Understanding theImmune SystemHow It WorksU.S. DEPARTMENT OF HEALTH AND HUMAN SERVICESNATIONAL INSTITUTES OF HEALTHNational Institute of Allergy and Infectious DiseasesNational Cancer Institute

Understanding theImmune SystemHow It WorksU.S. DEPARTMENT OF HEALTH AND HUMAN SERVICESNATIONAL INSTITUTES OF HEALTHNational Institute of Allergy and Infectious DiseasesNational Cancer InstituteNIH Publication No. 03-5423September

Contents1 Introduction2Self and Nonself3The Structure of the Immune System7 Immune Cells and Their Products19Mounting an Immune Response24Immunity: Natural and Acquired28Disorders of the Immune System34Immunology and Transplants36Immunity and Cancer39The Immune System and the Nervous System40Frontiers in Immunology45Summary47 Glossary

IntroductionTBacteria:streptococciVirus:herpes virusParasite:schistosomehe immune system is a network ofcells, tissues*, and organs that worktogether to defend the body against attacksby “foreign” invaders. These are primarilymicrobes (germs)—tiny, infection-causingorganisms such as bacteria, viruses,parasites, and fungi. Because the humanbody provides an ideal environment formany microbes, they try to break in. It isthe immune system’s job to keep them outor, failing that, to seek out and destroy them.When the immune system hits the wrongtarget or is crippled, however, it canunleash a torrent of diseases, includingallergy, arthritis, or AIDS.The immune system is amazingly complex.It can recognize and remember millions ofdifferent enemies, and it can producesecretions and cells to match up with andwipe out each one of them.The secret to its success is an elaborateand dynamic communications network.Millions and millions of cells, organizedinto sets and subsets, gather like clouds ofbees swarming around a hive and passinformation back and forth. Once immuneFungus:penicillium mold*Definitions of words printed in italics are listed in theGlossary on page 47.1

cells receive the alarm, they undergotactical changes and begin to producepowerful chemicals. These substancesallow the cells to regulate their owngrowth and behavior, enlist their fellows,and direct new recruits to trouble spots.Self and NonselfThe key to a healthy immune system isits remarkable ability to distinguishbetween the body’s own cells—self—andforeign cells—nonself. The body’s immunedefenses normally coexist peacefully withcells that carry distinctive “self” markermolecules. But when immune defendersencounter cells or organisms carryingAntigenMarker moleculeAntibodyAntigens carry marker molecules that identify themas foreign.2

markers that say “foreign,” they quicklylaunch an attack.Anything that can trigger this immuneresponse is called an antigen. An antigencan be a microbe such as a virus, or evena part of a microbe. Tissues or cells fromanother person (except an identical twin)also carry nonself markers and act asantigens. This explains why tissuetransplants may be rejected.In abnormal situations, the immune systemcan mistake self for nonself and launch anattack against the body’s own cells ortissues. The result is called an autoimmunedisease. Some forms of arthritis anddiabetes are autoimmune diseases. In othercases, the immune system responds to aseemingly harmless foreign substance suchas ragweed pollen. The result is allergy,and this kind of antigen is called an allergen.The Structure of the Immune SystemThe organs of the immune system arepositioned throughout the body. Theyare called lymphoid organs because theyare home to lymphocytes, small whiteblood cells that are the key players in theimmune system.3

Tonsils desLymphaticvesselsThe organs of the immune system are positionedthroughout the body.Bone marrow, the soft tissue in the hollowcenter of bones, is the ultimate source ofall blood cells, including white blood cellsdestined to become immune cells.The thymus is an organ that lies behindthe breastbone; lymphocytes known as4

Incominglymph aVeinArteryOutgoinglymph vesselThe lymph node contains numerous specializedstructures. T cells concentrate in the paracortex,B cells in and around the germinal centers, and plasmacells in the medulla.T lymphocytes, or just “T cells,” mature inthe thymus.Lymphocytes can travel throughout thebody using the blood vessels. The cells canalso travel through a system of lymphaticvessels that closely parallels the body’sveins and arteries. Cells and fluids areexchanged between blood and lymphaticvessels, enabling the lymphatic system tomonitor the body for invading microbes.The lymphatic vessels carry lymph, a clearfluid that bathes the body’s tissues.5

Small, bean-shaped lymph nodes are lacedalong the lymphatic vessels, with clustersin the neck, armpits, abdomen, and groin.Each lymph node contains specializedcompartments where immune cellscongregate, and where they canencounter antigens.Immune cells and foreign particles enterthe lymph nodes via incoming lymphaticvessels or the lymph nodes’ tiny bloodvessels. All lymphocytes exit lymph nodesthrough outgoing lymphatic vessels. Oncein the bloodstream, they are transported totissues throughout the body. They patroleverywhere for foreign antigens, thengradually drift back into the lymphaticsystem, to begin the cycle all over again.The spleen is a flattened organ at the upperleft of the abdomen. Like the lymph nodes,the spleen contains specializedcompartments where immune cells gatherand work, and serves as a meeting groundwhere immune defenses confront antigens.Clumps of lymphoid tissue are found inmany parts of the body, especially in thelinings of the digestive tract and theairways and lungs—territories that serve asgateways to the body. These tissues includethe tonsils, adenoids, and appendix.6

LymphnodeLymphaticvesselImmune cells and foreign particles enter the lymphnodes via incoming lymphatic vessels or the lymphnodes’ tiny blood vessels.Immune Cells and Their ProductsThe immune system stockpiles a hugearsenal of cells, not only lymphocytesbut also cell-devouring phagocytes andtheir relatives. Some immune cells take onall comers, while others are trained onhighly specific targets. To work effectively,most immune cells need the cooperation oftheir comrades. Sometimes immune cellscommunicate by direct physical contact,sometimes by releasing chemical messengers.The immune system stores just a few ofeach kind of the different cells needed torecognize millions of possible enemies.When an antigen appears, those fewmatching cells multiply into a full-scalearmy. After their job is done, they fade7

AntigenbindingsiteHeavychainLightchainVariable regionConstant regionAn antibody is madeup of two heavychains and two lightchains. The variableregion, which differsfrom one antibody tothe next, allows anantibody torecognize itsmatching antigen.away, leaving sentries behind to watch forfuture attacks.All immune cells begin as immature stemcells in the bone marrow. They respond todifferent cytokines and other signals togrow into specific immune cell types, suchas T cells, B cells, or phagocytes. Becausestem cells have not yet committed to aparticular future, they are an interestingpossibility for treating some immunesystem disorders. Researchers currently areinvestigating if a person’s own stem cellscan be used to regenerate damagedimmune responses in autoimmune diseasesand immune deficiency diseases.B LymphocytesB cells and T cells are the main typesof lymphocytes.B cells work chiefly by secretingsubstances called antibodies into thebody’s fluids. Antibodies ambush antigenscirculating the bloodstream. They arepowerless, however, to penetrate cells. Thejob of attacking target cells—either cellsthat have been infected by viruses or cellsthat have been distorted by cancer—is leftto T cells or other immune cells(described below).8

B cellPlasma cellAntibodyB cells mature into plasma cells that produce antibodies.Each B cell is programmed to make onespecific antibody. For example, one B cellwill make an antibody that blocks a virusthat causes the common cold, whileanother produces an antibody that attacksa bacterium that causes pneumonia.When a B cell encounters its triggeringantigen, it gives rise to many large cellsknown as plasma cells. Every plasma cellis essentially a factory for producing anantibody. Each of the plasma cellsdescended from a given B cellmanufactures millions of identicalantibody molecules and pours them intothe bloodstream.9

An antigen matches an antibody much as akey matches a lock. Some match exactly;others fit more like a skeleton key. Butwhenever antigen and antibody interlock,the antibody marks the antigenfor destruction.Antibodies belong to a family of largemolecules known as immunoglobulins.Different types play different roles in theimmune defense strategy. Immunoglobulin G, or IgG, worksefficiently to coat microbes, speedingtheir uptake by other cells in theimmune system. IgM is very effective at killing bacteria. IgA concentrates in body fluids—tears,saliva, the secretions of the respiratorytract and the digestive tract—guarding theentrances to the body. IgE, whose natural job probably is toprotect against parasitic infections, is thevillain responsible for the symptomsof allergy. IgD remains attached to B cells andplays a key role in initiating earlyB-cell response.Immunoglobulins10

T CellsUnlike B cells, T cells do not recognizefree-floating antigens. Rather, their surfacescontain specialized antibody-like receptorsthat see fragments of antigens on thesurfaces of infected or cancerous cells.T cells contribute to immune defenses intwo major ways: some direct and regulateimmune responses; others directly attackinfected or cancerous cells.Helper T cells, or Th cells, coordinateimmune responses by communicating withother cells. Some stimulate nearby B cellsto produce antibody, others call in microbegobbling cells called phagocytes, still othersactivate other T cells.Killer T cells—also called cytotoxic Tlymphocytes or CTLs—perform a differentfunction. These cells directly attack otherImmature T cellMature helperT cellMature cytotoxicT cellSome T cells are helper cells, others are killer cells.11

Killer cellTarget cellTarget-orientedgranulesSurface contactKiller cell makes contact with target cell, trains itsweapons on the target, then strikes.cells carrying certain foreign or abnormalmolecules on their surfaces. CTLs areespecially useful for attacking virusesbecause viruses often hide from other partsof the immune system while they growinside infected cells. CTLs recognize smallfragments of these viruses peeking outfrom the cell membrane and launch anattack to kill the cell.In most cases, T cells only recognize anantigen if it is carried on the surface of acell by one of the body’s own MHC, ormajor histocompatibility complex,molecules. MHC molecules are proteins12

recognized by T cells when distinguishingbetween self and nonself. A self MHCmolecule provides a recognizablescaffolding to present a foreign antigen tothe T cell.Although MHC molecules are required forT-cell responses against foreign invaders,they also pose a difficulty during organtransplantations. Virtually every cell in thebody is covered with MHC proteins, buteach person has a different set of theseproteins on his or her cells. If a T cellrecognizes a nonself MHC molecule onanother cell, it will destroy the cell.Therefore, doctors must match organrecipients with donors who have theclosest MHC makeup. Otherwise therecipient’s T cells will likely attackthe transplanted organ, leading tograft rejection.Natural killer (NK) cells are another kindof lethal white cell, or lymphocyte. Likekiller T cells, NK cells are armed withgranules filled with potent chemicals.But while killer T cells look for antigenfragments bound to self-MHC molecules,NK cells recognize cells lacking self-MHCmolecules. Thus NK cells have thepotential to attack many types offoreign cells.13

MonocyteEosinophilMast cellMacrophageNeutrophilBasophilPhagocytes, granulocytes, and mast cells, all withdifferent methods of attack, demonstrate the immunesystem’s versatility.Both kinds of killer cells slay on contact.The deadly assassins bind to their targets,aim their weapons, and then deliver alethal burst of chemicals.Phagocytes and Their RelativesPhagocytes are large white cells that canswallow and digest microbes and otherforeign particles. Monocytes arephagocytes that circulate in the blood.When monocytes migrate into tissues,they develop into macrophages.Specialized types of macrophages can befound in many organs, including lungs,kidneys, brain, and liver.14

Macrophages play many roles. Asscavengers, they rid the body of worn-outcells and other debris. They display bitsof foreign antigen in a way that draws theattention of matching lymphocytes. Andthey churn out an amazing variety ofpowerful chemical signals, knownas monokines, which are vital to theimmune responses.Granulocytes are another kind of immunecell. They contain granules filled withpotent chemicals, which allow thegranulocytes to destroy microorganisms.Some of these chemicals, such ashistamine, also contribute to inflammationand allergy.One type of granulocyte, the neutrophil, isalso a phagocyte; it uses its prepackagedchemicals to break down the microbes itingests. Eosinophils and basophils aregranulocytes that “degranulate,” sprayingtheir chemicals onto harmful cells ormicrobes nearby.The mast cell is a twin of the basophil,except that it is not a blood cell. Rather, itis found in the lungs, skin, tongue, andlinings of the nose and intestinal tract,where it is responsible for the symptomsof allergy.A related structure, the blood platelet, is acell fragment. Platelets, too, contain15

granules. In addition to promoting bloodclotting and wound repair, plateletsactivate s

key matches a lock. Some match exactly; others fit more like a skeleton key. But whenever antigen and antibody interlock, the antibody marks the antigen for destruction. Antibodies belong to a family of large molecules known as immunoglobulins. Different types play different roles in the immune defense strategy. Immunoglobulin G, or IgG, works