Editing Chapter 22 notes (Lymphoid and immune systems) (section)

=An introduction to the lymphoid system and immunity= 

==Anatomical barriers and defense mechanisms constitute nonspecific defense, and lymphocytes provide specific defense==
*There are lots of non-living things that can hurt us like UV light, bumps, temperatures, etc.
*There are lots of living things that can hurt us (pathogens) like viruses, bacteria, fungi, and parasites.
**Viruses are usually within cells and rupture them.
**Bacteria are usually in the ECF and produce toxic proteins.
**Parasites can burrow through entire internal organ systems.
*"The lymphoid system includes the cells, tissues, and organs responsible for defending the body against both environmental hazards, such as various pathogens, and internal threats, such as cancer cells."
*Lymphocytes respond to abnormal body cells, invading pathogens, and foreign proteins.
*The body has several nonspecific defenses which serve to block entry to the body or to attack anything that is foreign.
*Lymphocytes, however, are specific in their attacks.
*Specific defenses are considered an immune response.
*The immune system refers to not only the lymphocytes, but all the organs and tissues that are associated with specific immune response.
**These include the integumentary, cardiovascular, respiratory, digestive, and other systems.

==Lymphatic vessels, lymphocytes, lymphoid tissues, and lymphoid organs function in body defenses==
*The lymphatic system is made up of:
**lymph (which is much like ECF but with fewer proteins), 
**lymphatic vessels (which run from peripheral tissues to veins),
**some lymphoid tissues and organs (found throughout the body, think tonsils, spleen, thymus, etc.),
**lymphocytes and some phagocytes and several other cell types.

===Functions of the lymphoid system===
*The primary function of the lymphoid system is to produce and distribute lymphocytes.
*Lymphocytes are primarily generated in lymphatic tissues (like the tonsils) and organs (like the spleen and thymus) but are also generated in red bone marrow.
*Red bone marrow also generates other defense-related cells like monocytes and macrophages.
*The lymphocytes are carried throughout the body via the blood, interstitial fluid, and the lymphatic system.
*The lymphatic system helps circulate interstitial fluid and thus allows for elimination of local abnormalities of interstitial fluid and keeps nutrients moving.

===Lymphatic vessels===

====Lymphatics capillaries====
*Lymphatic capillaries run through peripheral tissue, draining interstitial fluid (including proteins, viruses, bacteria, and cellular debris) through endothelial cells that overlap, like shingles.
*Lymphatic capillaries differ from cardiovascular capillaries in four ways:
#they originate as pockets as opposed to tubes,
#they have larger diamters,
#they have thinner walls,
#they have flattened or irregular outlines in sectional views.
*Lymphatic capillaries are found throughout the body:
**They are not found where there are no capillaries; for example, in the cornea.
**They are not found in the central nervous system.
**They are particularly important in the digestive tract for transporting lipids (via ''lacteals'').

====Small lymphatic vessels====
*Lymphatic capillaries turn into lymphatic vessels as they progress toward the trunk and large veins.
*These larger vessels often appear bulbous because of valves that are placed rather close together.
*The valves are much like those in veins and are important for maintaining proper flow.
*Lymphatic vessels often occur in conjunction with veins.
*In living tissue, arteries are bright red, veins are dark red (illustrated as blue), and lymphatic vessels are pale golden.
*There are usually more lymphatic vessels than veins, but they are smaller, too.

====Major lymph-collecting vessels====
*Superficial and deep lymphatics collect lymph and deliver it to the even deeper lymphatic trunks.
*Deep lymphatics accompany deep arteries and veins to muscles, organs of the neck, limbs, trunk, and to the walls of visceral organs.
*Superficial lymphatics go everywhere else.
*The lymphatic trunks empty into two large ducts: the ''thoracic duct'' which collects from the left side of the body and everything below the diaphragm, and the ''right duct'' which drains from the right side of the body above the diaphragm.
*The thoracic duct has a saclike structure called the '''cisternae chyli''' at the base.
*The thoracic duct dumps into the left subclavian vein near the left internal jugular vein.
*The right lymphatic duct dumps into the right subclavian vein.
*Blockage of a lymph vessel can cause lymphedema--swelling associated with lack of interstitial fluid buildup.
**This can result in permanent swelling if connective tissue has a chance to loose it's elasticity.
**This can lead to bad things by way of toxin buildup.

===Lymphocytes===
*Lymphocytes account for 20-30% of all leukocytes.
*Lymphocytes in circulation are only a small fraction of the total lymphocytes in the body--massing up to a kilogram!

====Types of lymphocytes====
*There are lots of types of lymphocytes:
**'''Thymus-dependent (T) cells''':
***Make up 80% of circulating lymphocytes.
***There are sub-types of T cells:
****'''Cytotoxic T cells''': attack infected cells, usually through direct contact. These are the primary cells involve din the production of ''cell-mediated immunity'' or ''cellular immunity''.
****'''Helper T cells''': stimulate and activate both T and B cells.
****'''Suppressor T cells''': inhibit activation of both T and B cells.
****'''Suppressor / inducor T cells''': ''suppress B cells'' while ''activating T cells''.
****'''Inflammatory T cells''': stimulate regional inflammation and local defenses up injury.
***Suppressor and helper T cells are considered regulatory T cells.
**'''Bone marrow-derived (B) cells''':
***B cells are the primary cells involved in ''humoral'' (liquid, antibodies occur in body fluids) ''immunity''.
***B cells make up 10-15% of lymphocytes in the blood.
***B cells can convert into plasma cells and then produce antibodies.
***Antibodies are the same thing as immunoglobulins.
***Antibodies are generally proteins, but nucleic acids, lipids, and polysaccharides can also function to activate destruction of an antigen (target).
**'''Natural killer (NK) cells''':
***These cells maintain ''immunological surveillance''.
***NK cells are the same thing as large granular lymphocytes.
***These cells attack foreign cells, infected cells, and cancer cells.

====Life span and circulation of lymphocytes====
*The ratio of B to T cells is not ubiquitous throughout the body, it differs between the blood, thymus, spleen, etc.
*T cells move faster than B cells (think: 30 minutes in the blood, 15-20 hours in a lymph node).
*Most lymphocyte live for at least 4 years, some live for 20 years.  We make more as needed to maintain a proper balance.

====Lymphocyte production====
*Production of lymphocytes (lymphopoiesis) occurs in the red bone marrow, the thymus, and the peripheral lymphoid tissues.
*Hemocytoblasts (lymphocyte progenitors) are generated in the red bone marrow.
*B cells and NK cells are generated in the bone marrow.
*B cells develop through intimate contact with large stroma cells which secrete interleukin 7 to cause differentiation into B cells.
*B cells move into lymph nodes, the spleen, and other lymphoid tissues.
*The NK cells move through peripheral tissues in search of abnormal cells.
*Some lymphatic stem cells migrate (undifferentiated) to the thymus.
*In the thymus, stem cells are protected by the blood-thymus barrier.
*These stem cells divide under the control of (at least) 7 thymus hormones to generate the various kinds of T cells.
*T cells reenter the bloodstream and return to the bone marrow and also travel to peripheral tissues, including lymphoid tissues and organs, such as the spleen.
*Recall that not all T and B cells enter the blood stream or otherwise move on from the marrow or thymus.
*T cells and B cells that do move on retain the ability to divide (because they leave before their differentiation is complete) and this is crucial for proper immune response.

===Lymphoid tissues===
*Lymphoid tissues are just connective tissue with lots of lymphocytes in it.
*A '''lymphoid nodule''' or '''lymphtic nodule''' is when lots of lymphocytes are densely joined together.
*These nodules are found in connective tissue just under the epithelium in the respiratory, digestive, and urinary tracts.
**The nodules found in the respiratory tract are called '''tonsils'''.
*Note that there is not fibrous layer separating the nodes from one another.

====MALT====
*MALT = ''mucosa-associated lymphoidal tissue''.
*Lymphatic tissue of the digestive tract is called MALT.
*'''Aggregated lymphoid nodules''' = '''Peyer patches''': clusters of lymphatic nodules found on the intestinal wall.
*The vermiform (wormlike) appendix is a "blind pouch" found where the large and small intestines connect.
*The vermiform appendix is filled with fused lymphoid nodules.

====Tonsils====
*Tonsils are large lymphoidal nodules in the walls of the pharynx.
*We have five: a pair of palantine tonsils, a pair of lingual tonsils, and a single pharyngeal tonsil (also known as the adenoid).
*Tonsillitis refers to the inflammation of the lingual tonsils.

===Lymphoid organs===
*Lymphoid organs are separated from surrounding tissues by a fibrous, connective tissue.

====Lymph nodes====
*Nodes are 1-25 mm and distributed throughout the body.
*There is a dense connective tissue that surrounds them.
*Trabeculae run from the capsule to the interior of the node and are formed with collagen.
*Shaped like a kidney, the blood vessels and nerves arrive at the '''hillum''' or the indentation.
*Afferent vessels bring stuff to the node, efferent vessels take stuff away (toward the blood stream).

=====Lymph flow=====
*Lymph flows through the subscapular space where there are macrophages, dendritic cells, and a network of reticular fibers.
*Then lymph flows into the outer cortex where there are lots of B cells in germinal centers.
*Lymph then flows through the deep cortex (paracortical area) which is filled with T lymphocytes that have migrated here from the blood.  (This area has blood vessels flowing through it.)
*Then lymph flows into the medulla where there are lots of medullary cords made up of B cells and plasma cells.
*Finally, the lymph flows into the efferent vessels at the hillum.

=====Lymph node function=====
*The lymph node acts as a filter, running lymph and all the debris in it past macrophages and dendritic cells.
*This allows for macrophages to phagocytize and present antigens to and allows dendritic cells to activate T cells.
*99% of lymph will be filtered.
*Lymph nodes also provide a mechanism for early warning upon infection because antigens in the interstitial fluid often get washed into the nodes and set of an immune response.
*Lymph nodes are situated at all the major junctions of the lymphatic system: from the legs to the trunk (groin), head to body (neck), etc.
**These are bigger nodes and are often called lymphatic glands.
*"Aggregations of lymph nodes also exist in the mesenteries of the gut, near the trachea and passageways leading to the lungs, and in association with the thoracic duct."
*Nodes swell upon increased proliferation of lymphocytes or macrophages caused by peripheral infection of tissue.
*Chronic or excessive enlargement of lymph nodes constitutes lymphadenopathy, a condition that may occur in response to bacterial or viral infections, endocrine disorders, or cancer.

====Clinical note: Cancer and the lymphoid system====
*Cancers spread throughout the body via the lymphatic system because lymphatic capillaries offer little resistance.
*Because of this, we can examine lymphatic vessels to find out if cancer has spread.
*Knowing if it has spread changes treatment approaches.

====Thymus====
*The thymus sits behind the heart, from the neck down to the heart.
*It is biggest (relative to the rest of the body) at about 1-2 years of age.
*It declines in size and becomes more fibrous as puberty approaches, a process called '''involution'''.
*It may be the case that older people without their thymus are more susceptible to infection.
*The thymus is divided into two lobes and the lobes are divided into lobules, which each have a cortex and a medulla.
*In the cortex, T cells are dividing and moving into the medulla.
*The T cells migrate through the medulla over 2 or 3 weeks and finally enter the medullary blood vessels.
*Reticular cells surround groups of T cells and also surround the blood vessels, thus providing a blood-thymus barrier.
*Reticular cells also generate the factors that generate stem cell division and cause T cell differentiation.
*As T cells mature, they enter the medulla where there is not blood-thymus barrier.
*They are still surrounded by reticular cells, but they can enter the blood stream directly or enter the efferent lymphatic vessels.
*The thymus produces Thymusin (a mixture of Thymusin A / B / V, thymopoietin, thymulin and others) in order to promote the development and maturation of T cells.
*note that the rest, up to the immune system stuff is being skipped because it turns out she's not really covering it very thoroughly.

==Nonspecific defenses do not discriminate between potential threats and respond the same regardless of the invader==
*Nonspecific defenses prevent the entry, deny the approach, or limit the spread of pathogens.
*There are seven nonspecific defenses.

===Physical barriers===
*To cause problems a pathogen must get in but our epithelium, even in the dark recesses of our body has mechanisms to stop this.
*These include tight junctions, multiple layers, keratin coatings, a dense and fibrous basal lamina.
*We also have secretions from sabaceous glands and hair follicles that kill microorganisms or make it harder for them to penetrate the epithelium.
*The internal epithelium are more delicate but employ mucus and acids to keep out pathogens.

===Phagocytes===
*These are the first line of defense once through the physical barriers.
*These cells "eat" up bad cells and spit out their broken down remnants.
*These include microphages (neutrophils and eosinophils), macrophages, and basophils.
*There are free and resident macrophages in almost all tissues of the body.
*Alveolar macrophages are free floating while in the liver and CNS (kupffer and neuroglia, respectively) the macrophages are fixed.
*These cells can move through the vessel wall to get to their target.
*These cells are attracted by chemotactants and adhere to their target before engulfing them.

===Immunological surveillance===
*NK cells perform immunological surveillance and destroy abnormal cells, including host cells that have become abnormal in some way.
*NK cells are not specific in their epitope, they will recognize many different types of pathogens and abnormal cells.
*NK cells are good because they respond immediately upon meeting an abnormal cell, whereas T and B cells take a bit of time to have an effect.

====NK cell activation====
*First, an NK cell bumps into a cell and recognizes that it has antigens that are not like the host cell antigens so the NK cell adheres to the target cell.
*Then the golgi is rotated to a position between the junction of the two cells and the nucleus.  The golgi is also signaled to begin generating porferins and putting them in vesicles and sending them to the membrane.
*The vesicles are fused with the NK membrane such that the porferins dump in the narrow space between the NK cell and the target cell to which it is stuck.
*The porferins integrate into the target cell's membrane to generate pores large enough to allow ions, proteins, and cellular components through, thus killing the cell.
*We think NK cells might be immune to the actions of porferins because they express protectin.
*NK cells generally find and destroy cancerous cells and virus-infested cells because they present weird surface antigens.
*Cancer antigens are called '''tumor-specific antigens'''.
*However, if the cancer escapes recognition or death by NK cell '''immunological escape''' is said to have occurred and the cell can go on to proliferate, etc.
*In viruses, while the virus is replicating in the cell, antigens from the virus are often presented on the host cell's membrane surface alerting the NK cells of the problem.

===Interferons===
*Interferons are an example of a cytokine: a chemical messenger released by a cell to affect the cells nearby.
**Cytokines can also act like hormones.
*Interferons are proteins released by activated macrophages and lymphocytes and by infected tissues.
*Interferons augment the abilities of macrophages and lymphocytes to phagocytize pathogens and viral-infected cells.
*Interferons also tell cells to generate '''antiviral proteins''' which function ''inside the cell receiving the interferon signal'' to make it a harder target for viral infection.
*There are three types of interferons, each with it's own special function(s).
*Alpha interferon: Secreted by several leukocytes, attracts NK cells.
*Beta interferon: Secreted by fibrocytes, slows inflammation.
*Gamma interferon: Secreted by T cells and NK cells, increases macrophage activity.
*Most cells secrete beta interferon upon infection with a virus.

===Complement===
*Complement refers to the fact that this system complements the antibody system.
*There are 11 plasma proteins involved in the complement system.
*These proteins work together in a series for the end result of a proteinaceous tagging of pathogenic cells.

====Classical complement activation====
*Note that proteins being with "C", in this region of these notes, are complement proteins.
*The classical method begins when C1 binds to an antibody which is already bound to its target antigen, for example on a bacterial surface.
*Then C1's enzymatic properties are turned on and through a cascade of enzymatic activity, C3 is cleaved into the active form of C3b.
*This method is much faster than the alternative method.

====Alternative complement activation====
*The alternative pathway is also called the ''properdin pathway''.
*This pathway can be activated without the presence of antibody.
*This pathway is much slower than the clinical pathway.
*The alternative, or properdin, pathway begins when several complement proteins are catalyzed to interact by the presence of an antigen, for example the capsule proteins of a virus.
*The complement proteins that interact are factor P (for properdin), factor B and factor D.
*This interaction starts a cascade which, like the classical pathway, converts C3 to C3b.

====Effects of complement activation====
*Stimulation of inflammation through increased release of histamine by mast cells.
*Attraction of phagocytes.
*Increased phagocytosis by way of better pathogen marking via complement proteins.
*Destruction of target cell membrane via complement proteins C5-C9 which build pores through which the cell's life will flow.

===Inflammation===
*Inflammation results in "rubor et tubor cum calor et dalor" (redness and swelling with heat and pain), the cardinal signs of inflammation.
*Damaged cells, from physical injury or pathogenic injury, release prostaglandins, proteins, and potassium ions and the resulting changes in the interstitial environment results in inflammation.
*Inflammation has several effects:
**The injury is temporarily repaired and additional pathogens are prevented from entering the area.
**The spread of pathogens ''away'' from the area is slowed.
**The defense systems are activated to mount a response.

====The response to injury====
*Upon damage, mast cells release histamine, heparin, and prostaglandins which serve to:
**Increase blood flow to increase cell motility for phagocytes,
**Activate pain receptors to make organism aware of infection,
**Raise temperature to increase enzymatic activity, to increase phagocytic activity, and to denature foreign proteins,
**Increase vessel permeability and clotting,
**Activate the complement system through the alternative pathway,
**Increase phagocytic activity (by inducing respiratory burst),
*Once neutrophils and macrophages are on the scene they secrete cytokines that recruit even more of the same as well as eosinophils and the adaptive immune response cells.
*Cytokines also stimulate fibrocytes to start generating scar tissue.
*All this and the breakdown of surrounding tissue from released lysosomes generates '''pus'''.
*Accumulation of pus in an enclosed tissue is called an '''abscess'''.

===Fever===
*The inherent temperature of the body can be elevated by signaling to the hypothalamus through a type of cytokine called a pyrogen, which circulate through the blood.
*Pathogens, bacterial toxins, and antigen-antibody complexes can either act as pyrogens or stimulate macrophages to release pyrogens.
*A fever is considered to be the maintenance of the body temperature over 99F or 37.2C.
*Fever may inhibit some viruses and bacteria but the major benefit is from increased metabolism of cells in the body leading to increased motility of immune and phagocytic cells and increased enzymatic activity.

==Specific defenses (immunity) respond to individual threats and are either cell-mediated or antibody-mediated===
*The specific defenses are achieved by B cells and T cells.
*T cells provide cell-mediated immunity (cellular immunity) and respond to abnormal cells and intracellular pathogens.
*B cells provide antibody-mediated immunity (humoral immunity) and respond to antigens and pathogens.
*T cells don't respond to free floating antigenic material and B cells cannot respond to antigens within cells (that is, antibodies, which are generated by B cells can only identify antigens that are on the outside of cells).

===Forms of immunity===
*Innate immunity refers to the immunity granted through genetics; innate immunity is a certain set of pathogens and signals to which the body can respond, it does not change over the course of the individual's lifetime.
*Acquired immunity is not present at birth and must be acquired through exposure over time.
**Acquired immunity can be ''active'' or ''passive''.
*Active immunity is when the body produces its own antibodies against an antigen.
**Active immunity can be ''induced'' by purposefully administering an antigen to a patient or it can be ''naturally acquired'' by chance exposure from the environment.
**'''Naturally acquired active immunity''' begins at birth as a child is exposed to pathogens and the body reacts by generating antibodies and an immune response.
**'''Induced active immunity''' occurs when a vaccine is administered.
***A '''vaccine''' is a preparation of dead / inactive pathogen or just an antigen that is administered with the intention of inducing a controlled immune response.
*Passive immunity is when antibodies enter the immune system from an exongenous source.
**In '''naturally acquired passive immunity''' a mother's antibodies protect her offspring, either through the placenta or breast milk.
**In '''induced passive immunity''', antibodies are administered in order to protect a patient form an antigen.

===Properties of immunity===
*Immunity presents four characterisitcs: specificity, versatility, memory, and tolerance.

====Specificity====
*B and T cells provide specificity by their interaction with only a particular molecular structure.
*B cell antibodies do not bind to just any antigen, they bind to their specific antigen.
*T cells are not activated by just any antigen, they are only activated by their specific antigen.
*Furthermore, the response that B and T cells generate is equally specific: killing on the cells with that exact antigen, etc.

====Versatility====
*The body is able to respond to millions of different antigens, of which we're only likely to run into 10s of thousands, hence we have great immune versatility.
*This versatility is provided by the number of lymphocytes in the body and the variability in the structure of antibodies.
*We have a trillion or more lymphocytes and millions of distinct colonies of about 1000 cells.
*1000 cells is not enough to fight of an infection but when any of those cells is activated, it undergoes rapid proliferation to generate more secret ninja warriors.

====Memory====
*When a T cell population recognizes its antigen and undergoes proliferation, it generates two types of progeny: those that will go fight the infection and those that will remain dormant until ''the next time'' the antigen is encountered.
*In this way we generate "memory" about which antigens have been seen and can mount a bigger, faster response upon a second exposure.

====Tolerance====
*Tolerance is when the immune system does not react to an antigen.  Most obviously, this occurs with host cells--the immune system doesn't attack host cells.
*B and T cells mature in the bone marrow and thymus (respectively) and here are killed if they react to host cell antigens.
*This can also occur if one is exposed to an antigen chronically.  However, the tolerance will only last as long as the exposure continues.

===An introduction to the immune response===
*After a macrophage or other antigen presenting cell ingests and presents an antigen, T cells are activated, then B cells are activated, then T cells start attacking antigen-laden cells and B cells start generating antibodies which bind to antigen throughout the body.

==T cells play a role in the initiation, maintenance, and control of the immune response==
*T cells have varied responses depending on the three types:
**Cytotoxic T cells are responsible for the cell-mediated response; they enter tissues and attack antigens.
**Helper T cells activate T and B cells; reduction in the helper T cell population is largely responsible for the loss of immunity in AIDS.
**Suppressor T cells inhibit T and B cell response in order to moderate the immune response.
*Activation of T cells rarely happens by direct lymphocyte-antigen interaction.
*Furthermore, most antigens don't even cause an immune response, only an innate immune battle.

===Antigen presentation===
*'''Antigen presentation''' to a lymphocyte only works if the antigen is presented on a cell surface in combination with a special glycoprotein called '''major histocapatibility complex proteins'''.
*These proteins are coded on ch 6 in a region called the '''major histocompatibility complex'''.
*These proteins have a distinct three-dimensional shape with a narrow groove in which an antigen can fit enough to be held by hydrogen bonds.
*There are two classes of MHC proteins: I and II.

====Class I====
*Class one proteins are constantly expressed by all nucleated cells in the body.
*As the protein is made it picks up small parts of proteins found in the cytoplasm of its generating cell.
*The protein is moved to the surface and displays it's little chunk of the proteome to any passing T cells.
*If the protein chunk it is presenting is a host protein (that is, something that T cells recognize as being host-like) then the T cell will not be activated.
*However, if a virus or bacteria has entered that cell, the chunk of protein presented by a class I MHC protein may be foreign and would therefore activate cytotoxic T cells which would kill the cell.
**Note that class I MHC proteins serve to activate cytotoxic T cell and suppressor T cells.
*In this way, MHC class I proteins scream "Hey, I'm an abnormal cell.  Kill me!"
*MHC class I proteins are the reason that transplanted organs get rejected.

====Class II====
*'''Antigen presenting cells''' are certain cells responsible for activating T cell defenses against foreign cells and foreign proteins.
**These include macrophages (free and fixed) and dendritic cells.
*Note that the Langerhans cells are the same thing as dendritic cells.
*These APCs take in pathogens and antigens (macrophages through phagocytosis, dendritic cells through pinocytosis) and break up the material.
*Class II proteins are expressed on the surface of APCs '''only while they are processing antigenic material'''.
*When these MHC proteins are on the surface with an antigen, they will activate a T cell to respond.
**Note that class II MHC proteins serve to activate a Helper T cells.

===Antigen recognition===
*T cells have receptors that recognize Class I and Class II MHC proteins.
*The receptors also have binding sites for the antigen held by the MHC protein.
*If the antigen held by the MHC protein is not the antigen which that particular T cells is programmed to bind, the T cell will not be activated.
*A given T cell can either bind a class I or class II MHC protein.
*Proteins on the T cell's surface called '''cluster of differentiation''' (CD) markers determine which class the T cell receptors can bind.
**All T cells have a CD3 '''receptor complex''' on their surface.
**'''Cytotoxic T cells and Suppressor T cells''', which respond to antigens presented by '''Class I''' MHC proteins, have '''CD8''' markers on their cell membrane.
**'''Helper T cells''', which respond to antigens presented by '''Class II''' MHC proteins, have '''CD4''' markers on their cell membrane.

====Costimulation====
*CD8 or CD4 (depending on the T cell type) complexes with CD3.  This complex will ultimately activate the T cell.
*However, before a T cell is activated it must be exposed to the antigen, and then make a second binding interaction with the antigen presenting cell '''at a different site'''.
*The '''different site''' is a protein that is only expressed if the APC has engulfed antigen or is infected by a virus.
*This requirement is called costimulation and is important because it confirms that the antigen is being presented as a result of phagocytic or infectious action.
*Many costimulation proteins are structurally similar to cytokines and can stimulate transcription, proliferation, and differentiation of the T cell.

===Activation of CD8 T cells===
*Recall that CD8 marked T cells respond to class I MHC proteins.
*Two different classes of CD8 T cells exist.
**One rapidly generates lots of cytotoxic T cells and lots of memory Tc cells upon activation.
**The other, rather slowly, generates a modest amount of suppressor T cells upon activation.

====Cytotoxic T cells====
*Cytotoxic T cells = Tc cells = killer T cells.
*These cells move around in injured tissue, look for their specific antigen bound to a class I MHC protein, and kill abnormal or infected cells.
*Killer T cells can kill cells in three ways:
**by releasing perforin which makes pores in the target cell thus deregulating all sorts of vital concentrations,
**by releasing lymphotoxin (a cytokine) which "kill the virally infected cells by producing holes in the cell's cell membrane." (wikipedia).
***lymphotoxin = TNF-beta.
**by activating genes in the target cell that will engage apoptosis.

====Memory Tc Cells====
*Memory Tc cells are produced during the same cell divisions that generate cytotoxic T cells but they don't fully differentiate.
*Upon second exposure to the antigen, these cells are able to ''immediately'' differentiate into cytotoxic T cells to produce a rapid karate chop to that antigen presenting cell.

====Suppressor T cells====
*Suppressor T cells secrete cytokines that inhibit the activity of cytotoxic T cells and B cells which serves to keep the immune response in control.
*The effects of suppressor T cells are not immediately incurred because their activation takes much longer than that of other T cells.  Furthermore, most CD8 cells, upon activation, differentiate into killer T cells and memory Tc cells, and therefore the suppressor T cell effects build up more slowly.

===Activation of CD4 T cells====
*CD4 T cells, upon activation, undergo a series of divisions that produce helper T cells and memory Th cells.
*The memory Th cells remain in reserve.
*These helper T cells secrete cytokines in order to coordinate the specific and non-specific defenses and to stimulate cell-mediated and antibody-mediated immunities.
*Helper T cell-secreted cytokines have the following effects:
**stimulate the production of Th memory cells,
**stimulate maturation of cytotoxic T cells,
**enhance nonspecific defenses by attracting macrophages, preventing macrophages from leaving, and making them more effective,
**attracting and stimulating NK cells to the site of infection,
**promoting the activation of B cells, their division, their maturation to plasma cells, and thus antibody production.
*Remember that infected or abnormal cells present with Class I MHC proteins which are bound by CD8 T cells which become suppressor T cells and killer / memory Tc cells.
*Remember that extracellular pathogens and foreign proteins present with Class II MHC proteins (because they were eaten) which are bound by CD4 T cells which become helper T cells and memory Th cells.

===Clinical note: Graft rejection and immunosuppression===
*After transplantation, cytotoxic T cells are generated after CD8 T cells are activated by exposure to cells from the transplanted tissue presenting antigens.
*These killer T cells then destroy the implanted tissue.
*We used to use drugs that suppressed the entire immune system, like predinsone which decreases levels of circulating leukocytes.
*Now, however, we use more specific drugs like cyclosporin A which inhibits Helper T cells (thus inhibiting B cell activation and killer T cell maturation) while leaving the suppressor T cells intact (thus allowing them to damper the immune response of killer T cells).
*We even have drugs that inhibit the binding of antigen by antibodies.

==B cells respond to antigens by producing specific antibodies==
*B cells launch an attack on antigens by producing specific antibodies.

===B cell sensitization and activation===
*When a B cells binds its antigen in its membrane receptor, it prepares to go through '''sensitization'''.
*Sensitization generally occurs in one of the peripheral lymphatic tissues.
*During '''sensitization''', a B cell endocytizies it's antigen-bound receptors and then presents the antigen on it's membrane via MHC proteins.
*A Helper T cells that has been activated (that is, has interacted with an antigen presenting cell) can activate a B cell that is presenting antigen via MHC proteins.
*Helper T cell activation of a B cell occurs first via binding of the T cell to the MHC of B cell and then continues through stimulation via cytokines.
*The helper T cell stimulation leads to the generation of memory B cells, activated B cells, and plasma cells.
*When stimulated by T cell cytokins a plasma cell can generate up to 100 million antibody molecules each hour!
*On subsequent exposure, memory B cells can quickly divide and differentiate into plasma cells, thus generating antibodies much more rapidly upon second infection.
*So a helper T cell has to bind its antigen with a MHC II protein first, then the T helper cell is active and it can bind to a B cell that is presenting the same antigen and thus activate the B cell

===Antibody structure===
*There are one pair of heavy chains and one pair of light chains in antibodies, each with constant and variable segments.
*The heavy chain forms the bottom of the antibody.
*There are only 5 types of constant regions and they determine the class of the antibody, how it is secreted, and how it is distributed in the body.
*The heavy chains contain binding sites that can be used to activate the complement system.
**These are only revealed once the antigen has bound in the antigen binding site.
*Slight changes in the aa sequence generate the variable sites.
*A normal adult human has about 10 trillin B cells which generate about 100 million different antibodies.

====The antigen-antibody comples====
*The complex is held together by hydrogen bonding and other weak chemical forces.
*The epitope is also called the '''antigenic determinant site'''.
*A '''complete antigen''' is one that has an epitope that fits in each of the two antigen binding sites of the antibody.
*Most environmental antigens are complete antigens because they have multiple epitopes; most microorganisms have thousands of epitopes.
*Partial antigens are also called '''Haptens'''.
*A hapten does not normally cause an immune response.  However, sometimes haptens will bind with other molecules (called carriers) and then each of them will sit down in one of the two antigen binding sites of a B cell.  This can cause an immune reaction, which is bad when the carrier is actually a normal host molecule because it can lead to a reaction against host cells.  This is how penicillin allergic reactions to occur.

====Classes and actions of antibodies====
*Because the class of antibody is determined by the constant chain, it does not affect the antibodies antigen binding specificity.
*IgG:
**Largest class (80% of all Abs).
**Has several subtypes.
**Provide resistance against viruses, bacteria, and bacterial toxins.
**Can cross placenta (think Anti-RhD).
*IgE:
**Sits on basophils and mast cells.
**Stimulates basophils and mast cells to release histamine and other chemicals that accelerate inflammation.
**Important in allergic response.
*IgD:
**Sits on B cells, binds antigen from extracellular fluid.
**Can be part of B cell activation.
*IgM:
**First antibodies generated, then decrease in production once IgGs are being generated.
**Form 5-membered rings and are therefore particularly affective.
**Anti-A and Anti-B (think blood type) antibodies are of type M.
*IgA:
**Travel through blood until absorbed by epithelial cells.
**Epithelial cells put two IgAs together with a '''secretory piece''' to confer water solubility..
**IgA are excreted in glandular secretions like mucus, tears, saliva, and semen.
**Because they are secreted, IgA antibodies can attack pathogens before they gain entrance to the body.
*There are seven ways that antibodies can neutralize antigens:
**Antibodies can bind to the specific locations on a virus or toxin that needs to be free for their function.  Thus the antibodies binds there and '''neutralizes''' the virus or toxin.
**Antibodies can bind several different antigens and form '''immune complexes''' and cause '''precipitation''' or agglutination.
**Upon binding an antigen, an antibody may change conformations and thus recruit complement proteins.
**Antigens covered with antibodies attract eosinophils, neutrophils, and macrophages that destroy the antigen.
**Opsonization is the covering of a pathogen with antibodies and complement proteins which allow for easier phagocytosis.
**Antibodies can cause inflammation by stimulating basophils and mast cells.
**Antibodies coat many epithelials surfaces, making it more difficult for pathogens to bind and penetrate.

===Primary and secondary responses to antigen exposure===
*Both humoral and cell-mediated responses show differences in primary and secondary responses.
*The best way to understand the difference is by looking at antibody production over time.

====The primary response====
*In the primary response, the '''antibody titer''' (the highest level of antibody production) occurs at 2 weeks.
*Decline in antibody production occurs because B cells die quickly and T reg cells inhibit their action.
*IgM is produced first then IgG.
*IgG is more effective than IgM, but IgM provides a faster response.

====The secondary response====
*Memory B cells generate more and more effective antibodies at a lower threshold than primary B cells, thus the response is stronger and faster.
*Memory B cells can live for 20 years or more.
*Antibody titer levels are much higher in a secondary response.

===Summary of the immune response===

===Immune disorders===

====Allergies====
*Allergies are an inappropriate or excessive response to an antigen.
*Antigens that generate this inappropriate response are called allergens.
*The side effects of a huge immune response can be irritating: tissue damage and great inflammation.
*Type I, Immediate hypersensitivity:
**In these reactions, the body is sensitized and basophils are covered with antibodies such that secondary exposure results in basophils rapidly releasing histamine, heparin, several cytokines, prostaglandins, and other chemicals into the surrounding tissues thus destroying tissue and causing a huge inflammatory response.  The attraction of other cells only amplifies the situation.
**If this kind of response occurs in the blood or airway it can be fatal.
*Anaphylaxis:
**In response to a blood-bourne antigen, mast cells may be systemically activated.
**This will cause increased capillary permeability and thus swelling, edema, and hives.  Furthermore, smooth muscle of the respiratory tract will constrict potentially causing difficulty in breathing.  Peripheral vessel dilation may also cause a drastic drop in blood pressure.
*Fast response with anti-histamines can reduce the effects of activated mast cells.