Gastric juice, which is highly acidic, kills microbes in the stomach.
 * Symbiotic bacteria in the digestive tract and vagina out-compete other potentially harmful organisms.
 * Urine flushes microbes from the urethra.
 * Defecation and vomiting also expel microorganisms.

Second Line of Defense
The second line of defense deals with pathogens that have entered the body. It involves several nonspecific mechanisms.
 * Phagocytes are white blood cells (leukocytes) which engulf pathogens by extending pseudopods to surround it. This process is called phagocytosis. Leukocytes are formed in stem cells in bone marrow through the process of hematopoiesis (this term refers to all blood cells).
 * Macrophages are larger, long-living versions of monocytes. Monocytes circulate through the blood stream, and are known as macrophages when they mature. Macrophages move throughout blood, lymph, and body tissues. They are specialized in the removal of dying or dead cells and cellular debris as well as pathogens. Macrophages also play an important role in chronic inflammation.
 * Neutrophils are the most abundant type of white blood cell. They are normally present in the blood stream, but quickly enter tissues to phagocytize pathogens, primarily bacteria, in acute inflammation. They respond within minutes to the site of injury.
 * MAST Cells also secrete histamine, as well as seratonin. They help cause inflammation and respond to wound injuries.
 * Dendritic Cells are the messengers between the innate and adaptive immune systems. Dendritic cells acquire and present antigens to lymphocytes to activate them.
 * Basophils and Eosinophils are also white blood cells, but are not phagocytes. Basophils secrete chemicals such as histamine. Histamine triggers vasodilation, causing more phagocytes to be brought into the area. Histamine is also known as being responsible for the symptoms of allergies and the common cold. Eosinophils are short-lived and have a wide range of functions, including attacking parasites and helping with allergic responses. The proteins they make can be harmful to the body's own tissues as well as pathogens.
 * Natural Killer Cells (NK cells) attack abnormal or pathogen-infected body cells, such as tumors, by releasing toxic granules to kill the cells.
 * The Complement System is a group of about 30 proteins which assist defense reactions. They help by enhancing the process of phagocytosis, attracting phagocytes to foreign cells, and promoting cell lysis. They are generally synthesized by the liver.
 * Interferons are secreted by cells invaded by a virus. They stimulate neighboring cells to produce proteins that will help defend against the viruses.
 * Chemokines guide the movement of cells. Cells respond to certain chemokines by moving towards areas of higher concentrations of chemokines. In the immune system, they create a chemical gradient to attract neutrophils and other leucocytes to the wound site.
 * Fevers are an increase in body temperature. Substances that induce fevers are called pyrogens. The increased temperature inhibits bacterial growth and increases the rate of tissue repair during an infection. It may also help certain types of immune cells function more efficiently.

The Inflammatory Response
The inflammatory response is the biological response to harmful stimuli, such as burns, chemical irritants, frostbite, physical injury, or pathogen infection. (Given this is the Immune System page, this section will focus on the inflammatory response to pathogen infection.) It is characterized by swelling, pain, redness, warmth, and dysfunction of organs involved (tumor, dolor, rubor, calor, and functio laesa, respectively). Its purpose is to increase blood supply to the area to bring nutrients, proteins, and white blood cells to the affected tissues. Note that the epithelium and the capillaries are separated by interstitial fluid rather than being located right next to each other. In the example a splinter, the following events occur as part of the inflammatory response: The inflammatory response (and the immune system in general) often consists of reactions to certain stimuli which in turn cause more reactions. Signaling pathways like this can be referred to as biochemical cascades.
 * 1. Damaged cells release chemokines.
 * 2. MAST cells, responding to chemokines, direct contact with the splinter, or bacteria, release histamine.
 * 3. Histamine causes capillary endothelial cells to enlargen and move outwards, creating a swell in the capillary which encourages fluid collection. The capillary walls also become more porous. This process is called vasodilation. Vasodilation causes redness, temperature increase and swelling. The increase in temperature causes an increased metabolic rate in cells. Activated capillary endothelial cells also display adhesion molecules called selectins on the inner capillary surface.
 * 4. Phagocytes, namely neutrophils, are attraccted to, slowed down by, and roll along the wall due to the selectins. Chemicals in the bloodstream activate integrins, adhesion receptors on neutrophils. The integrins then bind to adhesion receptor molecules on the  capillary endothelial cell surfaces. The accumulation and adhesion of leukocytes to the blood vessel walls is called margination or pavementing.
 * 5. Leukocytes squeeze through openings in the capillary walls (extravasation, emigration, or more specifically diapedesis). Exudation, or the entering of fluid from the bloodstream into the interstitial fluid, also occurs. This fluid, mainly plasma, contains proteins and antibodies. Fluid buildup due to exudation is called an edema and is visible as a swelling (tumor). The plasma also help activate the complement, kinin (generates proteins that sustain physical inflammatory effects, namely vasodilation), coagulation (clotting), and fibrinolysis (counter-balances the coagulation effect) systems.
 * 6. Neutrophils and other phagocytes attack invading bacteria that have entered due to the splinter. Complement helps phagocytes engulf foreign cells, and stimulates additional histamine secretion by basophils.

The Immune Response
The Immune response is the third line of defense. It is a specific defense system, meaning it targets specific antigens. Antigens are molecules, usually proteins or polysaccharides, that are identified as foreign to the body. These molecules could be toxins, part of a viral protein cote, or molecules unique to certain bacteria, protozoa, pollen, or other foreign cells.

MHC
The major histocompatibility complex, or MHC, is the mechanism the immune system uses to differentiate between self and foreign cells. It is a collection of glycoproteins that exist on all body cell membranes. Each individual has a highly unique (but not always, especially in the case of identical twins) set of MHC molecules.

Lymphocytes and their Components
Lymphocytes are white blood cells that concentrate in lymphatic tissues such as the lymph nodes, thymus gland, and the spleen. They are the primary agents of the immune response.
 * B cells originate and mature in bone marrow (think: "B" for bone). They respond to antigens using specialized proteins called antibodies on their plasma membrane surface.
 * Plasma cells: release speciic antibodies which circulate through the body, binding to antigens
 * Memory cells: long-living B cells that do not release antibodies but circulate through the body and respond to subsequent invasions. Memory B cells provide immunity, as their response is much more quick and powerful than the first occurrence.
 * The antibodies, or immunoglobulins of B cells are antigen receptors only to a particular antigen. Antibodies inactivate antigens by binding to them, stimulating complement proteins to promote macrophage phagocytosis. There are 5 classes of antibodies, each a variation of the basic Y-shaped protein with variable regions which give them specificity to antigens. The 5 classes are as follows:
 * IgA: second most common, major class of Ig in secretions like mucus
 * IgD: not very common, mainly found on B cell surfaces
 * IgE: least common, involved in allergic reactions, helpful in diagnosing parasites
 * IgG: most common and versatile, only class transferred across placenta, is an opsonin (enhances phagocytosis)
 * IgM: third most common, first made by fetus, good at clumping microorganisms in preparation for excretions
 * T cells originate in the bone marrow but mature in the thymus gland (think: "T" for thymus). They have antigen receptors which are not antibodies but recognition sites for molecules displayed by nonself cells. Nonself cells, such as invaded body cells, cancer cells and tissue transplant cells, display different markers than self cells. When T cells encounter a nonself cell, they divide and produce two kinds of cells:
 * Cytotoxic T cells or killer T cells destroys nonself cells by causing them to lyse.
 * Helper T cells stimulate proliferation of B cells and cytotoxic T cells.

Clonal Selection
When an antigen binds to a B cell or a nonself cell binds to a T cell, the B or T cell divides to produce many identical copies. This results in an increased number of the B or T cell that can respond to the specific antigen.

Cell-Mediated Response
The cell-mediated response occurs as a response to nonself cells, and involves mainly T cells.
 * 1. In a celluar infection, antigens are broken down by the cell and presented at the cell surface by class I MHC proteins.
 * 2. T cells bind to the MHC detect antigens and undergo clonal selection, initiating the production of cytoxic T cells and helper T cells.
 * 3. Helper T cells bind to macrophages which are displaying marker combinations which signal with marks that they have engulfed a pathogen.
 * 4. Helper T cells produce interleukins, communication chemicals, to stimulate T cell and B cell proliferation. This initiates a posive-feedback cycle, increasing the concentratin of leukocytes in the area.

Humoral Response
The humoral response, or antibody-mediated response occurs as a response to antigens or pathogens circulating in the blood or lymph.
 * 1. An antigen is engulfed by a phagocyte. It displays the antigen on its surface using a class II MHC protein.
 * 1. B cells recognize the antigen and produce plasma cells, which release antibodies that bind with antigens or antigen-carrying pathogens.
 * 2. B cells produce memory cells, providing future immunity.
 * 3. Macrophages and helper T cells stimulate B cell production through cell-mediated response.

The Lymph System
The lymph system may be also be considered part of the circulatory system. Its purpose is to transport white blood cells and remove interstitial fluid. It consists of a network of lymphatic vessels, nodes and organs.
 * The spleen filters and stores blood. It is located above the left kidney.
 * The thymus stores immature lymphocytes and is the site of T cell maturation. It is located at the sternum.
 * The tonsils are part of the body's first line of defense, and also help produce T cells. However, they do not have a significant function and are often removed due to inflammation. They are located in the pharynx.
 * Lymph Nodes are oval-shaped filters placed throughout the lymphatic vessels.
 * A fluid called lymph circulates the lymphatic system.

Resources

 * Official soinc.org Training Handout 2013
 * Official soinc.org Training PowerPoint 2014
 * University of Illinois Biological Science: Immune System Lecture
 * Garland Science Excerpt: Innate Immunity
 * University of Washington: Phagocytosis
 * McGraw-Hill: Inflammatory Response Video
 * Khan Academy: Inflammatory Response Video
 * Boston University: the Immune System