The Immune System. Chapter 43. Lecture Outline. Overview: Recognition and Response

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1 Chapter 43 The Immune System Lecture Outline Overview: Recgnitin and Respnse An animal must defend itself against pathgens, agents that cause disease. Viruses, bacteria, fungi, and ther pathgens infect a wide range f animals, including humans. An animal bdy ffers a ready surce f nutrients, a prtected setting fr grwth and reprductin, and a means f transprt t new envirnments. Animals fight back in varius ways. Immune cells in the bdy fluids and tissues f mst animals interact with and destry pathgens. Respnses t infectin include prteins that punch hles in bacterial membranes r blck viruses frm entering bdy cells. Immune systems help animals t avid r limit many infectins. Innate immunity is cmmn t all animals. Such defenses are active immediately upn infectin and are the same whether r nt the pathgen has been encuntered befre. External barriers, frmed by the skin r shell, prvide a barrier t pathgens. Chemical secretins that trap r kill pathgens guard the bdy s entrances and exits. The internal defenses include macrphages and ther phagcytic cells that ingest and destry pathgens. An animal s immune system must detect freign particles and tissues that invade the bdy, distinguishing self frm nnself. This mlecular recgnitin f nnself is accmplished by receptrs that bind specifically t mlecules frm freign cells r viruses. In innate immunity, a small preset grup f receptr prteins bind t mlecules r structures that are absent frm animal bdies but cmmn t a grup f viruses, bacteria, r ther pathgens. Binding f an innate immune receptr t a freign mlecule activates internal defenses, enabling respnses t a very brad range f pathgens. Adaptive immunity is fund nly in vertebrates. Adaptive immune respnses are activated after innate immune defenses and develp mre slwly. These adaptive defenses are enhanced by previus expsure t the infecting pathgen. Animals with adaptive immunity have a large number f receptrs, each recgnizing a feature typically fund nly n a particular mlecule in a particular micrbe. As a result, adaptive immune systems detect pathgens with tremendus specificity. Lecture Outline fr Campbell/Reece Bilgy, 9 th Editin, Pearsn Educatin, Inc. 43-1

2 Cncept 43.1 In innate immunity, recgnitin and respnse rely n traits cmmn t grups f pathgens. Invertebrates have highly effective innate defenses. Insect exskeletns are a first line f defense against infectin. Cmpsed largely f the plysaccharide chitin, the exskeletn prvides an effective barrier defense against mst pathgens. A chitin-based barrier is als present in the insect intestine, where it blcks infectin by many pathgens ingested with fd. Lyszyme, an enzyme that digests bacterial cell walls, als prtects the digestive system. In insects, circulating cells called hemcytes travel thrugh the hemlymph, the insect circulatry fluid. Sme hemcytes can phagcytse pathgens. Other hemcytes trigger the prductin f chemicals that kill pathgens and entrap parasites. Hemcytes and ther cells secrete antimicrbial peptides that bind t and destry bacteria and fungi by disrupting their plasma membranes. Immune cells f insects bind t mlecules fund nly in the uter layers f bacteria r fungi. Fungal cell walls have unique plysaccharides, while bacterial cell walls cntain cmbinatins f sugars and amin acids nt fund in animal cells. Insect immune cells secrete specialized recgnitin prteins, each f which binds t the macrmlecule specific t a fungi r brad class f bacteria. Immune respnses are distinct fr different classes f pathgens. Fr example, when the fungus Neurspra crassa infects a fruit fly, pieces f the fungal cell wall bind a recgnitin prtein. Tgether, the cmplex activates the prtein Tll, a receptr n the surface f hemcytes. Signal transductin frm the Tll receptr t the cell nucleus leads t synthesis f a particular set f antimicrbial peptides active against fungi. When the bacterium Micrcccus luteus infects a fly, a distinct recgnitin prtein is activated, and the fly prduces a different set f antimicrbial peptides. Because fruit flies secrete many distinct antimicrbial peptides in respnse t a single infectin, it is difficult t study the activity f any ne peptide. Brun Lemaitre and fellw researchers in France used mdern genetic techniques t reprgram the fly immune system. They fund that the synthesis f a single type f antimicrbial peptide in the fly s bdy culd prvide an effective immune defense. Furthermre, particular antimicrbial peptides act against pathgens frm different subgrups. The skin and mucus membrane prvide first-line barriers t infectin. In mammals, epithelial tissues blck the entry f harmful viruses and bacteria. An invading micrbe must penetrate the external barrier frmed by the skin and mucus membranes, which line the digestive, respiratry, and geniturinary tracts. Lecture Outline fr Campbell/Reece Bilgy, 9 th Editin, Pearsn Educatin, Inc. 43-2

3 Mucus membranes prduce mucus, a viscus fluid that traps pathgens and ther particles. In the trachea, ciliated epithelial cells sweep ut mucus with its trapped pathgens, preventing them frm entering the lungs. Fungal and bacterial clnizatin is als inhibited by the washing actin f saliva, tears, and mucus secretins that cntinually bathe the expsed epithelium. Beynd their rle as a physical barrier, the skin and mucus membranes cunter pathgens with chemical defenses. Lyszymes in tears, saliva, mucus secretins, and tears kill bacteria that enter the upper respiratry tract r the penings arund the eyes. Pathgens present in fd r water, r thse in swallwed mucus, must cntend with the highly acidic envirnment f the stmach. The acid destrys mst pathgens befre they can enter the intestinal tract. Secretins frm sebaceus and sweat glands give the skin a ph ranging frm 3 t 5, which is acidic enugh t prevent clnizatin by many pathgens. Phagcytic cells functin early in infectin. Pathgens that penetrate the first line f defense face are subject t phagcytsis. Phagcytic cells detect fungal r bacterial cmpnents thrugh receptrs that are very similar t the Tll receptr f insects. Each mammalian TLR, r Tll-like receptr, binds t fragments f mlecules characteristic f a set f pathgens. TLR3 n the inner surface f endcytic vesicles is the sensr fr duble-stranded RNA, a frm f nucleic acid characteristic f certain viruses. TLR4 f immune cell plasma membranes recgnizes lipplysaccharide, a mlecule fund n the surface f many bacteria. TRL5 recgnizes flagellin, a prtein that cmpses bacterial flagella. In each case, the recgnized macrmlecule is nrmally absent frm the vertebrate bdy and is an essential cmpnent f a class f pathgens. After detecting invading pathgens, phagcytic cells engulf them and trap them in a vacule. The vacule then fuses with a lyssme. Pathgens are destryed within lyssmes in tw ways. Gases prduced by the lyssme pisn the engulfed pathgens. Lyszyme and ther enzymes degrade pathgen cmpnents. The tw main types f phagcytic cells in the mammalian bdy are neutrphils and macrphages. Signals frm infected tissues attract circulating neutrphils, which engulf and destry pathgens. Macrphages are larger phagcytic cells. Sme migrate thrughut the bdy, whereas thers reside permanently in rgans and tissues where they are likely t encunter pathgens. Sme macrphages are lcated in the spleen, where pathgens becme trapped. Tw ther types f phagcytic cells play a rle in innate defense. Dendritic cells ppulate tissues that are in cntact with the envirnment, acting t stimulate the develpment f adaptive immunity. Lecture Outline fr Campbell/Reece Bilgy, 9 th Editin, Pearsn Educatin, Inc. 43-3

4 Esinphils defend against large invaders, such as parasitic wrms. These cells psitin themselves against the external wall f a parasite and discharge destructive enzymes. Natural killer cells recgnize and eliminate diseased cells in vertebrates. Natural killer (NK) cells circulate thrugh the bdy and detect the abnrmal array f surface prteins characteristic f sme virus-infected and cancerus cells. NK cells d nt engulf stricken cells. Instead, they release chemicals that lead t cell death, inhibiting further spread f the virus r cancer. Many cellular innate defenses f vertebrates invlve the lymphatic system, a netwrk that distributes lymph thrughut the bdy. Sme macrphages reside in the lymph ndes, where they encunter and engulf pathgens that have flwed frm the interstitial fluid int the lymph. Dendritic cells reside utside the lymphatic system but migrate t lymph ndes after interactin with pathgens. Within the lymph nde, dendritic cells interact with ther immune cells, stimulating adaptive immunity. A variety f peptides and prteins attack pathgens. Pathgen recgnitin in mammals triggers the prductin and release f a variety f peptides and prteins that attack pathgens r impede their reprductin. Sme f these mlecules functin like the antimicrbial peptides f insects, damaging brad grups f pathgens by disrupting membranes. Others, including the interferns and cmplement prteins, have activities unique t vertebrate immune systems. Interferns prvide innate defenses by interfering with viral infectin. These prteins are secreted by virus-infected bdy cells and induce uninfected neighbring cells t prduce substances that inhibit viral reprductin. The interferns limit the cell-t-cell spread f viruses, helping t cntrl viral infectin. Sme white bld cells secrete a different type f interfern that helps activate macrphages, enhancing their phagcytic ability. Interferns can be prduced by recmbinant DNA technlgy and have prven effective in the treatment f certain viral infectins, such as hepatitis C. The cmplement system cnsists f rughly 30 prteins in bld plasma that circulate in an inactive state and are activated by substances n the surface f many pathgens. Activatin results in a cascade f bichemical reactins that lead t lysis f invading cells. The cmplement system functins in inflammatin as well as in adaptive defenses. Damage t tissue triggers an inflammatry respnse. Damage t tissue by a physical injury r the entry f pathgens leads t the release f chemical signals that trigger a lcalized inflammatry respnse. One f the chemical signals f the inflammatry respnse is histamine, which is stred in the granules (vesicles) f mast cells, a type f cnnective tissues. When injured, mast cells release histamine, which triggers bth dilatin and increased permeability f nearby capillaries. Lecture Outline fr Campbell/Reece Bilgy, 9 th Editin, Pearsn Educatin, Inc. 43-4

5 Activated macrphages and ther cells discharge cytkines, signaling mlecules that enhance the immune respnse. Cytkines increase lcal bld supply and cause the characteristic redness and heat f inflammatin. Bld-engrged capillaries leak fluid int neighbring tissue, causing swelling. During inflammatin, cycles f signaling and respnse transfrm the injured site. Enhanced bld flw and vessel permeability aid in delivering cltting elements and antimicrbial prteins t the injured area. Cltting marks the beginning f the repair prcess and helps blck the spread f pathgens elsewhere. Nearby endthelial cells secrete signals that attract neutrphils and macrphages. Increased bld flw and vessel permeability als increase the migratin f phagcytic cells frm the bld int the injured tissues. The end result is an accumulatin f pus, a fluid rich in white bld cells, dead pathgens, and cell debris. The bdy may als munt a systemic respnse t severe tissue damage r infectin. Injured cells secrete chemicals that stimulate the release f additinal neutrphils frm the bne marrw. In a severe infectin, the number f white bld cells may increase significantly within hurs f the initial inflammatin. Anther systemic respnse t infectin is fever, which may ccur when substances released by activated macrphages set the bdy s thermstat at a higher temperature. One hypthesis is that mderate fever enhances phagcytsis and hastens tissue repair. Certain bacterial infectins can induce an verwhelming systemic inflammatry respnse leading t a cnditin knwn as septic shck. Characterized by high fever and reduced bld flw thrugh capillaries, septic shck is a life-threatening medical emergency that is fatal in mre than ne-third f cases. Sme pathgens have adaptatins that enable them t avid destructin by phagcytic cells. The uter capsule that surrunds certain bacteria interferes with mlecular recgnitin and phagcytsis. Sme bacteria, after being engulfed by a hst cell, resist breakdwn within lyssmes. An example is the bacterium that causes tuberculsis (TB). Rather than being destryed within hst cells, this bacterium grws and reprduces, hidden frm the bdy s innate immune defenses. TB kills mre than a millin peple a year wrldwide. Cncept 43.2 In adaptive immunity, lymphcyte receptrs prvide pathgen-specific recgnitin. Vertebrates have adaptive immunity in additin t innate immunity. Lymphcytes prvide the specificity and diversity f the vertebrate immune system. The vertebrate bdy is ppulated by tw main types f lymphcytes: B lymphcytes (B cells) and T lymphcytes (T cells). Bth types f lymphcytes are critical fr adaptive immune defense. Lecture Outline fr Campbell/Reece Bilgy, 9 th Editin, Pearsn Educatin, Inc. 43-5

6 Lymphcytes that riginate frm stem cells in the bne marrw and migrate t the thymus mature int T cells. Lymphcytes that mature in the bne marrw develp as B cells. Lymphcytes f a third type remain in the bld and becme the natural killer cells active in innate immunity. Lymphcytes recgnize specific antigens. Any freign mlecule that is specifically recgnized by lymphcytes and elicits a respnse frm them is called an antigen. B and T cells bind t an antigen via a prtein called an antigen receptr. A single antigen receptr is specific enugh t bind t just ne part f ne mlecule frm a particular species f bacteria r frm a particular virus. The cells f the immune system can prduce millins f different antigen receptrs, but the antigen receptrs made by a single B r T cell are all identical. Infectin by a virus, bacterium, r ther pathgen triggers activatin f B and T cells with antigen receptrs specific fr parts f that pathgen. A single B r T cell actually has abut 100,000 antigen receptrs. Antigens are typically large mlecules, either prteins r plysaccharides that prtrude frm the surface f freign cells r viruses. Other antigens, such as txins secreted by bacteria, are released int extracellular fluid. A lymphcyte actually recgnizes and binds t a small prtin f an antigen called an epitpe r antigenic determinant. Because lymphcytes recgnize and respnd t particular pathgens and freign mlecules, they are said t display specificity fr a particular epitpe n an antigen. Each B cell receptr fr an antigen is a Y-shaped mlecule cnsisting f fur plypeptide chains: tw identical heavy chains and tw identical light chains linked by disulfide bridges. A transmembrane regin near ne end f each heavy chain anchrs the receptr in the cell s plasma membrane. A shrt regin at the end f the tail extends int the cytplasm. At the tw tips f the Y-shaped mlecules are the light- and heavy-chain variable (V) regins whse amin acid sequences vary frm ne B cell t anther. The remainder f the mlecule is made up f cnstant (C) regins, which d nt vary frm cell t cell. Each B cell receptr has tw identical antigen-binding sites frmed frm parts f a heavychain V regin and parts f a light-chain V regin. The binding f a B cell antigen receptr t an antigen is an early step in B cell activatin, leading t frmatin f cells that secrete a sluble frm f the receptr. This secreted prtein is called an antibdy, r immunglbulin (Ig). Antibdies have the same Y-shaped rganizatin as B cell antigen receptrs, but they are secreted rather than membrane-bund. It is the antibdies, rather than the B cells themselves, that actually help defend against pathgens. The antigen-binding site f a membrane-bund antibdy has a unique shape that prvides a lck-and-key fit fr a particular epitpe. Lecture Outline fr Campbell/Reece Bilgy, 9 th Editin, Pearsn Educatin, Inc. 43-6

7 Nncvalent bnds between an epitpe and the binding surface prvide a stable and specific interactin. Differences in the amin acid sequences f variable regins prvide the variatin in binding surfaces that enables this highly specific binding. B cell antigen receptrs and antibdies bind t intact antigens n the surface f pathgens r free in bdy fluids. Fr a T cell, the antigen receptr cnsists f tw different plypeptide chains, the chain and the chain, linked by a disulfide bridge. Near the base f the T cell antigen receptr is a transmembrane regin that anchrs the mlecule in the cell s plasma membrane. At the uter tip f the mlecule, the chain and chain variable (V) regins frm a single antigen-binding site. The remainder f the mlecule is made up f the cnstant (C) regins. T cell and B cell antigen receptrs functin in fundamentally different ways. While the antigen receptrs f B cells bind t epitpes f intact antigens circulating in bdy fluids, thse f T cells bind nly t fragments f antigens that are displayed, r presented, n the surface f hst cells. The hst prtein that displays the antigen fragment n the cell surface is called an MHC (majr histcmpatibility) mlecule. Antigen recgnitin invlving T cells begins when a pathgen r part f a pathgen either infects r is taken in by a hst cell. Inside the hst cell, enzymes in the cell cleave the antigen int smaller peptides. Each peptide, called an antigen fragment, then binds t an MHC mlecule inside the cell. Mvement f the MHC mlecule and bund antigen fragment t the cell surface results in antigen presentatin, the display f the antigen fragment in an expsed grve f the MHC prtein. If the cell displaying an antigen fragment encunters a T cell with the right specificity, the antigen receptr n the T cell can bind t bth the antigen fragment and the MHC mlecule. The interactin f an MHC mlecule, an antigen fragment, and an antigen receptr allws a T cell t participate in an adaptive immune respnse. Cnsider fur majr characteristics f adaptive immunity: First, there is an immense diversity f lymphcytes and receptrs, enabling the immune system t detect pathgens never befre encuntered. Secnd, adaptive immunity nrmally has self-tlerance, the lack f reactivity against an animal s wn mlecules and cells. Third, B cells and T cells prliferate after being activated. Furth, there is a strnger and mre rapid respnse t an antigen encuntered previusly, a feature knwn as immunlgical memry. Receptr diversity and self-tlerance arise as a lymphcyte matures. Prliferatin f cells and the frmatin f immunlgical memry ccur later, after a mature lymphcyte encunters and binds t a specific antigen. Hw d we generate such remarkable diversity in antigen receptrs? Each persn makes mre than 1 millin different B cell antigen receptrs and mre than 10 millin different T cell antigen receptrs. Lecture Outline fr Campbell/Reece Bilgy, 9 th Editin, Pearsn Educatin, Inc. 43-7

8 Yet there are nly rughly 20,000 prtein-cding genes in the human genme. By cmbining variable elements, the immune system assembles many different receptrs frm a much smaller cllectin f parts. T understand the rigin f receptr diversity, let s cnsider an immunglbulin (Ig) gene that encdes the light chain f bth secreted antibdies (immunglbulins) and membranebund B cell antigen receptrs. The capacity t generate diversity is built int the structure f Ig genes. A receptr light chain is encded by three gene segments: a variable (V) segment, a jining (J) segment, and a cnstant (C) segment. The V and J segments tgether encde the variable regin f the receptr chain, while the C segment encdes the cnstant regin. The light-chain gene cntains a single C segment, 40 different V segments, and 5 different J segments. These alternative cpies f the V and J segments are arranged within the gene in a series. Because a functinal gene is built frm ne cpy f each type f segment, the pieces can be cmbined in 200 (40 V 5 J 1 C) different ways. The number f different heavy-chain genes is even greater, resulting in mre diversity. Assembling a functinal Ig gene requires rearranging the DNA. Early in B cell develpment, an enzyme cmplex called recmbinase links ne light-chain V gene segment t ne J gene segment. This recmbinatin event eliminates the lng stretch f DNA between the segments, frming a single exn that is part V and part J. Because there is nly an intrn between the J and C DNA segments, n further DNA rearrangement is required. Instead, the J and C segments f the RNA transcript will be jined when splicing remves the intervening RNA. Recmbinase acts randmly, linking any ne f the 40 V gene segments t any ne f the 5 J gene segments. Heavy-chain genes underg a similar rearrangement. In any given cell, hwever, nly ne light-chain gene and ne heavy-chain gene are rearranged. The rearrangements are permanent and are passed n t the daughter cells when the lymphcyte divides. After bth the light- and heavy-chain genes have rearranged, antigen receptrs can be synthesized. The rearranged genes are transcribed, and the transcripts are prcessed fr translatin. Fllwing translatin, the light chain and heavy chain assemble tgether, frming an antigen receptr. Each pair f randmly rearranged heavy and light chains results in a different antigenbinding surface. Fr the ttal ppulatin f B cells in a human bdy, the number f such cmbinatins has been calculated as Furthermre, mutatins intrduced during VJ recmbinatin add additinal variatin, making the number f pssible antigen-binding specificities even greater. Hw des adaptive immunity distinguish self frm nnself? Lecture Outline fr Campbell/Reece Bilgy, 9 th Editin, Pearsn Educatin, Inc. 43-8

9 Because antigen receptr genes are randmly rearranged, sme immature lymphcytes prduce receptrs specific fr epitpes n the rganism s wn mlecules. If these self-reactive lymphcytes were nt eliminated r inactivated, the immune system culd nt distinguish self frm nnself and wuld attack bdy prteins, cells, and tissues. Instead, as lymphcytes mature in the bne marrw r thymus, their antigen receptrs are tested fr self-reactivity. Sme B and T cells with receptrs specific fr the bdy s wn mlecules are destryed by apptsis r prgrammed cell death. The remaining self-reactive lymphcytes are typically rendered nnfunctinal, leaving nly thse that react t freign mlecules. Since the bdy nrmally lacks mature lymphcytes that can react against its wn cmpnents, the immune system is said t exhibit self-tlerance. Only a tiny fractin f antigen receptrs are specific fr epitpes n a given antigen. Why is adaptive immunity s effective? First, in the lymph ndes, an antigen is presented t a steady stream f lymphcytes until a match is made. The secnd part f the answer lies in changes in cell number and behavir triggered by the binding f antigen t lymphcyte. The binding f an antigen receptr t an epitpe n a specific antigen initiates events that activate the lymphcyte. Once activated, a B cell r T cell underges multiple cell divisins. The result f this prliferatin is a clne, a ppulatin f cells that are identical t the riginal cell. Sme cells frm the clne becme effectr cells, which act against the antigen and any pathgens prducing that antigen. The effectr frms f B cells are plasma cells, which secrete antibdies. The effectr frms f T cells are helper T cells and cyttxic T cells. The remaining cells in the clne becme memry cells, lng-lived cells that prduce effectr cells if the same antigen is encuntered later in the animal s life. The prliferatin f an activated lymphcyte int a clne f cells in respnse t binding t an antigen is called clnal selectin. An encunter with an antigen selects which lymphcyte will divide t prduce a clnal ppulatin f thusands f cells, all specific fr a particular epitpe n that antigen. Immunlgical memry prvides lng-term prtectin frm a prir infectin r vaccinatin. Prir expsure t an antigen alters the speed, strength, and duratin f the immune respnse. The prductin f effectr cells frm a clne f lymphcytes during the first expsure t an antigen is the basis fr the primary immune respnse, which peaks 10 t 17 days after the initial expsure. During this time, selected B cells and T cells give rise t their effectr frms. If an individual is expsed again t the same antigen, the respnse is faster (peaking 2 t 7 days after expsure), f greater magnitude, and mre prlnged. This is the secndary immune respnse. Lecture Outline fr Campbell/Reece Bilgy, 9 th Editin, Pearsn Educatin, Inc. 43-9

10 Because selected B cells give rise t antibdy-secreting effectr cells, measuring the cncentratins f specific antibdies in bld ver time distinguishes the primary and secndary immune respnse. The secndary immune respnse relies n the reservir f T and B memry cells generated fllwing initial expsure t an antigen. Because these cells are lng-lived, they prvide the basis fr immunlgical memry, which can span many decades. Effectr cells have much shrter life spans, which is why the immune respnse diminishes after an infectin is vercme. If an antigen is encuntered again, memry cells specific fr that antigen enable the rapid frmatin f clnes f thusands f effectr cells specific fr this antigen, thus generating a greatly enhanced immune defense. Cncept 43.3 Adaptive immunity defends against infectin f bth bdy fluids and cells. The immune system can munt tw types f immune respnses t antigens: humral and cellmediated. The humral immune respnse ccurs in the bld and lymph. In this respnse, antibdies help neutralize r eliminate txins and pathgens in the bld and lymph. In the cell-mediated immune respnse, specialized T cells destry infected hst cells. Bth respnses include a primary immune respnse and a secndary immune respnse enabled by memry cells. Helper T lymphcytes functin in bth humral and cell-mediated immunity. A type f T cell called a helper T cell triggers bth the humral and cell-mediated immune respnses, althugh helper T cells themselves d nt carry ut thse respnses. Signals frm helper T cells initiate prductin f antibdies that neutralize pathgens and activate T cells that kill infected cells. Tw requirements must be met fr a helper T cell t activate adaptive immune respnses. First, a freign mlecule must be present that can bind specifically t the antigen receptr f the T cell. Secnd, this antigen must be displayed n the surface f an antigen-presenting cell. The antigen-presenting cell can be a dendritic cell, macrphage, r B cell. What distinguishes an antigen-presenting cell? Mst bdy cells have nly class I MHC mlecules, but antigen-presenting cells have bth class I and class II MHC mlecules. The class II mlecules prvide a mlecule signature by which an antigen-presenting cell is recgnized. The antigen receptrs n the surface f the helper T cell bind t the antigen fragment and t the class II MHC mlecule displaying that fragment n the antigen-presenting cell. At the same time, an accessry prtein n the helper T cell surface binds t the class II MHC mlecule, helping keep the cells jined. As the tw cells interact, signals in the frm f cytkines are exchanged in bth directins. Fr example, cytkines secreted frm a dendritic cell act in cmbinatin with the antigen t stimulate the helper T cell, causing it t prduce its wn set f cytkines. Lecture Outline fr Campbell/Reece Bilgy, 9 th Editin, Pearsn Educatin, Inc

11 Extensive cntact between the cell surfaces enables further infrmatin exchange. The different types f antigen-presenting cells interact with helper T cells in distinct cntexts. Antigen presentatin by a dendritic cell r macrphage activates a helper T cell. The helper T cell then prliferates, frming a clne f activated helper T cells. B cells present antigens t already activated helper T cells, which in turn activate the B cells themselves. Activated helper T cells als help stimulate cyttxic T cells, as we ll discuss next. In the cell-mediated immune respnse, cyttxic T cells are the effectr cells. T becme active, cyttxic T cells require signaling mlecules frm helper T cells as well as interactin with a cell that presents an antigen. The term cyttxic refers t their use f txic gene prducts t kill infected cells. Once activated, cyttxic T cells can eliminate cells that are infected by viruses r ther intracellular pathgens. Fragments f freign prteins prduced in infected hst cells assciate with class I MHC mlecules and are displayed n the cell surface, where they can be recgnized by cyttxic T cells. As with helper T cells, cyttxic T cells have an accessry prtein that binds t the MHC mlecule, helping keep the tw cells in cntact while the T cell is activated. The destructin f an infected hst cell by a cyttxic T cell invlves the secretin f prteins that disrupt membrane integrity and trigger apptsis. The death f the infected cell deprives the pathgen f a place t reprduce and expses cell cntents t circulating antibdies, which mark them fr dispsal. After destrying an infected cell, the cyttxic T cell may mve n and kill ther cells infected with the same pathgen. The secretin f antibdies by clnally selected B cells is the hallmark f the humral immune respnse. Activatin f the humral immune respnse typically invlves B cells and helper T cells, as well as prteins n the surface f pathgens. B cell activatin by an antigen is aided by cytkines secreted frm helper T cells that have encuntered the same antigen. Stimulated by bth an antigen and cytkines, the B cell prliferates and differentiates int memry B cells and antibdy-secreting effectr cells called plasma cells. The pathway fr antigen prcessing and display in B cells differs frm that in ther antigenpresenting cells. A macrphage r dendritic cell can present fragments frm a wide variety f prtein antigens, whereas a B cell presents nly the antigen t which it specifically binds. When an antigen first binds t receptrs n the surface f a B cell, the cell takes in a few freign mlecules by receptr-mediated endcytsis. The class II MHC prtein f the B cell then presents an antigen fragment t a helper T cell. This direct cell-t-cell cntact is usually critical t B cell activatin. B cell activatin leads t a rbust humral immune respnse: An activated B cell gives rise t thusands f identical plasma cells. Lecture Outline fr Campbell/Reece Bilgy, 9 th Editin, Pearsn Educatin, Inc

12 These plasma cells stp expressing a membrane-bund antigen receptr and begin prducing secreted antibdies. Each plasma cell secretes apprximately 2,000 antibdies every secnd f the cell s 4- t 5-day life span. Mst antigens recgnized by B cells cntain multiple epitpes. An expsure t a single antigen nrmally activates a variety f B cells, with different plasma cells prducing antibdies directed against different epitpes n the cmmn antigen. Antibdies d nt kill pathgens, but by binding t antigens they mark pathgens in varius ways fr inactivatin r destructin. In neutralizatin, antibdies bind t viral surface prteins and prevent infectin f a hst cell, thus neutralizing the virus. Similarly, antibdies smetimes bind t txins released in bdy fluids, preventing the txins frm entering bdy cells. In psnizatin, antibdies bund t antigens n bacteria present a readily recgnized structure fr macrphages r neutrphils and therefre increase phagcytsis. Each antibdy has tw antigen-binding sites, and antibdies may facilitate phagcytsis by linking bacterial cells, virus particles, r ther freign substances int aggregates. Antibdies may wrk tgether with the prteins f the cmplement system t dispse f pathgens. The name cmplement reflects the fact that these prteins increase the effectiveness f antibdy-directed attacks n bacteria. Binding f a cmplement prtein t an antigen-antibdy cmplex n a freign cell (r an envelped virus) triggers a cascade in which each prtein f the cmplement system activates the next prtein. Ultimately, activated cmplement prteins generate a membrane attack cmplex that frms a pre in the membrane f the freign cell. Ins and water rush int the cell, causing it t swell and lyse. Phagcytsis enables macrphages and dendritic cells t present antigens t and stimulate helper T cells, which in turn stimulate B cells whse antibdies cntribute t phagcytsis. This psitive feedback between innate and adaptive immunity cntributes t a crdinated, effective respnse t infectin. Antibdies can als bring abut the death f infected bdy cells. When a virus uses a cell s bisynthetic machinery t prduce viral prteins, these viral prducts can appear n the cell surface. If antibdies specific fr epitpes n these viral prteins bind t the expsed prteins, the presence f bund antibdy at the cell surface can recruit a natural killer cell. The natural killer cell then releases prteins that cause the infected cell t underg apptsis. B cells can express five different frms f immunglbulin (Ig). Fr a given B cell, each frm r class has an identical antigen-binding specificity, but a distinct heavy chain C regin. The B cell antigen receptr, knwn as IgD, is membrane bund. The ther fur classes cnsist f sluble antibdies. IgM is the first class f sluble antibdy prduced. Lecture Outline fr Campbell/Reece Bilgy, 9 th Editin, Pearsn Educatin, Inc

13 IgG, which fllws next, is the mst abundant antibdy in bld. The remaining antibdy classes are IgA and IgE). When a particular pathgen infects the bdy, clnes f memry cells frm, prviding active immunity. In cntrast, a distinct type f immunity results when the IgG antibdies in the bld f a pregnant female crss the placenta t her fetus. The transferred antibdies immediately react with any pathgens fr which they are specific. This prtectin is called passive immunity because the antibdies prvided by the mther guard against pathgens that have never infected the newbrn. Passive immunity des nt invlve the recipient s B and T cells, and persists nly as lng as the transferred antibdies last (a few weeks t a few mnths). After birth, a nursing mther cntinues t transfer prtectin against disease t her infant. IgA antibdies present in breast milk prvide additinal passive immunity t the infant s digestive tract while the infant s immune system develps. Later in life, IgA functins in active immunity: IgA antibdies secreted in tears, saliva, and mucus prtect the mucus membranes f bth males and females. Bth active immunity and passive immunity can be induced artificially. Active immunity can develp frm the intrductin f antigens int the bdy thrugh immunizatin. The first dcumented immunizatin r vaccinatin was the use f cwpx virus t induce adaptive immunity against the clsely related smallpx virus. Tday, many surces f antigen are used t make vaccines, including inactivated bacterial txins, killed pathgens, parts f pathgens, weakened pathgens that generally d nt cause illness, and even genes encding micrbial prteins. Because all f these agents induce a primary immune respnse and immunlgical memry, an encunter with the pathgen frm which the vaccine was derived triggers a rapid and strng secndary immune respnse. A wrldwide vaccinatin campaign led t eradicatin f smallpx in the late 1970s. Rutine active immunizatin f infants and children has dramatically reduced the incidence f diseases such as pli, measles, and whping cugh. Unfrtunately, nt all pathgens are easily managed by vaccinatin and sme vaccines are nt readily available in impverished areas f the glbe. Misinfrmatin abut vaccine safety and disease risk has led sme parents t refuse t immunize their children with available, effective vaccines. The cnsequence has been a substantial and grwing public health prblem. In artificial passive immunizatin, antibdies frm an immune animal are injected int a nnimmune animal. Fr example, humans bitten by venmus snakes are smetimes treated with antivenin, a serum frm sheep r hrses that have been immunized against the venm f ne r mre species f pisnus snakes. When injected immediately after snakebite, the antibdies in antivenin can neutralize txins in the venm befre the txins d massive damage. Antibdies are useful tls. Lecture Outline fr Campbell/Reece Bilgy, 9 th Editin, Pearsn Educatin, Inc

14 The pwer f antibdy specificity and antigen-antibdy binding has been harnessed in research, diagnsis, and therapy. Sme antibdy tls are plyclnal: They are the prducts f many different clnes f plasma cells, each specific fr a different epitpe. In cntrast, ther antibdy tls are mnclnal: They are prepared frm a single clne f B cells grwn in culture. The mnclnal antibdies prduced by such a culture are identical and specific fr the same epitpe n an antigen. Mnclnal antibdies have prvided the basis fr many recent advances in bimedicine in bth diagnsis and treatment. Hme pregnancy kits use mnclnal antibdies t detect human chrinic gnadtrpin (HCG). HCG is prduced as sn as an embry implants in the uterus, and the presence f this hrmne in a wman s urine is a reliable indicatr fr a very early stage f pregnancy. Mnclnal antibdies are being used t treat many human diseases. Fr this therapy, researchers use muse B cell clnes t identify antibdies specific fr an epitpe n diseased cells. The muse antibdy genes are altered t cde fr antibdies that appear less freign t the human adaptive immune defenses. Scientists then use the humanized genes t prduce large amunts f antibdy fr injecting int patients. Transplanted cells may be recgnized as freign and attacked by immune defenses. Like pathgens, cells frm anther persn can be recgnized as freign and therefre be attacked by immune defenses. Skin transplanted frm ne persn t a genetically nnidentical persn will lk healthy fr a week r s but will then be rejected by the recipient s immune respnse. It remains a largely unanswered questin why a pregnant wman des nt reject her fetus as nnself tissue. T avid a bld transfusin being recgnized as freign by the recipient s immune system, ABO bld grups f the dnr and recipient must be taken int accunt. Red bld cells are designated as type A if they have the type A carbhydrate n their surface. The type B carbhydrate is fund n type B red bld cells; bth A and B carbhydrates are fund n type AB red bld cells; and neither carbhydrate is fund n type O red bld cells. Cnsider the immune respnse f smene with type A bld. Certain bacteria nrmally present in the bdy have epitpes very similar t the A and B carbhydrates. By respnding t the bacterial epitpe similar t the B carbhydrate, a persn with type A bld makes antibdies that will react with the type B carbhydrate. N antibdies are made against the bacterial epitpe similar t the type A carbhydrate because lymphcytes reactive with the bdy s wn mlecules are inactivated r eliminated during develpment. If the persn with type A bld receives a transfusin f type B bld, that persn s anti-b antibdies cause an immediate and devastating transfusin reactin. Lecture Outline fr Campbell/Reece Bilgy, 9 th Editin, Pearsn Educatin, Inc

15 The transfused red bld cells underg lysis, which can lead t chills, fever, shck, and kidney malfunctin. Anti-A antibdies in the dnated type B bld will act against the recipient s type A red bld cells. In the case f tissue and rgan transplants, r grafts, MHC mlecules stimulate the immune respnse that leads t rejectin. Each vertebrate species has many different alleles fr each MHC gene, enabling presentatin f antigen fragments that vary in shape and charge. This diversity f MHC mlecules guarantees that n tw peple, except identical twins, will have exactly the same set. In the vast majrity f graft and transplant recipients, sme MHC mlecules n the dnated tissue are freign t the recipient. T minimize rejectin, physicians try t use dnr tissue bearing MHC mlecules that match thse f the recipient as clsely as pssible. The recipient takes medicines that suppress immune respnses; this leaves the recipient mre susceptible t infectins during the curse f treatment. Bne marrw transplants are used t treat leukemia and ther cancers as well as varius hematlgical (bld cell) diseases. The recipient is typically treated with radiatin t eliminate his r her wn bne marrw cells, destrying the surce f abnrmal cells. This treatment bliterates the recipient s immune system, eliminating graft rejectin. Hwever, lymphcytes in the dnated marrw may react against the recipient. This graft versus hst reactin is limited if the MHC mlecules f the dnr and recipient are well matched. Bne marrw dnr prgrams cntinually seek vlunteers because the great variability f MHC mlecules makes a diverse pl f dnrs essential. Cncept 43.4 Disruptins in immune system functin can elicit r exacerbate disease. Malfunctins f the immune system can prduce effects ranging frm the minr incnvenience f mild allergies t the serius and ften fatal cnsequences f certain autimmune and immundeficiency diseases. Exaggerated immune respnses can cause disease. Allergies are hypersensitive (exaggerated) respnses t certain envirnmental antigens, called allergens. The mst cmmn allergies invlve antibdies f the IgE class. Hay fever, fr example, ccurs when plasma cells secrete IgE specific fr pllen allergens. Sme IgE antibdies attach by their base t mast cells present in cnnective tissue. Later, pllen grains that enter the bdy attach t the antigen-binding sites f mast-cell assciated IgE, crss-linking adjacent antibdy mlecules. This event triggers the mast cell t release histamines and ther inflammatry chemicals frm vesicles called granules. Lecture Outline fr Campbell/Reece Bilgy, 9 th Editin, Pearsn Educatin, Inc

16 These inflammatry events lead t typical allergy symptms: sneezing, runny nse, teary eyes, and smth muscle cntractins that can result in breathing difficulty. Antihistamines diminish allergy symptms by blcking receptrs fr histamine. Smetimes, an acute allergic respnse can result in anaphylactic shck, a whle-bdy, lifethreatening reactin t injected r ingested allergens. Anaphylactic shck results when widespread release f mast cell cntents triggers abrupt dilatin f peripheral bld vessels, causing a precipitus drp in bld pressure and cnstrictin f branchiles. Death may ccur within minutes due t lack f bld flw and inability t breathe. Triggers f anaphylactic shck in susceptible individuals include bee venm, penicillin, r fds such as peanuts r fish. Sme hypersensitive individuals carry syringes with epinephrine, which cunteracts this allergic respnse. Self-directed immune respnses can cause disease. Smetimes the immune system is active against certain mlecules f the bdy, causing an autimmune disease. In systemic lupus erythematsus (lupus), the immune system generates antibdies against varius histnes and DNA released by the nrmal breakdwn f bdy cells. Lupus is characterized by skin rashes, fever, arthritis, and kidney dysfunctin. Rheumatid arthritis leads t damage and painful inflammatin f the cartilage and bne f jints. In Type I diabetes mellitus, the insulin-prducing beta cells f the pancreas are the targets f autimmune cyttxic T cells. Multiple sclersis (MS) is the mst cmmn chrnic neurlgical disease in develped cuntries. In MS, T cells reactive against myelin infiltrate the central nervus system and destry the myelin sheath that surrunds many neurns. Peple with MS may suffer frm muscle paralysis thrugh disruptin f neurn functin. Gender, genetics, and envirnment influence susceptibility t autimmune disease. Members f certain families shw an increased susceptibility t particular autimmune disrders. Wmen are tw t three times as likely as men t suffer frm multiple sclersis and rheumatid arthritis and nine times mre likely t cntract lupus. Much remains t be learned abut autimmune disrders. Exertin and stress influence immune system functin. Mderate exercise imprves immune system functin and reduces the risk f infectin. Exercise t the pint f exhaustin leads t mre frequent infectins with mre severe symptms. Physilgical stress disrupts immune system regulatin by altering the interplay f the hrmnal, nervus, and immune systems. Rest is imprtant fr immunity: adults wh averaged fewer than seven hurs a night f sleep gt sick three times as ften when expsed t a cld virus as individuals wh averaged at least eight hurs f sleep. Lecture Outline fr Campbell/Reece Bilgy, 9 th Editin, Pearsn Educatin, Inc

17 Diminished immune respnses can cause disease. In immundeficiency diseases, the immune system respnse t pathgens is defective r absent. An immundeficiency disease caused by a genetic r develpmental defect in the immune system is called an inbrn immundeficiency. An immundeficiency defect in the immune system that develps later in life, fllwing expsure t a chemical r bilgical agent, is called an acquired immundeficiency. Inbrn immundeficiencies result frm defects in the develpment f varius immune system cells r the prductin f specific prteins, such as antibdies r the prteins f the cmplement system. In severe cmbined immundeficiency (SCID), functinal lymphcytes are rare r absent. Individuals with this disease require a bne marrw r stem cell transplant in rder t supply functinal lymphcytes. Immune deficiencies may als develp later in life. Drugs used t fight autimmune diseases r prevent transplant rejectin suppress the immune system, leading t an immundeficient state. Certain cancers suppress the immune system. An example is Hdgkin s disease, which damages the lymphatic system. Acquired immundeficiency syndrme, r AIDS, is caused by the human immundeficiency virus (HIV). Pathgens may evade the immune system. Pathgens have evlved mechanisms t thwart immune respnses, using antigenic variatin, latency, and direct attack n the immune system. A pathgen may escape attack by the immune system by altering its appearance. Immunlgical memry is a recrd f the freign epitpes an animal has encuntered. If the pathgen that expressed thse epitpes n lnger des s, it can reinfect r remain in a hst withut triggering the rapid and rbust respnse that memry cells prvide. Such antigenic variatin is a regular feature f sme viruses and parasites. The parasite that causes sleeping sickness (trypansmiasis) prvides ne example. By peridically switching at randm amng 1,000 different versins f the prtein fund ver its entire surface, this pathgen can persist in the bdy withut facing an effective adaptive immune respnse. Antigenic variatin is the majr reasn the influenza, r flu, virus remains a majr public health prblem. Of much greater danger, hwever, is the fact that the human virus ccasinally exchanges genes with influenza viruses that infect dmesticated animals, such as pigs r chickens. When this exchange ccurs, influenza can take n such a radically different appearance that the memry cells in the human ppulatin are unable t recgnize the new strain. In 2009, an influenza virus called H1N1 appeared that cntains a nvel cmbinatin f genes frm flu viruses that nrmally circulate in pigs, birds, and humans. The rapid spread f this flu acrss the human ppulatin was declared a pandemic, defined as an epidemic f wrldwide prprtins. Lecture Outline fr Campbell/Reece Bilgy, 9 th Editin, Pearsn Educatin, Inc

18 Frtunately, a rapidly develped H1N1 vaccine sn prvided public health fficials with an excellent means f slwing the spread f this virus and reducing the impact f the utbreak. After infecting a hst, sme viruses becme drmant and cease making viral prteins. In this largely inactive state called latency, there are typically n free viral particles. The viral genme persists in the nuclei f infected cells, either as a separate small DNA r as a cpy integrated int the hst genme. Latency typically persists until cnditins arise that appear favrable fr viral transmissin r unfavrable fr hst survival. Such circumstances trigger the synthesis and release f particles that can infect new hsts. Herpes simplex viruses, which establish themselves in human sensry neurns, prvide illustrative examples f latency. The type 1 virus causes mst ral herpes infectins, whereas the type 2 virus is respnsible fr mst cases f genital herpes. Because sensry neurns express relatively few MHC I mlecules, the infected cells are inefficient at presenting viral antigens t circulating lymphcytes. Stimuli such as fever, emtinal stress, r menstruatin induce reactivatin f the virus and infectin f surrunding epithelial tissues. HIV attacks the immune system. The human immundeficiency virus (HIV), the pathgen that causes AIDS, escapes and attacks the adaptive immune respnse. HIV gains entry int cells by making use f prteins that participate in nrmal immune respnses. The main receptr fr HIV n helper T cells is the cell s CD4 mlecule. HIV als infects sme cell types that have lw levels f CD4, including macrphages and brain cells. Once inside the cell, the HIV RNA is reverse-transcribed, and the prduct DNA is integrated int the hst cell s genme. In this frm, the viral genme can direct the prductin f new viral particles. Althugh the bdy respnds t HIV with an immune respnse sufficient t clear mst viral infectins, sme HIV invariably escapes. One reasn HIV persists is antigenic variatin. It mutates at a very fast rate during viral replicatin, and altered prteins n the surface f sme mutated viruses reduce interactin with antibdies and cyttxic T cells. Sme viruses survive, prliferate, and mutate further, evlving within the bdy. The cntinued presence f HIV is als helped by latency. When the virus integrates int the chrmsme f an infected cell but des nt prduce new virus prteins r particles, it is shielded frm the immune system. The antiviral agents currently used against HIV attack nly an actively replicating virus. Over time, an untreated HIV infectin nt nly avids the adaptive immune respnse but als ablishes it. Virus reprductin and cell death triggered by the virus lead t lss f helper T cells, impairing bth humral and cell-mediated immune respnses. Lecture Outline fr Campbell/Reece Bilgy, 9 th Editin, Pearsn Educatin, Inc

19 The result is a susceptibility t infectins and cancers that can be successfully rebuffed by peple with a healthy immune system. Kapsi s sarcma, a cancer caused by a herpes virus, and pneumnia, caused by the fungus Pneumcystis carinii, are seldm fund in healthy peple but ccur in AIDS patients. Peple with AIDS are susceptible t pprtunistic diseases, neurlgical disease, and physilgical wasting. HIV infectin cannt yet be cured, althugh certain drugs slw HIV reprductin and the prgressin t AIDS. The mutatinal changes that ccur with each rund f virus reprductin can generate drug-resistant strains f HIV. The impact f viral drug resistance is reduced by the use f a cmbinatin f drugs; viruses newly resistant t ne drug can be defeated by anther. Strains resistant t multiple drugs reduce the effectiveness f multidrug ccktails in sme patients. Frequent mutatinal changes in HIV surface antigens als have hampered effrts t develp an effective vaccine. In 2007, 2 millin peple died f AIDS, which is the leading cause f death in Africa. Transmissin f HIV requires the transfer f bdy fluids cntaining infected cells, such as semen, bld, r breast milk frm persn t persn. Mst HIV transmissin is due t unprtected sex r the use f HIV-cntaminated needles. Peple infected with HIV transmit the disease mst readily in the first few weeks f infectin, befre they express HIV-specific antibdies that can be detected in a bld test. 10 t 50% f all new HIV infectins are caused by recently infected individuals. The frequency f certain cancers increases when the immune respnse is impaired. When adaptive immunity is inactivated, the frequency f certain cancers increases dramatically. The risk f develping Kapsi s sarcma is 20,000 times greater fr untreated AIDS patients than fr healthy peple. This bservatin was unanticipated: If the immune system recgnizes nly nn-self, it shuld fail t recgnize the uncntrlled grwth f self cells that is the hallmark f cancer. It turns ut, hwever, that viruses are invlved in abut 15 t 20% f all human cancers. Because the immune system can recgnize viral prteins as freign, it can act as a defense against viruses that can cause cancer and against cancer cells that harbr viruses. Scientists have identified six viruses that can cause cancer in humans. The Kapsi s sarcma herpes virus is ne such virus. Hepatitis B virus, which can trigger liver cancer, is anther. A vaccine directed against hepatitis B virus was the first vaccine t help prevent a specific human cancer. Rapid prgress n virus-induced cancers cntinues. In 2006, a vaccine against the human papillmavirus (HPV) that causes cervical cancer was released. Lecture Outline fr Campbell/Reece Bilgy, 9 th Editin, Pearsn Educatin, Inc