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Home , Adaptive immune system, Bone marrow, Innate immune system, Lymphocyte

UCSF Magazine, August 2002, © UCSF patterns that immunologists have The learned to recognize. Full-scale immune system The Body’s Armed mobilization requires the manufac- Services ture of more ammunition and weaponry. Most resource-intensive Military metaphors used to of all, soldier cells of the immune describe the immune system are system must enhance their often apt. The immune system numbers when an invader strikes. does indeed comprise the body’s This requires massive amounts of armed services. Different branches Ph a g o c y t e , which in turn requires fulfill different roles in defending that within leukocytes be the body against , , that fails to wind down once the switched on to direct this protein fungi and parasites. Immune enemy is vanquished. When the production. system success in the battle immune system targets harmless against these , like that particles, the result may be of any fighting force, depends on or ; when the immune getting enough of the right troops system targets our own tissues, First Line of Defense the result is autoimmune disease. in the right place at the right time. The Innate Immune As befits these needs, immune cell soldiers are mobile. To reach The Battle Plan Response embattled tissue, they deploy As a group, immune cells are Those immune cells that are ready through the bloodstream or via often called white cells, to fight as soon as bacteria, fungi, their own system of canals, called although immunologists prefer the viruses or parasites infect us are lymphatic vessels. The leukocyte term leukocytes. A small number part of what is called the “innate” cells and organs of the immune of constantly dividing stem immune system. The innate system are small and spread cells in the marrow, called immune system often ends the throughout the body. But taken “hematopoietic” stem cells, threat without our ever becoming together, the components of the generates all blood cells, including aware of the danger, thanks to immune system are as massive as leukocytes. (This is why bone sentinel cells that patrol the outer the or . During , marrow transplants, or transplants borders of our body. the immune system gets even of the stem cells themselves, can — cell eaters — are concentrated bigger, and its soldier cells be used to reconstitute immune near the surfaces of nearly all expand their numbers with a systems.) tissues. One of their major tasks is speed unrivaled by other cells in Most immune cells mature in to gobble up invading microbes the adult organism. the where they first that get through barriers along We might fail to appreciate arise. Each type has different these outer borders — the or the resources the body dedicates duties to perform and, depending the -covered linings of the to the immune system if we upon the nature of the threat, a respiratory and gastrointestinal were not sometimes reminded by different battlefield scenario in tracts, for example. swollen tissue, aches, , which to act. It is clear that a func- Phagocytes known as fatigue and inflammation — the tioning immune system depends , which patrol the blood byproducts of a vigorous immune on the orderly, coordinated stream, are the first to arrive. response and the evidence of a deployment of its various com- Other troops geared struggle. ponents. But, surprisingly, there is toward rapid response are the To limit the resources spent on no apparent commander in chief. — “big eaters,” warfare — and our own aches and Instead, signals and status reports which are stationed in all tissues. pains — the cells of the immune from cells within the immune Macrophages increase their system work together, exchanging system help in the shape and numbers in response to invasion feedback and mustering just the execution of a battle plan. The and begin to hit the battlefield level of response needed to signals sent between leukocytes, en masse shortly after the counter only real threats. Once a as well as the character of the neutrophils. Natural killer cells, threat is eliminated, leukocyte cell that unfolds as another component of the innate populations and immune tissues a result, depend largely on the immune system, knock off infected return to normal size. Failure to nature of the and the cells that harbor invading viruses. mount an adequate immune site of invasion. Within these Even more abundant are response to infection can be parameters, the mobilization and dendritic cells. Dendritic cells deadly, but so too can an immune demobilization of immune forces quickly ferry captured foreign response that is too vigorous, or normally unfold according to molecules to nearby nodes,

14 (Italicized words are also defined in the glossary on page 20.) where other immune cells, particu- Signal transduction involves spe- moment. Among the , larly those known as , cialized inside the cell that a special class called garrison themselves. The dendritic integrate incoming signals from guides soldier cells to their cells sound the alert, put the cell-surface receptors and transmit fighting destinations via chemo- enemy target on display and -switching orders to the attractant signals. rouse the garrisoned cells to the nucleus. Failures in signal trans- The innate immune response, challenge. duction have been implicated in with its engulf-and-destroy These brothers-in-arms are certain im m u n o d e fi ciency diseases, tactics, is a primitive but still called to the fray because in which the immune system is vital throwback. Although it leukocytes exchange information weakened, and also may play a quickly responds to pathogens and send orders to each other by role in some autoimmune disorde r s . that breach the borders, the secreting specialized chemical Different cytokines carry weaponry used by its forces is signals, called cytokines. The different messages, resulting in a generic — some is anti-viral, process of getting the message different mix of specially trained some is anti-bacterial, and from a cell-surface receptor to the immune-cell fighting forces. some works especially well on , where it can be acted This makes the forces well-suited parasitic . It is not tailored upon, is called signal transduction. to fighting the pathogen of the to particular enemy species. Two Kinds of Immune Response The immune response has two mechanisms. The innate response involves phagocytes (cell-eaters) and natural killer cells, which patrol the pathogen’s normal points of entry and gobble up invaders or cripple cells harboring viruses. The innate response is generic, immediate and often successful. Should the infectious agent get past this first line of defense, the adaptive immune response — which arises anywhere from three to seven days after the initial infection — sets in motion a different set of fighting forces with weaponry aimed at specific targets. One key feature of the adaptive immune response is that it remembers the enemy (see “All-Out War ,” page 17).

MM E D I AT E 3 –7 DAYS Invading pathogens First line of defense Second line of defense

Natural killer cells B cells

An t i b o d i e s

Ph a g o c y t e s T cells 15 Even after the pathogen is All-Out War The Adaptive Immune Response defeated, some specialized T cells, called memory Increasing the Ranks; Ma t u r e activated helper T cells, remain. Memory T Aiming at Specific Targets T cells can in turn activate cells can get the immune While our pre-human ancestors proliferation their brothers-in-arms, response rolling much retained an the B lymphocytes, or mo r e quickly and effectively during their evolutionary journey, If the T cell is presented with the pathogen marker B cells. B cells make free - if the same pathogen should they added additional layers of it can recognize by one of the immune system’s floating that ever be encountered again. defense along the way. In the presenting cells, and if it receives additional target the same antigen in same way that the brain’s primitive “co-stimulatory” signals req u i r ed for activation, the blood stream or on the the T cell will expand its numbers. The resultant M e m o ry T cells cerebellum, sitting atop the brain surfaces of infected cells. T cells will mature into fighting forces capable of stem, is in communication with fulfilling many functions. the overlying, highly evolved Helper T cell cerebral cortex, the dendritic cells, phagocytes and natural killers of the innate immune system are in communication with cells from the more evolutionarily advanced branches of the immune system. These more evolved branches, T cell found in almost all , are collectively known as the . Antigen-presenting cell From the time sentinel cells of () the innate immune system first detect an infectious threat, full activation of the adaptive immune response takes from three to production seven days. An adaptive response involves more fighting forces and weaponry aimed at specific targets. An extremely important aspect stimulation of the adaptive immune system is that it remembers the enemy. The immune response is When the war is over, a few characterized by feedback. p r o d u c t i o n veteran soldiers of the adaptive For instance, the macrophages immune system stick around. T cells release a variety of that help trigger T cell C y t o t o x i c Their presence ensures a faster activation by engulfing signaling molecules, such as T cells cytokines. Some cytokines, build-up and a better-honed pathogens and presenting response if the same microbial foe antigen bits to T cells are such as IL-2, spur specialized Some mature T cells to multiply, and some is ever encountered again. in turn spurred to greater T cells serve activity by mature T cells. spur inflammatory res p o n s e s , , with bits of weak- as cytotoxic such as tissue swelling, ened or killed pathogen as their lymphocytes which serves to limit the centerpiece, are designed to take (CTLs), which sp r ead of infection. advantage of immune system target and de s t r oy memory. The immune system infected cells. mounts a small response after , enough to generate I n f l a m m a t o ry cells veteran lymphocytes (leukocytes that take up residence in the lymph nodes). It is these lympho- cytes that will spring into action T lymphocyt e s , or T cells for short, are the driving infection begins (see “T wo Kinds of Immune Response,” that has caused infection. This specificity is made pos- rapidly if that same enemy force for the adaptive immune response. The adaptive page 15). The adaptive immune response, unlike the sible by the tremendous variation among T cells. Each reappears in virulent form. immune response is a second onslaught launched earlier innate immune response, is powerfully and T cell is targeted only against a certain molecular marker, against invading microbes about three days after specifically targeted against the particular pathogen called an antigen, found on a particular foreign invad e r . 16 17 Suppressor T cells call the troops invaded by a pathogen also may Special Forces home when the war is ending. display targets from the pathogen in slightly different form, like T Cells and B Cells B Cells and Antibodies warning flags or distress signals. A target properly displayed The bulk of the troops mustered Specialized B cells can also target by a sentinel or infected cell fits during an adaptive immune infected cells, as well as secrete into a receptor on the surface response are called T lympho- mobile versions of antigen-target- of the appropriate cytes and B lymphocytes (short- ing molecules, called antibodies in lock-and-key fashion. hand for the and the bone or immunoglobulins. These float- Immunologists refer to these marrow, the organs where the ing antibodies attack pathogens targetable bits of pathogens as cells mature), or simply T cells and that roam freely, unassociated . Dendritic cells and B cells. Each lymphocyte is spe- with any of the body’s own cells. macrophages, to a lesser extent, cialized, outfitted to strike target Antibodies can also neutralize are the main antigen-presenting molecules with one particular produced by infectious cells of the immune system. shape, and to ignore all others. organisms, and like T cell recep- When antigen-presenting cells display captured pathogen targets, and when non-immune cells in distress wave their warning flags, they do so by holding out antigen targets between molecular arms. The arms consist of MHC proteins; “MHC” stands for major histo - compatibility complex. The Failsafe

Co-stimulation The engagement of lock and key is a necessary step in the activa- tion of T cells and the initiation of an adaptive immune response. But as a failsafe, another event, called co-stimulation, must also Pr oliferation of T lymphocytes during the adaptive immune res p o n s e occur. Co-stimulation is governed by proteins that provide “second In response to invasion by a tors, they can bind to targets signals” needed to accelerate particular pathogen, specialized on infected cells or on foreign, T cell activation. Once T cells are lymphocytes equipped with pathogenic cells, leading to the activated, the adaptive immune weaponry to target a specific demise of those cells. response can really get rolling, with the proliferation of additional enemy may be called on to Antigens and expand their numbers — to T cells and B cells that also themselves. They are the chosen T Cell Activation specifically target molecular ones; few lymphocytes ever Sentinel cells of the innate features found on the invading encounter the enemies they immune system must present pathogen. When the adaptive were born to fight, and most die enemy targets to T cells before immune response comes into untested in battle after just one or the T cells can become activated play, the innate immune response two months. and in turn activate B cells. The does not end. In fact, just as the There are different divisions target presented is almost always innate immune forces spur the within the T lymphocyte army. a bit of protein from a captured adaptive immune system, so can Helper T cells, also called CD4 pathogen that has been engulfed cytokine signals from T cells, as cells, direct the action and help and repackaged on the surface of well as cytokines and antibodies other immune cells do their jobs. the presenting cell. Non-immune, secreted from B cells, in turn Cytotoxic T cells, also known “civilian” cells that are in distress rekindle the appetites of microbe- as CD8 cells, kill infected cells. or dying as a result of being gobbling phagocytes.

18 Diversity Key to the Immune System Repertoire

Collectively, lymphocytes can But the real answer to the create close to a billion different mystery is that the immune specialized weapons to target system has an unusual just about any molecule, propensity to shuffle and especially protein molecules, recombine its allotment of the that might be encountered on genetic code. The result is a pathogen. These weapons millions of sequential permuta- can also target toxins secreted tions, with each reconfigured by pathogens. The immune gene serving as the blueprint system can even target for a different receptor or molecules the world has never antibody. seen before, such as new, Furthermore, that man-made chemicals. splice these gene fragments For decades, the central together add bits of DNA at mystery of the immune system the splice site. In addition, the was how to explain this genes are unusually susceptible staggering lymphocyte diversity. to — spelling It doesn’t seem to make sense, changes in the DNA sequence. given the limited number of These features combine to genes available to encode further enrich the diversity of so many different receptors. lymphocyte receptors made Some esteemed scientists once from the genes and to deepen favored the idea that a single our appreciation for a system type of receptor can change that scientists continually seek shape to fit many different to demystify and influence in targets, like a glove accommo- our own best defense. dating a variety of hands.

Two natural killer cells attacking a cell.

19 Glossary

ADAPTIVE IMMUNE RESPONSE: communication between cells of LYMPHOCYTE: A cell of the adap- An immune response that is the immune system. tive immune system. Lymphocytes specifically directed at particular include B and T lymphocytes, DENDRITIC CELL: A type of antigens on a disease pathogen. which target specific antigens and immune cell that presents antigens, Certain lymphocyte cells of the which are also responsible for attached to MHC proteins, to adaptive immune system retain immunologic memory. lymphocytes. a memory of prior exposure to MACROPHAGE: A type of antigens from pathogens, including : A type of immune tissue-based immune cell that antigens in vaccines. This permits cell that is important in defense engulfs and kills microbes, secretes a stronger immune response if the against parasites. inflammatory cytokines, and same pathogen is encountered : A state of presents antigen to lymphocytes. again later. exhibiting an uncontrolled or MAJOR HISTOCOMPATIBILITY ANTIBODY: A free-floating, excessive immune response COMPLEX (MHC): A large set antigen-receptor protein made against microbes or harmless of genes that encodes proteins and secreted by B lymphocytes, foreign antigens, as in an allergic used to display antigens to specialized for targeting a specific or asthmatic immune response. T lymphocytes. antigen and especially valuable : A response of the : A type of immune for combating toxins or pathogens innate immune system in which cell residing near blood vessels, that are not inside cells. leukocytes and associated proteins which secretes irritants and plays ANTIGEN: A molecule that binds to exit the bloodstream to accumulate a major role in hypersensitivity. an antibody or antigen receptor. at sites of infection, exposure or injury. Inflammation is protective NATURAL KILLER: A cell of the ANTIGEN RECEPTOR: A special- but may also sometimes cause innate immune system that kills ized protein that populates the tissue damage. infected cells and that has the surface of a T or B lymphocyte. It potential to kill tumor cells. permits recognition of pathogen DISEASE: A invasion when it binds to its target disease in which the dysfunction or PATHOGEN: An infectious, antigen, in turn leading to the absence of certain components of disease-causing entity. Pathogens proliferation of lymphocytes and to the immune system compromises include certain bacteria, viruses, the inactivation or destruction of the ability of the immune system fungi, and parasites. to defend against pathogens. pathogens. PHAGOCYTE: An immune cell, : A destructive IMMUNOGLOBULIN: An antibody. such as a macrophage, capable of engulfing particles or bacteria. process in which the disease- : Medical inter- fighting mechanisms of the immune ventions aimed at strengthening an : A lymphoid system are directed against certain immune response against disease. situated in the upper left abdomen of the body’s own molecules, that plays a major role in adaptive INNATE IMMUNE RESPONSE: An cells and tissues. immune responses to blood-borne early and relatively nonspecific antigens. BONE MARROW: Spongy tissue response to infection coordinated concentrated at the core of major by certain cell types, such as THYMUS: A lymphoid organ, in which stem cells give neutrophils, macrophages and situated near the lower throat, rise to all the cells of the immune natural killer cells, and their where T lymphocytes mature early system, to red blood cells and to associated cytokines. in life. the cells that permit blood-clotting. LEUKOCYTE: A cell of the : A situation in which system, also called a white blood the adaptive immune system does CHEMOKINE: A large family of cell. not respond to an antigen. cytokines that direct leukocyte movements and govern the : A capsule of tissue : migration of leukocytes from the incorporating many lymphocytes, An immune response in which a blood to tissues. situated along lymphatic vessels, transplanted organ is regarded and a major site for lymphocyte as a foreign invader, due to a CYTOKINE: A type of protein activation by antigen-presenting mismatch in donor and recipient produced by many different cell cells. major histocompatibility complex types that mediates inflammatory proteins, and is attacked by the and immune reactions. Cytokines transplant recipient’s immune are principal mediators of system.

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