The lymphatic system is a network of vessels that transport a fluid called lymph. There are also several structures and organs that contain lymphatic tissue.

The functions of the lymphatic system are:

1. Draining interstitial fluid from tissues and returning it to the vascular system.

2. Transporting dietary lipids from the intestines to the blood stream.

3. Protection against foreign substances as well as from cancer and microorganisms.

Lymphatic vessels begin as closed-ended lymph capillaries in the tissue spaces between cells. (Thus, lymph is not a circulating fluid). They do tend to run in paths similar to the blood capillaries.

Interstitial fluid drains into lymphatic capillaries, forming lymph.

Lymph capillaries merge to form lymphatic vessels, which carry lymph into and out of structures called lymph nodes and finally back to the vascular system.

Like blood capillaries, lymphatic capillaries are made of a single layer of squamous epithelial cells. Lymphatic capillaries are slightly larger in diameter than blood capillaries and have a unique structure that allows interstitial fluid to flow into, but not out of, lymphatic capillaries. The ends of the endothelial cells that make up the wall of the lymphatic capillaries overlap and act like valves. Whe the pressure increases in the interstitial fluid, it pushes the flaps open, and fluid enters the capillary. When the pressure of the fluid is greater inside the capillary, it forces the overlapping cells closer together, trapping the fluid inside the lymph capillary. At right angles to the lymphatic capillaries are structures calles anchoring filaments which attach lymphatic endothelial cells to the surrounding tissue. When edema causes swelling of the tissue, these filaments pull on the endothelial cells, opening the spaces wider so that more fluid can enter the lymphatic capillary. Lymphatic capillaries are found everywhere in the body except: 1) avascular tissues, 2) the central nervous system, 3) the splenic pulp, and 4) bone marrow.

Lymphatic vessels resemble veins ( same three layers), but have thinner walls and more valves. In the skin, lymphatic vessels usually follow veins, but in the viscera generally follow arteries.

The larger lymphatic vessels lead through lymph nodes, and then merge to form larger vessels called lymph trunks, which are named after the areas of the body that they serve . These trunks then join to form two large collecting ducts:

the thoracic duct and the right lymphatic duct, and then into the subclavian veins. The thoracic duct drains about 3/4 of the body, and right lymphatic duct drains the rest - the right arm, the right side of the head, neck and upper torso.

Where does the lymph fluid come from? More fluid seeps out of capillaries by diffusion and filtration than returns to them. This excess fluid, about 3 liters per day, as well as escaped proteins such as albumin, drains into the lymph vessels and becomes lymph. What does albumin do for the blood? What happens when the return of lymph is blocked? Edema.

Along with the tissue fluid and lost proteins, lymph also transports foreign particles and bacteria and viruses to lymph nodes.

Lymph flows as a result of skeletal muscle contraction (milking action) and respiratory movements, aided by valves, as well as by the contraction of smooth muscle in the walls of larger lymph vessels.

Specialized lymph capillaries are associated with the vili of the small intestine. These vessels are called "lacteals" because the lipid they transport makes the lymph look milky. This fluid is called chyle.

The lymphatic organs are the red bone marrow, the thymus gland, lymph nodes, lymph nodules, and the spleen.

Lymph nodes: On its way back to the blood, lymph is filtered through lymph nodes, that are located in clusters along the pathway of the lymphatic vessels. In our sewer analogy, these would be the waste water treatment plants. These nodes vary in size from about the size of the head of a pin to the size of a lima bean or an olive.

The main groupings of lymph nodes are in the neck (cervical), armpit (axillary) and in the groin (inguinal) regions, as well as the in the pelvic, abdominal and thoracic cavities. They are also found in mammary glands. There are superficial and deep groups. Clusters of lymph nodes allow for a very effective biological filtration of lymph. Unfortunately, these nodes can also become infected, or can contain growing cancer cells. The lymphatic system can even serve as the route through which cancer cells spread to other parts of the body or metastasize.

Lymph enters a lymph node through afferent lymphatic vessels on the convex side of the lymph node. Inside the node, the lymph travels through a series of irregular channels called sinuses and then leaves the node through one or two efferent lymphatic vessels. There is a slight indentation here, called a hilum. This is also where blood vessels enter and leave the node.

Each node has a connective tissue capsule which extends into the lymph node and partially divides it into compartments.

Lymph nodes also have a cortex and a medulla.

The cortex contains lymph nodules (follicles) which are regions of densely packed, actively dividing lymphocytes. The outer rim of each nodule contains T-cells plus macrophages and follicular dendritic cells, which participate in the activation of T cells. The macrophages consume bacteria, soot, cancer cells, and other harmful particles, so they are not spread through out the body. Other microorganisms and foreign particles are destroyed by immune responses. The nodules have lighter staining germinal centers, where B cells multiple and change into antibody secreting plasma cells.

The medulla of the lymph node also contains t-cells, plasma cells and macrophages.

Lymph nodules also occur singly or in groups throughout the mucous membranes of the respiratory, urinary, reproductive and digestive tracts. This lymphatic tissue is referred to as mucosa-associated lymphoid tissue (MALT).

Some lymphatic nodules also occur in multiple, large aggregations in specific parts of the body. Among these are Peyer’s patches in the ileum of the small intestine, and the tonsils. Some lymphatic nodules also occur in the appendix.

Tonsils are masses of lymphoid tissue located under the mucous membranes in a protective ring in the throat. (the palatine tonsils are located on either side of the throat. The pharyngeal tonsil, also called the adenoid, is near the posterior opening of the nasal cavity. The lingual tonsils are near the base of the tongue.) Because of their location, they serve as the first line of defense from germs entering the nose and mouth. They are subject to chronic infection, and may need to be removed surgically (tonsillectomy).

Thymus gland lies in the mediastinum between the sternum and the large blood vessels above the heart.

The thumus gland large in the infant, and reaches its maximum size at the age of about 10-12 years of age. After puberty, adipose and connective tissue begin to replace the thymus tissue, and by the time a person is mature, the gland has atrophied considerably. Although most T cells are formed before puberty, some continue to mature throughout life.

The capsule that surrounds the thymus gland gives off extentions called trabeculae which divide the gland inot lobules. The lobules contain macrophages, epithelial cells, and many lymphocytes that came from the bone marrow. These thymocytes, or Pre-T cells migrate from the red bone marrow to the thymus gland, where they divide and develop into mature T cells that then travel to the spleen, tonsils, lymph nodes, and othey lymphatic tissues. The epithelial cells produce the hormone thymosin, which stimulates the maturation of T cells after they leave the thymus.

The spleen is the largest lymphatic organ in the body. It is located in the upper left quadrant of the abdomen, lateral to the stomach. Like a lymph node, it also has a hilum, and a capsule of dense irregular connective tissue surrounds it, and partially divides it into lobules. The sinuses in the spleen however, contain blood instead of lymph.

The functional part of the spleen contains white pulp and red pulp.

The white pulp is found in little islands throughout the spleen. It is lymphatic tissue, mostly B cells, arranged around arteries.

The red pulp contains venous sinuses filled with blood and thin plates of tissue called splenic cords. These cords are made up of red blood cells, macrophages, lymphocytes, plasma cells and granulocytes. Although the spleen is protected by the ribs, it can be injured by trauma. Since it has a rich blood supply and can contain over one pint of blood, (about half a liter) surgical removal (splenectomy) may be necessary to stop the loss of blood.

The spleen has three basic functions:

1.Blood formation: in the embryo all types of blood are formed here, but in the adult, only lymphocytes and monocytes are produced.

2. Blood filtration : it removes bacteria and foreign particles, as well as worn out red blood cells and platelets. The iron from the RBC’s is salvaged for recycling.

3. Blood storage: Blood can be stored here, and when needed, smooth muscle fibers and elastic tissue in the spleen allow it to contract and return the blood to circulation.

Ability to ward off disease is called resistance

Lack of resistance is called susceptibility.

Nonspecific resistance - a wide variety of body responses against a wide range of pathogens.

Immunity involves activation of specific lymphocytes to fight off a specific foreign substance.

Species Resistance - certain species can come down with certain diseases, while other species do not. We do not catch feline leukemia virus or canine distemper.

Skin and Mucous Membranes: are the first line of defense against the entry of pathogens. The thickness of the epidermis and the periodic shedding of dead cells are a strong physical barrier against microbes.

The mucus secreted by mucous membranes is very thick and sticky and traps many microbes and foreign particles. Mucous membranes are less effective barriers than skin.

The hairs at the entrance to the nose and ears trap foreign substances (or at least let us know they are there!)

The cilia of the respiratory tract propel mucus and trapped particles up and out of the system.

Coughing and sneezing also expel bacteria. The production of saliva, the production of tears, the flow urine, vaginal secretion, the production of acid by the stomach, defecation and vomiting are all means of physically removing harmful substances.

Chemical protection.

Sebaceous glands produce sebum which contains fatty acids which inhibit the growth of certain pathogenic bacteria and fungi. The sebum, plus lactic acid, lower the pH of the skin to further inhibit microbial growth. Accumulation of salt from perspiration also kills certain bacteria.

Vaginal secretions are also slightly acidic, which discourages the growth of bacteria.

Gastric juice, produced by the stomach, is a mixture of hydrochloric acid, enzymes, and mucus. The strong acid destroys many bacteria and toxins.

Lysozyme, an enzyme capable of breaking the cell walls of some bacteria can be found in perspiration, tears, saliva, nasal secretions and tissue fluids. The gel like texture of hyaluronic acid found in areolar connective tissue physically slows the spread of local infections. Gastric juice, produced by the stomach is a mixture of hydrochloric acid, enzymes, and mucus.The strong acid destroys many bacteria and toxins. Vaginal secretions are also slightly acidic, which discourages bacterial growth.

The normal microbiota of the skin also prevent the growth of potentially harmful bacteria. Many produce substances that prevent the growth of other bacteria.

Antimicrobial Substances - are a second line of defense against microorganisms that make it past the barriers of skin and mucous membranes.

Transferrins are proteins which tie up the free iron in the blood and interstitial fluid. Since bacteria require iron to grow and reproduce, transferrin inhibits bacterial growth.

Interferon is a glycoprotein produced by lymphocytes, macrophages, epithelial cells and fibroblasts. When released from infected cells, these substances diffuse to neighboring uninfected cells and bind with receptors which cause these cells to produce anti-viral proteins. These proteins inhibit or interfere with viral replication. ("Paul Revere chemicals). Interferons also enhance the activity of phagocytes and can suppress the growth of tumor cells.

The Complement System is a group of about 20 normally inactive proteins in blood plasma and on plasma membranes. When activated, these proteins "complement" or enhance certain immune, allergic and inflammatory reactions.

Complement activation is a cascade effect, much like blood clotting, with one step activating the next, and so on.

Once Complement is activated, it can result in any of a number of complements activities which are:

1. Activation of inflammation: some complement proteins contribute to the development of inflammation by dilating arterioles, and causing the release of histamine which increases the permeability of capillaries. Other complement proteins serve as chemotaxic agents that attract phagocytes to the area of microbe invasion.

2. Opsonization is any process that enhances phagocytosis. Complement does this by binding to the surface of the microbe, and then interacting with receptors on the phagocyte to promote phagocytosis. (Put a fork in it)

3. Cytolysis Several complement proteins come together to form a membrane attack complex (MAC). The complement molecules form doughnut shaped complexes in a bacteria's plasma membrane. Holes in the complement complex allow Na+ to rush into the cell. Water follows the sodium, causing the cells to swell and burst or lyse; this process is called cytolysis.

Fever is an abnormally high body temperature. Elevated body temperature causes the liver and spleen to sequester iron. It also increases phagocytosis - the phagocytes can attach more vigorously. It is also thought to intensify the effects of interferon, inhibit the growth of microbes and speed up body reactions that aid repair.

Inflammation helps to get rid of microbes, toxins, or foreign material at the site of an injury and prepares the site for tissue repair. It is characterized by four cardial signs : redness, pain, swelling, and heat, and sometimes loss of function.

There are three basic stages:

1. vasodilation and increased permeability of blood vessels: vasodilation allows more blood cells and defensive substances into an area, and also carries away toxins and dead cells. This is responsible for many of the signs of inflammation.

2.Phagocyte migration occurs within a hour after the inflammatory process starts. First the neutrophils leave the vessels to enter the infected area. They are followed hours later by monocytes which become macrophages. Macrophages are more powerful phagocytes, and consume damaged tissue, worn-out neutrophils, and microbes. These cells also die, and the accumulation of dead white cells and fluid in a tissue is called pus.

3. Tissue repair - phagocytes clean up the area, and cell reproduction replaces lost cells.

Phagocytosis is the ingestion (eating) of microbes or any foreign particles by cells called phagocytes. The two major types of phagocytes are neutrophils and macrophages ( 100 bacteria at a time, vs 20). Phagocytosis has three phases:

1. Chemotaxis: is the chemical attraction of phagocytes to a particular location (like a perfume). Some chemotaxic agents are microbial products, components of white blood cells and damaged tissue cells, and activated complement proteins.

2. Adherence: simply the attachment of a phagocyte to a microbial surface. Sometimes it is easy; other times it is more difficult because of bacterial defenses, such a capsule. - like grabbing a greased pig. Opsonization by complement makes adherence easier.

3. Ingestion: the phagocyte consumes and digests the invader. Some microbes may produce toxins which kill the phagocyte, or just remain dormant within the phagocyte. Some microbes, like the tubercle bacillus, can multiply within the phagocyte and destroy the cell.

Phagocytes can be found in the blood stream, and in tissues. Some macrophages wander through tissues, and others take up residence in certain tissues, remaining there as fixed macrophages.

Natural Killer Cells After the physical barriers and the antimicrobial substances in the blood, the body's next line of defense is the natural killer cells and phagocytes. Natural killer cells are lymphocytes. Unlike T cells and B cells, natural killers cells don't have receptors for specific antigens. They are capable of killing a wide variety of microbes, plus some tumor cells. NK cells are found in the spleen, lymph nodes, red bone marrow and blood. How they function is not completely known. They may work by releasing perforins, chemicals which make holes in the bacteria, or they may attack the microbes dirrectly. How they recognize their targets is also unknown. It may be due to a cell not displaying the correct major histocompatibility antigens (starship without the correct identification codes). They function as tumor surveillance cells, and may destroy potential cancers before they get started.

IMMUNITY

Specific resistance to disease involves the production of a specific lymphocyte or antibody against a specific antigen and is called immunity.

An antigen is any substance that elicits an immune response. The best antigens are large, (recognized as) foreign, and complex. Proteins are the prime examples (not cellulose or plastics), complex polysaccarides, like those found on bacterial surfaces are also good. Lipids and nucleic acids and uncomplicated polysaccarides are generally good antigens (the body ignores them).

Haptens are small foreign and complex. To elicit an immune response, haptens must first piggyback on a larger molecule to be noticed by the immune system. Example, allergy to penecillin. Often these attach to blood proteins. Epitopes : A foreign protein injected into someone may result in not one, but several different antibodies. This is because each antibody recognizes a different portion of the protein molecule. These different regions on the protein are called epitopes.

The Story

During inflammation, a macrophage, in the process of cleaning up the site of infection, phagocytizes a bacterium, and destroys it. The macrophage then takes a bacterial antigen, fuses it with an MCH II protein, and moves the complex to the surface of the macrophage. MHC I is the UPC code present on all cells of the body (except RBCs) which identify the cell as "self". MHC II is present on macrophages, and other lymphatic cells.

This macrophage displays this complex much a like a proud cat with a mouse. It displays this antigen to T helper cells. When it finds a T helper cell which has a receptor matching this antigen complex, the T helper cell binds to the complex by means of its specific antigen receptor. The T and B cells of the immune system have antigen receptors which are specific for virtually every antigen the body will encounter, even those which are man-made and did not exist a few years ago!

This binding causes the macrophage to produce the cytokine Interleukin-1. A cytokine is a protein hormone which regulates normal cell functions, such as growth and differentiation.

Every step in the immune system needs two signals in order to proceed.

The interleukin-1 produced by the macrophage binds to the IL-1 receptor on the T helper cell causing it to clone itself and to produce interleukin-2. IL-2 causes lymphocytes to multiply. So the T cells which are producing it, are causing themselves to multiply and to continue to produce IL-2.

These steps are common to both cell mediated and humoral immune responses.

Humoral (AMI) immunity.

In order for B cells to become activated and produce antibody against a specific antigen, two things must happen. First, the B cell must encounter the specific antigen on its own. The antigen will bind to the antigen receptor (IgD) on the B cell. Next, IL-2, produced by the T helper cell, needs to stimulate the B cell. This makes sure the "threat" is real, since two cells are responding to the antigen.

With these two signals, the B cell responds by cloning itself. Some of these cells undergo a physiological transformation necessary to produce a large quantity of protein, specifically, the specific antibody which reacts with the antigen. A few cells do not produce antibodies, but do multiply to remain in the immune system as memory cells, ready to respond to future invasions by this antigen bearing agent. Because thousands of memory cells exists after an encounter with an antigen, the next time the same antigen appears, they can proliferate and differentiate into plasma cells within hours. This is the basis for immunization.

Antibodies are soluble proteins called gamma globulins. They are made of four chains of amino acids liked together- two light chains and two heavy chains - that form a "Y" shape. In the tips of the Y are variable regions of the antibody, and are shaped to fit around a very specific antigen. The other end is a constant region, also called the Fc region of the antibody. This is the end which can act as the "handle of the fork" for opsonization, and it is also the area which can activate complement.

The first antibodies produced by the activated B cells (plasma cells) are IgM. IgM are pentomeric antibodies (five unit) with ten combining sites for antigens. These are effective opsonins, mostly because they are effective in clumping bacteria. It is also the most efficient antibody class for activating complement. Starting several days after antibody production begins, IgG antibodies begin to replace IgM. IgG are single unit antibodies and are the most abundant antibodies in serum and interstial fluid. These cross the placenta and have the longest half-life.

These antibodies can cause clumping, which improves phagocytosis. Once the antibody has attached to a bacterium the end of the antibody (Fc end) not attached to the bacterium acts as the "handle end" which allows a phagocyte to grab the bacterium (fork). They also activate compliment, causing lysis of the cell. By binding to attachment structures on viruses and bacteria, antibodies prevent the viruses and bacteria from binding to host cells, which is the first step in most infections. Antibodies can also bind to toxins, which ties them up so they cannot bind to cells and cause damage. (This is also the way RhoGAM prevents hemolytic disease of the newborn - erythroblastosis fetalis)

IgA is a double unit of antibody which is found in body secretions, such as saliva and breast milk. IgD is the receptor shed by the B cell.

A virus is a particle of protein and nucleic acid capable of self replication. When it enters an animal cell, the DNA of the virus takes over the cell's machinery, causing it to produce viral proteins and viral DNA. Some of these proteins are inserted into the cell membrane, where they can be noticed by the body's immune system. When a macrophage encounters a dead or dying virus infected cell, it can process these viral proteins as antigens, and display them with the MHC-II for the T helper cell. Antibodies can't get at viruses located inside a cell. In order to kill a virus infected cell and prevent it from releasing more viruses, a cytotoxic T cell specific for the viral antigen, needs to be activated. As usual, two signals are needed to activate the T cell. The Tc cell needs to encounter the viral antigen on the surface of infected cell. The viral antigen is present in conjunction with the MHC-I protein on the infected cell. The second stimulus is interleukin-2 produced by the T helper cells. (note parallels) IL-2 causes the Tc cell to clone itself. Some cells become memory cells. Other cells become activated Tc cells. When the activated Tc cells encounter an infected cell showing viral antigens on its surface, the cell binds to those antigens and releases perforins and lymphotoxins which destroy the infected cell.

Perforins are similar to activated complement, and act by punching holes in the cell membrane.

Lymphotoxins activate the infected cells self-destruct mechanisms. The Tc cell then detaches and seeks out another infected cells. Tc cells are effective against bacteria which are intracellular parasites, viruses, fungi, cancer cells associated with viral infections and transplanted cells.

T helper cells are involved in activating both CMI and AMI. The AIDS virus attacks T helper cells, thereby effectively shutting down the immune system.

Immune responses:

The first time you encounter an antigen, you may have only a few cells capable of responding to that antigen. When they react to the antigen the first time it is called the primary immune response. Production and release of antibodies can continue for several weeks. The plasma cells die off, but the memory cells remain.

The next, and any following time you meet an antigen, the response is much more rapid and intense. The memory cells spring into action, and may be able to produce enough antibodies that the infectious agent (germ) is destroyed before it has a chance to cause disease. This is called the secondary immune response. Vaccinations generate the primary immune response, so that if we ever encounter that agent (germ), the secondary immune response kicks in.
 Follicular dendritic cells in the lymph nodes may help memory by harboring and slowly releasing viral antigens after the initial infection. This keeps the immune system geared up.

Hypersensitivity

Delayed type hypersensivity is a form of cell mediated immunity. The T cell which carries out this immune response is the Tdth cell. It requires the usual two signals, IL-2 and exposure to the specific antigen on the surface of the macrophage. The cells then clone themselves, and become activated. The next time the antigen is encountered, again on the surface of the macrophage, it responds by producing a variety of cytokines. These ctyokines act to attract and activate macrophages, resulting in an inflammatory reaction. Ex. reaction of urushiol (oo- roo-she-al), which is the oil of poison ivy, and the TB skin test. This inflammatory response can be very intense, resulting in tissue damage, which furthers the inflammatory response.(positive feedback).

Exposure to certain antigens (such as pollen or bee venom) results in the production of IgE antibody instead of IgM or IgG. IgE is unusual because it attaches to mast cells by the Fc end (the end that complement binds to). Upon a second exposure, the antigen (or "allergen") is bound by the IgE antibody causing a characteristic shape change in the molecule. This causes the mast cell to dump its granules of histamine into the surrounding tissue fluid. If this reaction, called anaphylaxis, occurs locally, the effects are felt locally. Examples are asthma (constriction of bronchioles), hives (on skin), or diarrhea (intestinal exposure as in food allergy). If mast cells throughout the body are activated by an allergen that escapes into the circulation, histamine release causes widespread vasodilation leading to a massive drop in blood pressure. This is the cause of anaphylactic shock. Epinephrine reverses many of the effects of histamine and is administered in emergency cases.

Hypesensitivities that take 1- 3 hours to develop (type II and Type III are also caused by antibodies. Reaction to a bad blood transfusion is a antibody-dependent cytoxic reaction. Forms complexes that cannot easily be cleared by phagocytosis and lysis and block vessels.

Immediate type hypersensitivity differs from delayed type in the following ways: a) it takes less time for the symptoms to be expressed (minutes vs hours), b) it involves an antibody-antigen reaction rather than a cell-mediated inflammatory response. People with allergies can obtain relief by taking antihistamines.

Sometimes a process called desensitization is used to attempt to cure allergies. The theory is to inject very small quantities of the allergen in an attempt to elicit the formation of IgG antibodies without activating the IgE bound to mast cells. Increasing amounts of allergen are injected, further stimulating IgG production. Ultimately, if successful, the levels of IgG in the body are high enough so that any amount of allergen entering the body is immediately bound by IgG, preventing the allergen from reaching the IgE bound to mast cells.

Autoimmunity - loss of ability to tolerate self antigens.

tissue transplants Tissue rejection reaction and Graft vs. Host

Isograft - genetically identical twin

Autograft- from self

Allograft - from same species

Xenograft - from different species

Immunity can be classified as inherited or acquired. Inherited immunity can also be called inborn immunity. We are naturally immune to certain organisms which cause disease in animals, e.g. canine distemper or feline leukemia virus. We are also born with antibodies to foreign blood types.

Aquired immunity can be broken down into natural or artificial depending on how the body is exposed to the disease agent. Natural exposure is not deliberate, and occurs in the process of everyday living. Artificial exposure is deliberate, and called immunization.

Acquired immunity may be active or passive.

Active immunity occurs when an individual's own immune system responds to an invading organism. This can be natural, as when a person is exposed to a disease organism, comes down with the disease, and becomes immune; or artificial as when we are vaccinated with a killed or modified organism.

Passsive immunity occurs when immunity to a disease occurs in one individual, and is transferred to a second individual who was previously not immune. This occurs when a mother breast feeds her child. The first "milk" that is produced is very high in antibodies which protect the infant from diseases the mother has experienced. This is a natural, passive immunity. Antibodies and other immunity conferring substances can be injected into an individual who has been exposed to a disease which could pose a serious threat to that individual, such as rabies. Passive immunity lasts only as long as the antibodies remain in the circulatory system. Active immunity usually lasts much longer.