Immune System: - Weebly



Immune System:

This is the first system of the homeostatic systems. Homeostasis: Tendency of the body to maintain a constant internal environment in the face of insults from the external environment. This includes invasion from the outside. How is homeostasis maintained? Usually by negative feedback—A stimulus causes a response that reduces the stimulus. Positive feedback is usually a bad thing in nature—A stimulus causes a response that increases the stimulus. However, the immune system is one of the only examples where a positive feedback response is a good thing.

The immune system wants to defend against outside invaders. The first line of defense would be to keep things out of your body.

A) Non-Specific Defenses: The first line of defense, the external barriers.

1) External Barrier: skin and mucus membranes cover the animal's body. Bacteria or viruses usually cannot penetrate skin, although a small abrasion may allow a way for foreign substances to invade. The epithelium is composed of multiple layers, the skin is made up of cells that contain keratin, and the epithelial cells are bound together by tight junctions—the skin is tough to penetrate. In addition, the skin is supported by a dense fibrous basal lamina. The pH of the skin, due to the presence of sweat and oil, ranges from 3-5. The low pH will kill most foreign bacteria. Hair provides some protection against abrasion and may keep hazardous material and insects off of the skin. Saliva and tears wash away bacteria and contain antimicrobial proteins, for example, lysozyme, which attacks the cell wall of bacteria. Your skin is also covered with a normal flora of bacteria. This prevents other bacteria (harmful) from invading. Actually, there are about 100,000 bacteria per square centimeter of skin.

2) Mucus membranes that line the respiratory, digestive and excretory tracts prevent harmful microbes from entering the body. Foreign substances stick to the mucus. The lining of the trachea is ciliated epithelium, which sweeps the particles into the mucus and digestive tract. Saliva, tears, and mucous secretions are constantly bathing exposed surfaces. The secretions contain antimicrobial proteins such as lysozymes that can digest the bacterial cell wall. The gastric acid digests other bacteria and viruses that are ingested. However, the hepatitis A virus and H. pylori can survive the stomach environment.

If the external barrier doesn’t work, then the invader gets inside the body. Don’t worry, you have a non-specific and specific lines of defense.

B) The second line of defense: Non-specific internal defenses.

All animals have in common one very effective line of defense ameboid cells that engulf and eat any foreign particle including microorganisms. Some are fixed in places, such as the spleen or lymph nodes and these cells engulf any foreign substance that passes through. Others roam freely; these cells are called phagocytes. There are two types of phagocytes—eaters and pokers. All phagocytes have the following common characteristics:

• All can move through capillary cell walls, by squeezing between the endothelial cells. These endothelial cells of the injured areas have markers that tell the phagocytes were to enter.

• They move to certain areas by chemotaxis. Phagocytes are sensitive to cytokines.

• Either the phagocyte engulfs the pathogen through phagocytosis or binds to the foreign cell and releases perforin. Perforin will poke a hole in the cell membrane.

1) Types of Phagocytes:

A) Neutrophils make up 60-70% of our white blood cells. They are attracted to body parts via a chemical signal (this is chemotaxis). Neutrophils can leave the blood and enter infected tissue via ameboid movement and destroy invaders. As they destroy invaders, neutrophils tend to self-destruct. Neutrophils live for only a few days. They usually die after they engulf 25 or more bacteria.

B) Monocytes make up 5% of our white blood cells. They provide a more effective phagocytic defense. After they mature, monocytes circulate for a few hours in the blood and migrate into tissues to develop into macrophages.

C) Macrophages are the largest phagocytic cells and live a long time. The macrophage pseudopods grab invaders; the invaders are pulled into the macrophage and destroyed by digestive enzymes and reactive oxygen. Some bacteria evade macrophages; a bacterial capsule can prevent the bacteria from being pulled into the macrophage and some cell walls resist digestive enzyme. Some macrophages reside permanently in organs and tissues, such as the alveoli, the liver and the lymph nodes. These are fixed macrophages (histiocytes). In organs, these macrophages have specialized names: microglia in the central nervous system, and Kuppfer cells in the liver, for example. Macrophages use oxygen (free radical), tumor necrosis factor, or NO to kill invaders.

D) Eosinophils make up 1.5% of white blood cells. They phagocytize and contain destructive enzymes within the cytoplasm. Eosinophils defend against large parasites, such as worms, by positioning themselves against the external wall of the worm and discharging enzymes from the cytoplasm. Basically, they poke holes in them. These pathogens are usually covered with antibodies.

E) Natural Killer Cells: They attack body's own infected cells. Natural killer cells can also attack cells that are precancerous. They attack the outer cell membrane; then the cell opens up and lyses. These cells attack any cell membrane that contains an antigen. They attach to cells and release perforin.

2) Inflammation.

Physical damage to tissue, such as a scratch, allows microbes to invade. This invasion triggers an inflammatory response.

1) The small blood vessels in the area of the injury dilate; this increases the blood flow to the injured area causing the redness and heat of the injury.

2) The blood vessels become more permeable and fluids from the blood move into neighboring tissues. This action causes swelling (edema).

Both of these actions are started by chemical signals. Histamine is a chemical signal, which is contained, in a circulatory white blood cell called a BASOPHIL and in cells called MAST CELLS found in the connective tissue. If these cells are injured, they release histamine, which triggers local vasodilation and increases capillary permeability. White blood cells and damaged tissues release PROSTAGLANDINS (this is a local regulator—we’ll discuss this in the endocrine system) and other substances to promote blood flow to the injured area. The vasodilation and increased blood flow also brings platelets and other clotting factors to the injured area. The clotting process begins the repair on the body and helps block further invasion of microbes.

Within an hour after injury, phagocytes will migrate from the blood to the injured area. This migration is mediated by a chemotatic factor called chemokine (a cytokine, this is secreted by cells in the blood vessel). These phagocytes move via chemotaxis. The chemokine also starts to change the leukocytes, as they get ready for the invaders. Neutrophils arrive first followed by the monocytes that change into macrophages. Macrophages not only devour invaders but also clean up the tissue remains and the neutrophils that have self-destructed. Pus is mostly dead cells and fluid leaked from the capillaries. The body slowly absorbs the pus.

The cytokines will also stimulate fibroblasts to begin the formation of scar tissue.

3) Fever:

The body's reaction to an infection may be more systematic: Normal body temperature is 37.2oC (99oF). The hypothalamus maintains the body temperature.

The injured cells emit molecules that stimulate the bone marrow to release more neutrophils. The White blood cells and damaged cells release prostaglandins. The pathogen also may release a toxin. The prostaglandins and toxin may stimulate the macrophage to release PYROGENS. Pyrogens set the body's thermostat at a higher temperature. The hypothalamus will increase body temperature by increasing body metabolism. Bacterial toxins, pathogens, antibody-antigen complexes can all act as Pyrogens to increase body temperature. A fever can be helpful. An increase of 1oC will increase the metabolic rate by 10%. This will increase the rate of enzyme reactions, which can lead to faster moving cells, which can lead to a quicker defense. However, if the temperature gets too high, the proteins of your body can denature. Aspirin inhibits prostaglandin.

4) Complement Proteins:

A set of proteins that make up the complement system (later in these notes). These proteins start out a series of reactions that lead to the lysis of an invading cell. The proteins attach to invaders and poke holes in the cell membrane. Complement proteins are part of the non-specific and specific internal response.

5) Interferons: Produced by the cells that prevent viral infection. Prevent the spread of viruses in the body. This protein is produced by lymphocytes (B and T cells), macrophages, and body cells. Interferon binds to the cell receptors and stimulate the production of antiviral proteins. These antiviral proteins interfere with viral replication. There are, at least, three types of interferon.

A) Alpha interferon: this is produced by WBC. This attracts and stimulates natural killer cells.

B) Beta interferon: secreted by fibroblasts and slows inflammation in an area.

C) Gamma interferon: secreted by T and natural killer cells and stimulate macrophages.

Interferons are examples of cytokines. These compounds can act as local regulators and coordinate local responses, or act as hormones and stimulate cells around the body.

C) Third line of defense: The immune system.

1) Specific Defenses: Basics—Background information.

Third line of defense is the IMMUNE SYSTEM. This specific system is different than the nonspecific system by having four features:

a) Specificity is the ability of the immune system to recognize and eliminate particular microorganisms and foreign molecules.

An antigen is any foreign substance that elicits an immune response.

An antibody is a specific protein made by lymphocytes against foreign substances.

Each antigen has a specific molecular shape and stimulates a specific antibody.

b) Diversity results from the immune system's ability to respond to millions of types of invaders. Each invader is recognized by their antigen markers. The immune system can do this because of the large variety of lymphocytes.

c) Self/Nonself recognition occurs because of the immune system's ability to differentiate between the body's molecules and foreign substances. Immune system failure leads to autoimmune responses.

d) Memory is the immune system's ability to remember antigens and react more quickly upon subsequent exposures.

2) Active/Passive Immunity:

Active immunity is the immunity gained by recovery from an infectious disease. This can be acquired naturally or artificially through vaccinations. Vaccines may be inactive bacterial toxins, killed microbes or living but weaker microbes. Vaccines create a memory in the immune system for a quicker response on subsequent exposures.

Passive immunity occurs when an individual acquires the antibodies.

a)Natural Passive Immunity: Examples.

1) Mother passing antibodies through the placenta to the fetus.

2) Mother passing antibodies to child when nursing.

b)Artificial Passive Immunity:

Injecting antibodies, such as Gamma globulin shots.

3) Humoral/Cell-mediated Immunity: This is active immunity:

a) The immune system is broken down into the humoral and cell mediated immunity. Humoral Immunity is the production of antibodies that are secreted by lymphocytes and circulate as soluble proteins in blood plasma and lymph. These proteins defend against toxins, free bacteria and free viruses. This is the immunity that occurs before the body/cell becomes infected.

b) Cell-mediated Immunity is the immunity that depends on the direct action of cells. This immunity defends against bacterial infected cells, viral infected cells, fungi, protozoans, worms, and cancer cells. This is the immunity that occurs after the body/cell has become infected.

4) B and T cells:

Lymphocytes are responsible for humoral and cell-mediated immunity. There are two types of lymphocytes: B and T Cells.

B cells carry out humoral immunity.

T cells are responsible for cell-mediated response and assist the B cells with the humoral response.

Lymphocytes originate from the stem cells in the bone marrow (or in the liver in babies). All cells look alike initially. The cells later differentiate depending on where they mature. T cells mature in the thymus. B cells mature in the bone marrow.

Mature B and T cells are most concentrated in the lymph nodes, spleen, and other lymphatic organs. They both are equipped with specific antigen receptors on their cell membranes. The B cells receptor is an antibody bound to the cell membrane.

When an antigen binds to the receptor, it activates the lymphocyte to divide and produce a population of EFFECTOR CELLS. These cells do the actual defending. B cells give rise to PLASMA CELLS, which secrete antibodies. T cells give rise to CYTOTOXIC T CELLS, which destroy infected, or cancer cells, or HELPER T CELLS, which help B cells. When the invader gets into the blood, it will eventually enter the lymph system, then it travels to the lymph nodes. Once in the lymph nodes, the invader will activate the B and T cells. These cells and products (antibodies) will move into the blood and tissues.

5) Antigen-Antibody Specificity: Molecular Basis:

Antigens are proteins or large polysaccharides. Most of these particles are the outer components of viral coats, and the capsules and cell wall of bacteria. Foreign cells, pollen and other foreign substances often have antigens on their surface. Antibodies recognize only a portion of the antigen; this portion is called the EPITOPE. A single antigen can have several epitopes eliciting many different antibodies to be produced against it.

Antibodies make up a class of proteins called IMMUNOGLOBINS (Ig), which have at least two identical sites that bind to the epitope of the specific antigen. A basic antibody (IgG) has four polypeptide chains, two light and two heavy, joined together to form a Y shaped molecule. Both the light and heavy chains have a constant region. The amino acid sequences in the constant region vary little among the antibodies of a class. At the tip of the Y shaped molecule, the variable region can be found in both the heavy and light chains. This region varies extensively from antibody to antibody and is the antigen binding sites. The association between an antigen-antibody binding site is analogous to the enzyme substrate association.

The antigen-binding site is responsible for an antibody's recognition function. The stem of the antibody molecule is responsible for the antibody's effector function, which is to inactivate or destroy the antigen.

In mammals there are five types of constant regions that correspond to the five classes of immunoglobins: IgG (the standard and most common antibody0, IgM (this is a pentamer—5 antibodies bound together), IgA (this is a dimer—two antibodies bound together), IgD (these are used on B cells as receptors), and IgE (these bind to mast cells—will discuss in allergic reactions). A type of constant region that enables the antibody to perform certain defense functions characterizes each class of antibodies.

6) Antibody: Specificity and Diversity.

Each lymphocyte recognizes and responds to only one antigenic epitope. The immune system's ability to defend against an almost unlimited variety of antigens depends on the diversity of antigen-specific lymphocytes.

Each lymphocyte's specificity for an antigen is predetermined during embryonic development, before an encounter with an antigen (Note: refer to notes of eukaryotic genes on the move in the Regulation of Eukaryotic Genes section). The lymphocyte displays the antigen receptor on its cell membrane. If an antigen does come into contact with the lymphocyte, the lymphocyte is activated and initiates an immune response. The selected cells divide and develop into a large number of identical effector cells. These clones combat the antigen that caused the response. This is called the CLONAL SELECTION. Since bacterial proteins have many epitopes, several cell lines can be cloned at once.

7) Immunological Memory:

Clonal selection is the PRIMARY IMMUNE RESPONSE. Between exposure to the antigen and the production of cloned effector cells is a time lag of ten to 17 days. If the body is exposed to the same antigen at a later time, the response time is between two to seven days. This is the SECONDARY IMMUNE RESPONSE.

The 'memory' ability of the immune system is based on MEMORY CELLS. During the primary response, the memory cells are not active. These cells survive long periods of time and divide quickly when exposed to the same antigen again.

8) Self Tolerance is the lack of the immune system's response to ones own body cells. During embryonic development, any lymphocytes with receptors for molecules found in the body are destroyed.

The marker for 'self' is the MAJOR HISTOCOMPATIBILITY COMPLEX (MHC), also known as: HLA (human leukocyte antigen). These molecules are glycoproteins embedded in the cell membrane. A large family of genes consisting of 20 MHC genes with at least 50 alleles for each gene makes it almost impossible for two people (except identical twins) to have the same MHC.

There are two classes of MHCs.

a) Class I MHC are located on all nucleated cells. Since the RBC don’t have a nucleus, then they don’t have MHCs. This is important for blood typing.

b) Class II MHC are restricted to macrophages and B lymphocytes. These play an important role in how cells of the immune system interact.

The job of the MHC is antigen presentation. Each MHC holds a piece of the antigen and presents it to a T cell. Cytotoxic T and Helper T cells have antigen receptors that bind to these Ag fragments. Cytotoxic T cells bind to MHC I on infected cells, and helper T cells bind to MHC II on infected macrophages.

All that was background information! Now the Antigen is in the body and you need the specific defense. Once the Ag gets into the body, it can be free floating in the blood and tissues, or it can infect cells. The antigen/pathogen ends up in the lymph system and is transported to the lymph nodes (usually by the person’s muscle contractions). In the lymph nodes, there is a high concentration of macrophages, T cells and B cells. The T cells, B cells and Macrophages bind to the antigen/pathogen. The B cells and macrophages take in the antigen/pathogen.

D) Humoral Response:

1) T Cell Dependent Response:

a) B cells: Binding of an antigen to specific receptors on the B cell surface. The B cell takes in the antigen and then presents the antigen in the class II MHC. It is now an antigen presenting B cell, APC-B. Usually the B cell just displays the antigen and doesn’t go through Clonal selection, for that it needs the TH cell.

b) T cells: The T cells bind to the antigen/pathogen. When this happens, the T cells undergo Clonal selection to produce TH cells, Tc cells and Ts cells.

c) Macrophages: After a macrophage engulfs a pathogen by phagocytosis, pieces of the pathogen are displayed on the surface of the macrophage. In this stage, the macrophage is called the ANTIGEN-PRESENTING CELL (APC). The APC-macrophage produces a cytokine called interleukin 1 (IL1). IL1 has two functions: it can stimulate the production of IL2 in T cells and also can act as a pyrogen. The antigen fragments are found in the class II MHC.

d) A helper T cell's receptors recognize this combination of MHC and antigen. Contact between the T cell and the APC activates the T cell. The interaction between the APC and T cell is helped by a surface protein, CD4, on the T cell. CD4 has an affinity for part of the MHC II glycoprotein. This helps with the binding of the T cell to the infected macrophage. The T cells divide and forms clones of helper T cells. At the same time the TH cells will produce a cytokine called interleukin 2 (IL2). IL2 stimulates TH cells to grow and divide and those cells produce more IL2 (a positive feedback loop). This causes an explosion of T cells. These helper T cells selectively stimulate B cells that have encountered the same antigen. The T cell binds to a B cell that is displaying the antigen fragments bound to the class II MHC on the cell surface. The B cell is then stimulated to develop into a plasma cell and produce antibodies. B memory cells are also produced which stay inactive for this immune response. The B memory cells basically increase the number of B cells, so that the next exposure will have more B cells to produce more plasma cells that will produce more antibodies, quicker. The IL2 will also stimulate the B cells and TC cells.

2) There are T-INDEPENDENT ANTIGENS that initiate a humoral immune response without involving macrophages or T cells. These antigens are usually long chains of repeating units, such as polysaccharides or protein subunits, which are usually found in bacterial capsules and bacterial flagella. Usually, the numerous subunits of such antigens bind to a number of the antigen receptors on the B cell surface, providing enough stimuli for the B cells to work without the T cells. The T-independent antigen response is weaker than the T-dependent response.

Once activated a B cell gives rise to clones of plasma cells and each cell can secrete up to 2,000 antibodies per second for the four to five day life span of the cell.

2) Antibodies: How they work.

Antibodies don't usually destroy an invader directly. Here are the ways that an antibody works:

a) Neutralization: the antibody blocks certain sites on an antigen to make it ineffective, for example, antibodies binds to viral attachment site then viruses can't attach to cells. Eventually phagocytes will engulf the invaders. This process is called Opsonization. The antibodies enhance the macrophages to phagocytize the complex.

b) Agglutination: clumping. This is possible because each antibody has at least two different binding sites and can cross link antigens. This makes it easy for phagocytes to eat the antigen. One Ab binds to more than one Ag. This usually occurs with IgM or IgA because they can hold more than one Ag.

c) Precipitation: antibodies cross link antigen molecules (NOT CELLS) to form precipitates that are eaten by phagocytes. Many Ab binds to many Ag.

d) Complement: a group of proteins that act cooperatively with elements of the nonspecific and specific defense systems. Antibodies often combine with complement proteins; the antibodies activate the complement protein called the membrane attack complex (MAC) that produces lesions in the cell membrane of a foreign cell. Lysis of the foreign cell is the result.

e) The antibodies have been discovered to produce H2O2 from oxygen. This can form free radicals, hydroxyl radicals and hypopholous acid which will kill the Ag.

3) Monoclonal Antibodies:

Monoclonal cells are all descendants of a single cell and produce identical antibodies. New technologies rely on this method to produce specific antibodies inexpensively.

One product of monoclonal antibody technology is a HYBRIDOMA. This is a hybrid cell formed from a cancer cell (myeloma) and a B cell. Antibodies can be produced indefinitely.

E) Cell-Mediated Response:

1) This response battles pathogens that have already entered cells. The key components are T lymphocytes, which are lymphocytes that mature in the thymus and migrate to the lymphoid organs like the lymph nodes and spleen.

Free antigens cannot activate T cells. T cells only respond to the antigenic epitopes displayed on the surfaces of the body's own cells. These bound antigens are recognized by T-cell receptors. T cells respond to the MHC-antigen complex or the macrophage. This is the class 1 MHC. The body cells don’t have a class 2 MHC.

The T cells with the correct receptors divide to form clones of effector cells specialized to fight the pathogen. There are two main types of T cells called into action:

a) Helper T cells (TH): these help produce antibodies and stimulate TC cells.

b) Cytotoxic T cells (TC): these poke holes in infected cells.

2) Cytotoxic T cells are the only T cells that kill other cells. Host cells infected by viruses or other intracellular pathogens display antigens and class I MHC. Each TC cell has a receptor that can bind to a specific antigen combined with class I MHC. (TH cells look at class II MHC and antigen complexes.) The Cytotoxic T cells have a surface protein, CD8, which helps with the binding of the Cytotoxic T cell with the class I MHC on the target cell. The CD8 is analogous to the CD4 (on helper T cells). When TC cells bind with an infected cell, they release PERFORIN, which is a protein that forms an open lesion in the infected cell's membrane. The cell loses cytoplasm through the lesion, the cell lyses, pathogens are released, and antibodies bind to the pathogens.

Cytotoxic T cells also defend against cancer cells.

Natural killer cells do not respond to antigens although they kill cells in the same manner.

A third type of T lymphocyte is the SUPPRESSOR T CELL (TS)-- not well understood. TS cells probably turn off the immune system.

F) Complement System: About 20 different complement proteins circulate in the blood in inactive form. These must be activated through a series of reactions.

1) The activation of the complement system is called the CLASSICAL PATHWAY.

a) The pathway is initiated when antibodies (IgM or IgG) bind to the invader.

b) A complement protein bridges the gap between two adjacent antibody molecules. The antibodies and complement activates complement proteins (membrane attack complex).

c) The complement produces a small lesion (7 to 10 nm in diameter) in the pathogen membrane.

d) The cell lyses.

2) The ALTERNATIVE PATHWAY doesn't require antibodies and the targets aren't specific virus-infected cells, and protozoans can activate complement proteins to form a complex. Through the alternative pathway, complements can also contribute to inflammation. Complement proteins bind to histamine containing cells (mast cells or basophils) and histamine is released. This alarms the body to a local injury. Several complex proteins attract phagocytes to the infected area.

3) In IMMUNE ADHERENCE, complement, antibodies, and phagocytes work together. An invader is coated with antibodies and complement proteins and adheres to a surface where phagocytes eat them.

G) Applications:

1) Blood groups: If given the wrong blood type, the transfused cells would be destroyed

through the cell-mediated response. Red blood cells have no nuclei, so they don’t have any MHC. The only antigens are the A/B proteins on the red blood cell.

2) Tissue Grafts and Transplants:

MHC is responsible for tissue rejection. A foreign MHC causes TC cells to be activated. To avoid this, tissues must be matched and suppressor drugs given. The immune system must be suppressed. Usually cyclosporin is used, which is a fungal product.

3) Immune System Disorders:

An autoimmune response occurs when the immune system attacks the body's own cells.

Examples: Rheumatoid arthritis-- attacks joints.

Insulin dependent diabetes-- attacks insulin cells in pancreas

Rheumatic fever-- attacks heart muscle/valves

Graves disease-- attacks thyroid. Too much thyroid hormone is produced.

Lupus—systemic autoimmune response.

Multiple Sclerosis—T cells act against the myelin sheath of the neurons. The nerves basically short circuit.

Alopecia—hair follicles

4) Allergies are the hypersensitivity to environmental antigens and often involve IgE. Instead of producing IgG antibodies, your body produces IgE instead. These antibodies attach to Mast cells (contain histamine). For example, IgE recognizes allergen (pollen) and attaches to the allergen. IgE is already attached to a mast cell at the stem. Once attached to the allergen the mast cell disintegrates releasing histamine. Histamine causes the dilation of small blood vessels, runny nose, sneezing, and smooth muscle contractions, which causes difficulty in breathing. Anaphylactic shock is a severe allergic reaction. IgE and histamine was good for large parasites. You itched or sneezed the parasites off of your body.

5) Immunodeficiency is the deficiency in hormonal or cell-mediated immunity, for example, HIV and AIDS. The HIV attaches to cells with the CD4 receptor.

6) Hodgkin’s disease: damages the lymph system. Be sure to tie in the lymph system with the immune system.

7) Cytokines can also stimulate the brain. This causes you to act sick. This can also cause depression.

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