Janeway's Immunobiology, 8th Edition

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Dynamics of AdaptiveImmunityThroughout this book we have examined the separate ways in which theinnate and the adaptive immune responses protect the individual from invad-ing microorganisms. In this chapter, we consider how the cells and moleculesof the immune system work as an integrated defense system to eliminate orcontrol an infectious agent and how the adaptive immune system provideslong-lasting protective immunity. This is the first of several chapters thatconsider how the immune system functions as a whole in health and dis-ease. The next chapter describes the role and specializations of the mucosalimmune system, which forms the front-line defense against most pathogens.Subsequent chapters examine how immune defenses can fail (Chapter 13)or unwanted immune responses occur (Chapters 14 and 15), and how theimmune response can be manipulated to benefit the individual (Chapter 16).In Chapters 2 and 3, we saw how innate immunity is brought into play in theearliest phases of an infection and is probably sufficient to prevent coloniza-tion of the body by most of the microorganisms encountered in the environ-ment. However, pathogenic microorganisms, by definition, have developedstrategies that allow them to elude or overcome innate immune defenses andto establish a focus of infection from which they can spread. In these circum-stances, the innate immune response sets the scene for the induction of anadaptive immune response. In the primly immune response, which occursagainst a pathogen encountered for the first time, several days are requiredfor the clonal expansion and differentiation of naive lymphocytes into effec-tor T cells and antibody-secreting B cells, as described in Chapters 9 and 10.In most cases, these cells and antibodies will effectively target the pathogenfor elimination (Fig. 11.1).

During this period, specific immunological memory is also established. Thisensures a rapid reinduction of antigen-specific antibody and effector T cellson subsequent encounters with the same pathogen, thus providing long-lasting and often lifelong protection against it. Immunological memory isdiscussed in the last part of the chapter. Memory responses differ in severalways from primary responses. We discuss the reasons for this, and what isknown about how immunological memory is maintained.The course of the immune response to infection.The immune response is a dynamic process, and both its nature and intensitychange over time. It starts with the relatively nonspecific responses of innateimmunity and becomes both more focused on the pathogen and more pow-erful as the adaptive immune response is initiated and rapidly develops. Inthis part of the chapter, we discuss how the different phases of an immuneresponse are orchestrated in space and time, how the response develops inboth strength and precision, how changes in specialized cell-surface mole-cules and chemokines guide effector lymphocytes to the appropriate site ofaction, and how these cells are regulated during the different stages.An innate immune response is an essential prerequisite to a primary adaptiveimmune response, because the co-stimulatory molecules induced on cells ofthe innate immune system during their interaction with microorganisms areessential for the activation of the antigen-specific lymphocytes (see Chapter9). Cells of the innate immune system hand on other important signals in theform of secreted cytokines that influence the characteristics of the adaptiveresponse and tailor it to the type of pathogen encountered. For this to hap-pen, cells from different locations must engage to coordinate the specificactivation of naive T cells and B cells, and the migration of cells to preciselocations within lymphoid tissues is thus critical for the coordination of anadaptive response.11-1 The course of an infection can be divided into several distinct phases.An infection can be broken down into various stages (see Fig. 2.5), but inChapters 2 and 3 we considered in detail only the responses of innate immu-nity. In this chapter, we return to the various stages of an infection but willnow integrate the adaptive immune response into the picture.In the first stage of infection with a pathogen, a new host is exposed to infec-tious particles either shed by an infected individual or present in the environ-ment. The numbers, route, mode of transmission, and stability of an infectiousagent outside the host determine its infectivity. Some pathogens, such as theanthrax bacterium, are spread by spores that are highly resistant to heat anddrying, whereas others, such as the human immunodeficiency virus (HIV),are spread only by the exchange of bodily fluids or tissues because they areunable to survive as infectious agents outside the body.The first contact with a new host occurs through an epithelial surface, suchas the skin or the mucosal surfaces of the respiratory, gastrointestinal, orurogenital tracts. As most pathogens gain entry to the body through mucosalsurfaces, the immune responses that occur in this specialized compartmentof the immune system are of great importance and are considered in detail inChapter 12. After making contact, an infectious agent must establish a focusof infection. It must either adhere to the epithelial surface and colonize it,or penetrate it to replicate in the tissues (Fig 11.2, first two panels). Wounds

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T"1 cells protect RAG2-deficient mice, butmice lacking the IL-12 p40 subunit showprogressive growth of the parasite

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Dendritic cells expressing high levelsof B7 as a result of infection canactivate naive CD8 T cells

Cytokines IL-12 and IL-18 made by dendriticcells can induce bystander CD8 T cells toproduce IFN"'Y

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After smallpox vaccination, antibody levelsshow no significant decline, and T-cellmemory shows a half-life of 8-15 years

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Fig. 11.17 Antiviral immunity aftersmallpox vaccination is long lived.

Because smallpox has been eradicated,recall responses measured in peoplewho were vaccinated for smallpox canbe taken to represent true memory in theabsence of reinfection. After smallpoxvaccination, antibody levels show an earlypeak with a period of rapid decay, whichis followed by long-term maintenance thatshows no significant decay. CD4 and CD8T-cell memory is long-lived but graduallydecays, with a half-life in the range8-15 years.

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Many effector cellsare short lived anddie by apoptosis

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Memory CDS T cells are allowed to developin mice infected with LCMV

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Same individual at 20 years infected with anew variant influenza virus makes antibodyonly against epitopes shared with originalvirus, not against epitopes shared with thevariant encountered at age 5 years

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A B C D E F GResponse to epitope