Chapter 20 - Lymphatic System and Immunity

Immune and Lymphatic Systems

*Immunity*: set of diverse processes that protect body from both cellular injury and disease-causing cells and molecules known as *pathogens* -*Immune system* works to defend body against internal and external threats (Contains *no* organs or tissues but instead consists of *cells and proteins* located in blood and tissues of *other* systems) (Includes *leukocytes* and immune protiens) -*Lymphatic system* - group of organs and tissues that not only works with immune system but also participates in a number of functions such as fluid homeostasis: (*Lymphatic vessels*) *Lymphatic tissue and organs* - includes clusters of *lymphoid follicles* such as *tonsils, lymph nodes, spleen, and thymus*

The Inflammatory Response

*Inflammatory response*: Innate response that occurs when a cell is *damaged* by anything: -Damaged cells release *inflammatory mediators* that cause local changes in damaged tissue -*Phagocytes* arrive at area and clean up damaged tissue *Cardinal signs* of inflammation include four signs (redness, heat, swelling, and pain) -*Vasodilation*- due to mediators histamine and bradykinin (Allows blood to flow through vessels more freely to injured tissues, and area becomes *congested* with blood) (Accounts for *redness and heat* accompanying inflammation as blood is *warmer* than surface body temperature) -*Increased capillary permeability*- inflammatory mediators *increase* "leakiness" of local capillary beds (Allows fluid to *leak* from blood vessels into tissue spaces; leads to cardinal sign of *swelling*) -*Occurrence of pain*- bradykinin and prostaglandins trigger action potentials in peripheral processes of sensory neurons, which leads to pain; lets us know when our tissues are being *damaged* to avoid further damage -*Recruitment of other cells*- inflammatory mediators *recruit* leukocytes to damaged tissue (*chemotaxis*), particularly macrophages and neutrophils while complement proteins are simultaneously being *activated* *Part 2: Phagocyte response*- arrival and activation of phagocytes is divided into stages that are based on *which* phagocytes enter area and processes occurring there -*Local macrophages* ("first responders") are activated within minutes of cellular injury; begin to phagocytize pathogens and damaged cells; *only* phagocytes present within first hour or so of inflammatory response; perform critical function of *containing* invading pathogens -Neutrophils *migrate (chemotaxis)* to damaged *tissue* and phagocytize bacteria and cellular debris -Inflammatory mediators and activated complement proteins attract neutrophils and enable them to leave blood and enter tissue; make capillary endothelium in damaged area "sticky", and neutrophils *adhere* to capillary wall (process called *margination*) -*Monocytes* migrate to tissue and become *macrophages*; phagocytize pathogens and cellular debris -Bone marrow increases production of leukocytes, leading to *leukocytes*; cytokines produced by activated phagocytes act on cells in bone marrow to increase production of neutrophils and monocytes over next 3-4 days -Leads to an *elevated* number of circulating leukocytes, a condition called *leukocytosis* Elevated numbers of leukocytes allow damaged area to be cleared and any pathogens removed so that cells such as fibroblasts can begin process of *healing* *Accumulation* of dead leukocytes, dead tissue cells, and fluid leads to a whitish mixture known as *pus* *Fever* is defined simply as a body temperature above normal range (97-99° F) Fever is a *critical* warning sign of inflammatory processes occurring somewhere in body Fever is an *innate* response to cellular injury; initiated when chemicals called *pyrogens* are released from damaged cells or certain bacteria Pyrogens act on hypothalamus

Innate Immunity

*Internal Defenses* Rapid response of innate immunity consists of two main components: a group of *antimicrobial molecules*, and several types of *cells* -*Cells of innate immunity*- Pathogens that are able to bypass body's surface barriers next meet second line of defense: cells of innate immunity are divided into two broad types: *phagocytic* cells and *nonphagocytic* cells *Cells* *Phagocytes*- include *macrophages, neutrophils, and eosinophils* -*Monocytes* exit bloodstream and take up residence in various tissues where they develop into *macrophages* -*Activated* by a variety of stimuli - molecules present on pathogens, chemicals secreted by damaged cells, and signals from cells of adaptive immunity -Activated local macrophages are generally *first* cells respond to a *cellular* injury -Macrophages also have *cytotoxic* effects, meaning that they can secrete these substances onto pathogens that are too large to ingest -Macrophages function as *antigen-pressing cells (APC)* (cells that display portions of pathogens (antigens) they ingest on their plasma membrane) -T cells become activated by these antigens and in turn secrete substances that *increase activity* of macrophages *Neutrophils*- kill their ingested pathogens with chemicals such as hydrogen peroxide, hypochlorous acid, and lysozyme -Can ingest many types of cells, but are particulary effective at destroying *bacterial* pathogens -Release cytotoxic contents of their granules onto large pathogens to damage their plasma membranes -Generally reside in blood and must be *recruited* to damaged tissues by chemical signals *Eosinophils*- phagocytes that can migrate from blood to tissues where they are needed -Primarily involved in responses to *parasitic* pathogens -Cover parasites and release contents of their granules -Chemicals from granules damage parasite and either destroy it or make it easier for other immune cells to destroy *Nonphagocytic* cells include NK cells, dendritic cells, and basophils: -*NK cells* have ability to recognize cancerous cells and cells infected with certain viruses in spite of fact they *cannot* recognize specific antigens (Also *cytotoxic*, releasing substances that destroy their target cells) (Secrete an antimicrobial cytokine that *activates* macrophages and enhances phagocytosis) -*Dendritic cells*- function as antigen-presenting cells -*Basophils*- their granules contain chemicals that mediate *inflammation(inflammatory mediators)* (Located primarily in blood (although a related type of cell (mast cells) are located in mucous membranes)) (Like regular basophils, mast cells contain granules with chemicals that trigger inflammation; particularly involved in *allergic* responses)

Antimicrobial Proteins

Innate immune response is mediated by a variety of plasma antimicrobial proteins, including complement proteins and several types of cytokines: *Complement*- group of molecules collectively known as *complement system* consists of 20 or more plasma proteins: -Complement proteins are designated with a "C" and a number; play a critical role in *both* innate and adaptive immunity -Circulate primarily in their *inactive* forms (must be activated by a complex cascade of events mediated by enzymes) -Two main pathways activate complement proteins: classical and alternative pathways (*Classical pathway*- begins when inactive complement proteins bind to antibodies bound to antigens) (*Alternative pathway*- begins when inactive complement proteins encounter foreign cells such as bacteria) -Two pathways *converge* at cleavage of an inactive complement protein called *C3* into its active form *C3b*, which in turn cleaves inactive protein *C5* into its active component *C5b* Activated complement proteins lead to following main effects: -*Cell lysis*- some complement proteins are able to lyse plasma membranes of pathogens, leading to their destruction; mediated by *C5b* -C5b binds to surface of a pathogen and provides a docking site for several other activated complement proteins; together these complement proteins from a subculture collectively known as *membrane attack complex, or MAC* -MAC inserts itself into plasma membrane of target cell, creating a *pore* that causes it to lyse -*Enhanced inflammation*- several complement proteins *enhance* this response by triggering basophils and mast cells to release chemicals that mediate inflammation -*Neutral Viruses*- C3b and components of membrane attack complex bind to certain viruses and *neutralize* them, or block them from *infecting* host cells -*Enhancing phagocytosis*- C3b acts as an *opsonin* by binding to pathogens; opsonization makes phagocytes bind more *strongly* to a pathogen and enhances phagocytosis -*Clearance of immune complexes*: C3b binds to *immune complexes* (clusters of antigens bound to antibodies) and triggers their phagocytosis; clears complexes from circulation, which is critical to preventing these complexes from *lodging* in different tissues about body *Cytokines*- proteins produced by several types of immune cells that enhance immune response -*Tumor necrosis factor*- cytokine secreted by activated macrophages in response to certain bacteria and other pathogens; attracts phagocytes to area of infection, *increases phagocytes activity*, and stimulates phagocytes to release additional cytokines -*Interferons*- cytokines produced by macrophages, dendritic cells, NK cells, and cells of adaptive immunity; produced in response to infection with intracellular agents such as viruses or intracellular bacteria; primary action is to *inhibit viral replication (INF)* inside host cells -*Interleukins*- produced by various leukocytes; stimulate production of neutrophils by bone marrow, stimulate NK cells, trigger production of interferons, and activate T cells -Many cytokines induce "flu-like" symptoms; including *fever, chills, and aches* (aches are due to stimulation of inflammation)

Lymphatic System

Lymphatic system basic functions: -*Regulation of interstitial fluid volume*- net filtration pressure in blood capillaries favors *filtration*, meaning that water is lost from plasma to interstitial fluid -*Absorption of dietary fats* - breakdown products of fats in diet are too *large* to pass between endothelial cells of blood capillaries -*Immune functions* - lymphatic system plays an important role in immune system; lymphoid organs *filter* pathogens from lymph and blood; also *house* several types of leukocytes, and play a role in their *maturation* Lymph is collected in vessels called *lymph-collecting vessels* which merge to form larger vessels, *lymph trunks* -Nine lymph trunks drain lymph from *specific* body regions -Intestinal trunk and lumbar trunks all drain into *cisterna chyli* -Cisterna chyli and trunks on left drain into the *thoracic duct*; drains into *junction* of left internal jugular and left subclavian veins -Remaining trunks drain into *right lymphatic duct*, which drains into junction of right internal jugular and right subclavian veins -Lymphatic vessels make up a *low-pressure* circuit because there is no main pump to drive through vessels, and most of them are transporting lymph *against* gravity: (Valves prevent lymph from flowing *backward*) (Like deeper veins, often found lodged between muscles, where contracting muscles *massage* lymph up *toward heart*) (Lymph flow through vessels is driven in part by *contractions of smooth muscle* found in walls of lymph-collecting vessels) -Lymphatic vessels begin in tissues with tiny *lymphatic capillaries*; form a weblike network that *surrounds* blood capillary beds (Specialized lymphatic capillaries known as *lacteals* collect fat in the small intestine) (Lymphatic capillaries are *blind-ended*, which makes lymphatic vasculature a one-way system that only moves lymph *away* from tissues (not continues)) (Fluid that leaks from blood capillaries *increases* interstitial fluid pressure; forces lymphatic endothelial cells *apart* and allows large volumes of fluid to *enter* lymphatic capillaries) -Along pathway of lymphatic vessels are clusters of lymphoid organs called *lymph nodes (filter/checkpoints)* (Pathogens such as bacteria and cancer cells in interstitial fluid have an easier time entering lymphatic capillaries than blood capillaries) (Lymph nodes *limit spread* of pathogens through body by acting as filters, *trapping* pathogens and preventing them from traveling elsewhere) *Lymphedema* is generally due to*removal* of lymphatic vessels during surgery or *blockage* of vessels from pathogens such as parasites -Both conditions *prevent* lymphatic vessels from transporting excess interstitial fluid back to cardiovascular system; fluid therefore *accumulates* in tissues of affected body part, causing it to enlarge Predominant tissue type of lymphatic system is *reticular tissue* Lymphoid organs house: -*Macrophages* - mature monocytes that are very active phagocytes -*B and T lymphocytes* - have diverse immune functions -*Dendritic cells* - immune cells derived from bone marrow and from connective tissue -*Reticular cells* - particularly abundant in organs such as spleen and lymph nodes; produce reticular fibers *Mucosa-associated lymphatic tissue (MALT)* -clusters of lymphoid tissue that protects mucous membranes: -Much of MALT in body consists of loosely organized clusters of B and T cells that *lack* a connective tissue capsule -Oral and nasal cavities; scattered throughout GI tract, respiratory passages, and genitourinary tract Specialized MALT is found in three locations in gastrointestinal tract: -*Tonsils* - located around oral and nasal cavities (*tonsillar crypts* that trap bacteria and debris) -*Peyer's patches*- located in *ileum* (allows them to defend against any bacteria that have escaped from large intestine) -*Appendix* - protrudes from large intestine (decoration) (defends body from bacteria in large intestine) *Lymph nodes* - bean-shaped clusters of lymphatic tissue located along lymphatic vessels throughout body: -Specific *clusters* of lymph nodes include: *axillary* lymph nodes in axillae, *cervical* lymph nodes in neck, *inguinal* lymph nodes in groin, and *mesenteric* lymph nodes in abdominal cavity -Lymph nodes have an external connective tissue *capsule* that surrounds a network of reticular fibers filled with macrophages, lymphocytes, and dendritic cells -Interior of a node is divided into two main regions: outer *cortex and inner medulla* -Cortex consists of *lymphoid follicles* divided by inward extensions of capsule, called *trabeculae* -Between cortex and medulla is a zone composed primarily of T cells -Lymph flows into node through multiple small lymphatic vessels then through reticular network, where pathogens in lymph become trapped in reticular "net" -Trapped pathogens then encounter leukocytes and dendritic cells, which *eliminate* these threats -Lymph that has been "cleaned" of pathogens drains out through efferent lymphatic vessels on other side of node at hilum -Lymph nodes trap approximately 90% of pathogens in lymph; prevents these pathogens from being delivered to blood, where they could easily *spread* to other tissues and organs *Spleen* - *largest* lymphoid organ in body: -Internal structure consists of a network of reticular fibers -Two distinct histological regions are found in reticular network: (*Red pulp* contains macrophages that destroy old erythrocytes) (*White pulp* filters pathogens from blood and contains leukocytes and dendritic cells) *Thymus* - small, encapsulated organ in superior mediastinum; doesn't trap pathogens: -Secretes hormones that enable it to carry out its primary function: generating a population of *functional* T cells capable of protecting body form pathogens -Reaches max size at ~14; then begins to *atrophy* and thymic tissue is replaced with fat -Adult thymus consists of subunits called *thymic lobules* -Each lobule contains two regions: an *outer cortex and an inner medulla* (Cortex contains densely packed T (THYmus) cells) (Medulla contains fewer of these cells, and is thought instead to be mostly site of *destruction* of certain populations of T cells that could react to body's own cells) -There are no lymphoid follicles in thymus because it *lacks* B cells

Adaptive immunity - Antibody-Mediated Immunity

Antibody-mediated immunity involves *B cells* and *antibodies* -B cells have *B cell receptors* that bind to specific antigens -A group of B cells that bind to a specific antigen is known as a *clone* -Antibodies *secreted* by a B cell clone bind to *same* antigen as B cell *receptor* Antibody-mediated immune responses have three basic phases: -*First phase*- B cell clone recognizing its specific antigen; secretes antibodies -*Second phase*- antibody level in blood rises dramatically; antibodies (*immunoglobulins*) are directly responsible for actions that lead to *destruction* of antigens to which they bind -*Third phase*- the persistence of a population of B cells called *memory B cells*; react much more rapidly and efficiently if antigen is encountered *again* First phase of antibody immune response: B cells develop and mature within bone marrow from lymphoid cell line -B cell clones that recognize self antigens (self-reactive B cells) are *destroyed* -B cell clones that complete maturation enter circulation and eventually take up residence in lymphoid organs -When antigens enter body, they are *captured* in these lymphoid organs -B cells that are *not* exposed to their specific antigens within a few days to a few weeks *die* B cells that *do* encounter their antigens become *activated* by following process: -*B cell clone binds its antigen and is activated*; clonal selection is process when an antigen binds to a B cell receptor on surface of a specific B cell clone (said to be *sensitized*) -Sensitized B cell processes the antigen and presents it on its *class II MHC molecules*. It then binds to a TH cell, which secretes *cytokines* that activate the B cell (B cell then binds to a TH cell to become fully activated) -B cell *divides repeatedly*; resulting cells differentiate into: (*Plasma cells*- which secrete antibodies) (*Memory B cells*- long-lived cells that do not secrete antibodies but will respond to antigens upon a *second* exposure) *Second phase* of antibody-mediated immune response involves the *antibodies* and their *effects* Structural features and classes of antibodies: -Basic subunit of an antibody is a Y-shaped molecule formed from four peptide chains -Each of these chains has two types of regions: (*Constant (C) region*- relatively similar among antibody classes; responsible for many of antibodies' effects) (*Variable (V) region*- unique sequence of amino acids responsible for antigen recognition and binding) -An antibody has V regions at tips of two arms of molecule, so the basic subunit of an antibody has two *antigen-binding sites*, one on each arm -There are five basic *classes* of antibody; grouped according to *structure* of their C regions -Each antibody is named with two-letter abbreviation "Ig," which stands for "immunoglobulin," followed by a *letter* that designates its class (*IgG*- The most prevalent antibody in body; consists of a single subunit; *only* antibody able to cross through *placenta*) (*IgA*- consists of two Y-shaped subunits; has four antigen-binding sites; present in secretions from the skin, mucous membranes, and exocrine glands (tears, saliva, sweat, and breast milk)) (*IgM*- The largest (m for massive) antibody; consists of five subunits in a starlike arrangement, for a total of 10 antigen-binding sites; generally by plasma cells when body is invaded by a pathogen; also exists as a *single* subunit embedded in B cell plasma membrane, where it functions as a B cell *receptor*) (*IgE*- single-subunit antibody; present in very low amounts in body's fluids -Binds to two types of antigen: antigens associated with parasitic pathogens such as tapeworms, and environmental antigens known as *allergens* -Bind to mast cells in mucous membranes, and when they come into contact with their specific antigens, they trigger mast cells to release the contents of their granules (*degranulation*) -Mast cell granules contain inflammatory mediators such as *histamine*; *initiate* a localized inflammatory response; responsible for common allergy symptoms such as a runny nose and watery eyes) (*IgD*- unique because it is the only antibody not secreted by B cells in significant amounts; its single subunit is located on surface of B cells, where it acts as an antigen *receptor* that helps activate B cells in a similar manner to IgM) -Antibodies in a particular class feature *similar* C regions, but each antibody has a unique V region that determines its ability to recognize and bind a certain antigen *Functions of secreted antibodies*- actions of antibodies are based on their ability to bind antigens -*Agglutination and precipitation* (Antibodies can bind to antigens on *more* than one cell; creates a clump of cells that are *cross-linked* by their attachment to antibodies; known as *agglutination*) (*Precipitation*- similar to agglutination; involves *soluble* antigens (proteins and other biological molecules) instead of *whole* cells) (Both agglutination and precipitation *decrease* solubility of antigen-antibody complexes; easier for phagocytes to ingest) -*Opsonization*- involves molecules such as complement and IgG antibodies; IgG antibodies are also opsonins able to coat pathogens and bind and activate phagocytes, which greatly *enhances* phagocytosis -*Neutralization*- antibodies bind to harmful bacterial toxins, viral proteins, and animal venoms to *prevent* them from *interacting* with our cell; this renders the toxin inactive (neutralization) (most neutralizing antibodies are either the IgG or the IgA class) -*Complement activation*- IgM and IgG bind to and activate complement proteins of innate immunity; particularly to activate and lyse the foreign cell with its foreign complex -*Stimulation of inflammation*- IgE *directly* triggers inflammation by initiating *release* of inflammatory mediators from mast cells and basophils; antibodies also trigger inflammation *indirectly* through their *activation* of complement *Phase 3: Immunological Memory* Memory B cells are responsible for *antibody-mediated immunological memory*, which allows B cells to respond more *efficiently* when antigen is encountered a second time; phase three of immune response; Upon first exposure to an antigen, a B cell clone specific for that antigen recognizes it, proliferates, and differentiates into plasma and memory B cells, and plasma cells begin to secrete antibodies; response is called *primary immune response* -*Effective*, but slow—there is an initial *lag phase* (4-5 days) as the B cells proliferate, differentiate into plasma cells and memory cells, and begin to secrete antibodies -Antibody levels peak about 7-14 days after antigen is encountered; it is during lag phase that you generally feel "sick" -*Future* exposure to same antigen results in activation of memory B cell formed during primary immune response -When these memory B cells encounter antigen for which they are specific, *secondary immune response* begins; there are key differences than primary response -Has a shorter lag phase (about 1-3 days), and its antibody levels peaks more rapidly (3-5 days) and reach a peak 100-1000 times *larger* -Major antibody *IgG* -Antibodies secreted in secondary immune response are more *effective*—they bind more tightly A *vaccination*, also known as an *immunization*, involves exposing an individual to an antigen to elicit a primary immune response and generate memory cells; then if individual is exposed to antigen a *second* time, a secondary immune response will occur and symptoms will be *minimal* -*Live, attenuated vaccines*- attenuated (pathogens ability to cause disease has been greatly reduced), pathogens divide to a limited extent in the body and so induce a *primary immune response*. Not used with patients with compromised Immune systems -*"Killed" Vaccines*- (prepared with inactivated pathogens) not capable of dividing in body, so they generate a *weaker* primary immune response, requires several repeat vaccinations ("boosters") -*Subunit Vaccines*- only portion of the pathogen that causes disease is required to develop immunity. Induce a *weaker* primary response and need "boosters" There are two types of antibody-mediated immunity; active and passive: *Active immunity* -Body's cells actively respond to an antigen -Results in production of memory cells and large numbers of antibodies; relatively long-lasting, ranging from *years* to a *lifetime* *Passive immunity* -*Preformed* antibodies are passed from one organism to another -Lasts only amount of time that antibodies *stay in bloodstream*, which is about three months on average

Adaptive Immunity - Cell-Mediated Immunity

Cell-mediated immunity is the 1st arm of the adaptive immune system: -Cell-mediated immunity involves different classes of T cells, including: *helper T (TH) cells, or CD4 cells*, and cytotoxic *T (TC) cells, or CD8 cells* (Note that "CD" stands for *cluster of differentiation*) -These cells respond primarily to cells infected with *intracellular* pathogens, *cancer* cells, and *foreign* cells such as those from a transplanted organ -T cells undergo *gene rearrangements* that lead to a variety of genetically distinct T cells -Each population of T cells that can respond to a specific antigen is known as a *clone* -Some clones are capable of recognizing and responding to pathogens, whereas others are not (thymus "screens" these cells and mediates *destruction* of those clones that *cannot* recognize antigens) -Thymus ensures that an individual is *immunocompetent (normal response for foreign antigens)* Only certain antigens, called *immunogens*, are capable of generating a *response* from immune system -Antigens present on your own cells, called *self antigens*, are *not* immunogens in your body -*Haptens* are very small antigens that are immunogenic *only* if they are attached to a protein carrier -*T cell receptors* are found on surface of every T cell; this receptor must bind a specific antigen before cell can be activated -Unique portion of antigen to which receptor binds is known as its *antigenic determinant* T cells can only interact with pieces of antigen bound to glycoproteins called *major histocompatibility complex (MHC) molecules*: -Name comes from fact that MHC molecules are major determinants of *compatibility* among tissue and organ donors and recipients -MHC molecules are found on nearly all nucleated cells (not erythrocytes) -MHC molecules serve as "docking sites" for specific components of antigens that are then displayed to T cells There are two types of MHC molecules: -*Class I MHC molecules*- found on surface of plasma membrane on nearly all nucleated cells (Present *endogenous antigens*, or those synthesized) (*Cytotoxic T (TC)* cells generally interact *only* with class I MHC molecules) -*Class II MHC molecules* are found *only* on surfaces of antigen-presenting cells (*Helper T (TH)* cells generally interact with class II MHC molecules) (Class II MHC molecules present *exogenous antigens*, or those cell takes in by phagocytosis) Endogenous antigens can be foreign or self, but exogenous antigens are nearly *always* foreign An endogenous antigen is those that *originate* in cell: -Either a foreign antigen present on a pathagen the *lives inside* your cell, such as an bacterium -Or a foreign or self antigen encoded by your DNA; includes normal self antigens, foreign cancer antigens made by mutated DNA, and foreign viral antigens Basic steps by which a class I MHC molecule processes and displays an *endogenous* antigen: -Cell *synthesizes* either a self antigen or a foreign antigen -The antigen is *broken* by enzymes in cytosol -An antigen fragment containing antigenic determinant is transported into rough endoplasmic reticulum; is coupled with a class I MHC molecule in RER membrane -MHC-antigen complex leaves RER by a vesicle and is inserted into cell's plasma membrane Basic steps of how *exogenous* antigens are displayed by class II MHC molecules: -Cell *ingests* a pathogen by phagocytes -Phagocytic vesicle fuses with a lysosome; pathogen is *degraded* and its antigens are fragmented -Lysosome fuses with a vesicle from RER that contains class II MHC molecules, and an antigen fragment binds to a MHC molecule -MHC-antigen complex is inserted into cell's plasma membrane (These MHC-antigen complexes then interact with and activate T cells) T cell activation consists of following steps: Cells display antigen fragments on their MHC molecules, and the MHC-antigen complex binds to a receptor of a specific TH or TC cell clone Process of T cell activation begins a cell processing and displaying antigen fragments on its MHC molecules; then presents antigen to a particular T cell clone, which is specific for its individual MHC-antigen complex When T cell receptor recognizes and binds this complex, multiple changes are triggered inside T cell and process of activation begins; known as clonal selection T cell activation consists of following steps: *Cells display antigen fragments on their MHC molecules, and the MHC-antigen complex binds to a receptor of a specific TH or TC cell clone* -Process of T cell activation begins a cell processing and displaying antigen fragments on its MHC molecules; then presents antigen to a particular T cell clone, which is *specific* for its *individual* MHC-antigen complex -When T cell receptor recognizes and binds this complex, multiple changes are triggered inside T cell and process of *activation* begins; known as *clonal selection* *TH or TC cell binds a co-stimulator and becomes activated* -Full T cell activation requires the interaction of the T cell with other molecules on antigen-presenting cells called *co-stimulators* *Activated TH or TC cell clone proliferates and differentiates into effector cells and memory T cells* (those that cause *immediate* effects) and *memory T cells* (responsible for cell-mediated *immunological memory*) Memory cells respond more *quickly* and efficiently to subsequent exposures to an antigen; do *not* need a co-stimulator *Effects of T Cells* -TH and TC cells have very different roles, although they do interact and depend on one another to function properly -*Role of TH cells*- helper T cells no phagocytic/cytotoxic abilities; TH cells exert their effects through the secretion of cytokinesis that then activate and enhance various components of immune response -They "help" the immune response TH cells are required for normal function of all components of immune system: -*Innate immunity: stimulation of macrophages* (TH cells secretes the cytokine *interleukin-3*, which stimulates macrophages to become more *efficient* phagocytes) (Causes macrophages to produce *interleukin-12*, which stimulates TH cells to generate *more* interleukin-3) -*Adaptive cell-mediated immunity: activation of TC cells* (TH cells secrete cytokine *interleukin-2 (IL-2)*; required to *activate* TC cells) In absence of TH cells and IL-2, most TC cells fail to activate and become *unresponsive* to antigen -*Adaptive antibody-mediated immunity: stimulation of B cells* (TH cells directly bind to B cells and stimulate them to *proliferate* and *differentiate*) (Also secrete various interleukins that stimulate B cell proliferation and increase antibody production) *Role of TC cells*- primary function of cytotoxic T cells is to kill other cells, specifically those with foreign antigens bound to class I MHC molecules -Can interact with class I MHC molecules means they can detect abnormalities in any cell type with a nucleus; critical for detection of cancer cells, foreign cells, and cells infected with intracellular pathogens -Activated in same way as TH cells, with addition that they require IL-2 from TH cells in order to activate fully -An activated TC cell binds its target cell, after which it releases a protein called *perforin* -Perforin forms pores in the target's cells plasma membrane (TC cell then releases enzymes that can now *enter* target cell's cytosol) -These enzymes catalyze reactions that degrade target cell proteins and eventually lead to fragmentation of target cell's DNA and its *death* -TC cells also bind to proteins on plasma membrane of target cells; induce process of *apoptosis* (cell death) When target cell begins to degrade, TC cell *detaches* and searches for a *new* target cell *Organ and Tissue Transplantation and Rejection* -*Autograph*- tissue transplanted from one to another in the same individual -*Isographs*- organ/tissue transplant between 2 genetically identical individuals (twins; rare) -*Allografts*- organ/tissue transplant between 2 genetically unidentical individuals (most common) (may lead to *immune response*) -*Xenografts*- organ/tissue transplant between two individuals of different species (rare) (may lead to *immune response*)

Immunity

Combined components of immune system offer three lines of defense against pathogens: *First line of defense* - cutaneous and mucous membranes that act as *surface breakers* to block entry of pathogens into body *Second line of defense* - responses of cells and proteins that make up *innate immunity (non-specific)* -*Third line of defense*- includes responses of cells and proteins of *adaptive immunity (specific)* Immunity is classified according to way it responds to different pathogens or forms of cellular injury: *Innate, or nonspecific, immunity responds* to all pathogens in the *same* way -Innate immune system consists of antimicrobial proteins and certain cells that respond quickly; dominant response to pathogens for 1st *12 hours* after exposure -Cells and proteins exist in bloodstream, even in *absence* of a stimulus Components of *adaptive, or specific, immunity* respond *individually* to unique glycoproteins markers called *antigens* Antigens are present on *all* cells and most biological molecules, including our own cells; identify a cell or molecule as belonging to a *specific group* There are two "arms" of adaptive immune system: -First arm is cell-mediated immunity; brought about by two types of *T cells* -Second arm is antibody-mediated immunity (*humoral immunity*); carried out by *B cells* and proteins they produce, called *antibodies* Adaptive immunity responds more *slowly* than innate immunity because one must be exposed to a specific antigen for response to be *initiated* -Also referred to as *acquired immunity* (it takes 3-5 days to mount a response, but after this point, it is (dominant( response) Adaptive immunity has the capacity for immunological *memory* in which exposure to an antigen is "remembered" by specific lymphocytes and antibodies -This allows a more *rapid and efficient* response on *subsequent* exposures -Innate immunity *lacks* capacity for immunological memory and will respond in *same* way with repeat exposure to a pathogen *Surface barriers*- first line of defense against any potential threat to body is *coverings* of body surfaces and certain products they secrete: -Both skin and mucosae provide a *continuous* physical barrier to block entry of potential pathogens in body (Skin is relatively resistant to mechanical stresses because of its several layers of epithelial cells filled with hard protein *keratin*) (Sebaceous glands in skin secrete oil, which has a slightly acidic pH that deters growth of most pathogenic organisms) *Mucous membranes* line all passageways in body that open to *outside* (respiratory, GI, and genitourinary tracts) -These epithelia *lack* keratin; *less* resistant to mechanical abrasion -Also secrete products that discourage pathogen invasion, *mucus* (Mucus *traps* pathogens and other debris and *protects* underlying cells from chemical and mechanical trauma) -Mucous membranes of stomach *secrete acid*, which kills ingested pathogens *Overview of Cells and Proteins of Innate and Adaptive Immune Systems* Cells and proteins of innate and adaptive immune systems produce response of second and third lines of defense: Main cells of immune system are different leukocytes: -*Agranulocytes* and *granulocytes* -Many cells of innate immunity can function as (macrophages, neutrophils main ones) -*Natural killer (NK) cells*, located in blood and spleen, function primarily in innate immunity -*Dendritic cells*- activate T cells of adaptive immunity -*Antibodies*- proteins produced by B lymphocytes that function in adaptive immunity *Complement system*- functions in innate immunity *Cytokines*- diverse group of proteins secreted by cells of both innate and adaptive immunity; have a variety of effects *How the Lymphatic and Immune Systems Work Together* Lymphatic and immune systems are closely connected both structurally and functionally: -*Lymphoid organs and tissues provide a residence for cells of the immune system* -*Lymphoid organs and tissues trap pathogens for immune system* -*Lymphoid organs activate cells of immune system* -Lymphatic system plays a *greater* role in adaptive immunity than in innate immunity

Immune System Disorders

Disorders of immune system take three forms: -*Hypersensitivity disorders* cause immune system to *overreact* -*Immunodeficiency disorders* occur when one or more components of immune system *fail* -Immune system may treat self-antigens as foreign and *attack* own tissues in an *autoimmune disorder* Four types of *hypersensitivity disorders* classified according to exact immune components causing hypersensitivity: *Type I*: immediate hypersensitivity (allergens) -Occur when an individual reacts to a foreign antigen -First exposure to an allergen- allergen binds a B cell which triggers B cell differentiation into plasma cells that secrete *antibodies* -Plasma cells secrete IgE- first exposure generates a primary immune response, which results in formation of IgE molecules that *bind* to mast cells and basophils -Subsequent exposures to identical allergens in a sensitized individual result in a *rapid* response (occurs within a few minutes) -Cells release inflammatory mediators (*degranulation*): histamine, leukotrienes, and prostaglandins -Vasodilation, increased capillary permeability *Type II: Antibody-mediated hypersensitivity*:antibodies produced by immune response to foreign antigens also bind to *self* antigens -These reactions occur when foreign antigens bind to *normal* self antigens, when donor erythrocytes infused into another individual are *mismatched* using the ABO/Rh antigen groups, or when self-reactive B cells are *not destroyed* in bone marrow, which leads to autoimmunity *Type III: Immune complex-mediated hypersensitivity* reactions are mediated by immune complexes of clusters of *soluble antigens* (those not attached to cell surface) bound to antibodies -Immune complexes are generally cleared by phagocytes, but some are difficult for macrophages to ingest and become *deposited* in various places in body, including capillary beds in kidneys, blood vessel walls, synovial membrane of joints, and choroid plexus in brain *Type IV: Delayed-type hypersensitivity (DTH)* is unique in that it is mediated by T cells *rather* than antibodies -TH cells recognize antigens bound to MHC molecules as foreign and mediate their destruction by activating and recruiting *macrophages* and in some cases *TC cells* -Reaction generally takes 2-3 *days* to manifest, hence its name; TH cells must be sensitized by an initial exposure, and reaction occurs with *subsequent* exposures *Immunodeficiency disorders* are caused by a *decrease* in function of one or more components of immune system: *Primary immunodeficiencies*- genetic or developmental in nature *Secondary immunodeficiencies*- acquired through infection, trauma, cancer, or certain medications -AIDS is caused by *human immunodeficiency virus 1 (HIV-1)*; spread through contact with infected blood, semen, vaginal fluid, or breast milk; HIV-1 preferentially binds and interacts with cells displaying *CD4 molecules* -*Acute phase* lasts about three months; characterized by a sharp *decline* in TH cells and a sharp rise in HIV-1 virions; patients may exhibit *flu-like symptoms* during this phase, although condition often goes unnoticed -*Chronic phase* begins with production of antibodies to HIV-1 virions, an initial slight recovery in number of TH cells, and a decline in number of HIV-1 virions; may last eight or more years in *untreated* individuals, during which many patients show few to no signs of HIV-1 infection -It is during *final phase* when an individual is said to have *AIDS*; characterized by progressively declining numbers of TH cells and progressively increasing numbers of HIV-1 virions *Autoimmune disorders* occur when populations of self-reactive T cells or B cells that secrete antibodies bind to self-antigens (called *autoantibodies*) -Release of self antigens not previously encountered by T cells (multiple sclerosis) -Foreign antigens mimic self antigens (rheumatic fever) -Cells may inappropriately express class II MHC molecules (type I diabetes) -Certain pathogens nonspecifically activate B cells (lupus)