《Kuby免疫学》新章解析：免疫系统精要与适应性/先天性防御

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《库比免疫学》是一本深受实验背景启发的免疫学教材，经过全面更新后，它引入了全新的"先天免疫"章节，探讨了免疫反应在时间和空间中的动态变化，并增加了许多聚焦框，强调了临床、进化和实验领域的关联，使理论内容更加生动和实际。本书的核心内容围绕免疫系统的复杂性和多样性展开。第一部分，"历史视角"回顾了免疫学的发展历程，介绍了免疫系统从古代生物防御机制逐渐演化成现代生物学的核心组成部分的过程。这一章节为理解当前免疫学理论提供了历史背景。 "先天免疫"章节是新添加的内容，这部分着重讲解了人体最初的非特异性防御机制，如物理屏障、吞噬细胞（如巨噬细胞）和炎症反应，它们在抵抗外来病原体入侵中起着至关重要的作用。这些非特异性防御是适应性免疫应答的基础，它们在免疫系统的早期阶段提供即时保护。 "适应性免疫"则是书中核心内容之一，介绍了B细胞和T细胞的分化、发育以及它们如何通过免疫记忆形成针对特定抗原的特异性反应。这部分涵盖了T淋巴细胞与单个巨噬细胞的众多互动，展示了免疫网络中细胞间的精细协作。 "比较免疫"章节探讨了不同物种间免疫系统的异同，这对于理解人类免疫系统的进化和疾病的发生具有重要意义。通过对不同生物的免疫系统进行比较，可以揭示出普遍规律和物种特有的适应策略。 "免疫功能失调及其后果"章节深入剖析了免疫系统失调可能导致的各种疾病，包括自身免疫疾病、免疫缺陷病以及肿瘤等。这部分内容强调了免疫系统的动态平衡在健康和疾病状态中的关键作用。《库比免疫学》以其详实的内容和新颖的视角，为读者呈现了一个高度灵活且复杂的免疫防御体系，涵盖了从识别到响应的免疫过程，以及其在个体和生态系统层面的深远影响。这本书不仅适合专业研究者，也是医学、生物学等领域的学生和教师的重要参考资源。

primary response; a later contact of the host with antigen

will induce a more rapid and heightened secondary re-

sponse. The amplified population of memory cells accounts

for the rapidity and intensity that distinguishes a secondary

response from the primary response.

In the humoral branch of the immune system, antigen in-

duces the clonal proliferation of B lymphocytes into anti-

body-secreting plasma cells and memory B cells. As seen in

Figure 1-11a, the primary response has a lag of approxi-

mately 5–7 days before antibody levels start to rise. This lag is

the time required for activation of naive B cells by antigen

and T

cells and for the subsequent proliferation and differ-

entiation of the activated B cells into plasma cells. Antibody

levels peak in the primary response at about day 14 and then

begin to drop off as the plasma cells begin to die. In the

secondary response, the lag is much shorter (only 1–2 days),

antibody levels are much higher, and they are sustained for

much longer. The secondary response reflects the activity

of the clonally expanded population of memory B cells.

These memory cells respond to the antigen more rapidly

than naive B cells; in addition, because there are many

more memory cells than there were naive B cells for the

primary response, more plasma cells are generated in the

secondary response, and antibody levels are consequently

100- to 1000-fold higher.

In the cell-mediated branch of the immune system, the

recognition of an antigen-MHC complex by a specific ma-

ture T lymphocyte induces clonal proliferation into various

T cells with effector functions (T

cells and CTLs) and into

memory T cells. The cell-mediated response to a skin graft is

illustrated in Figure 1-11b by a hypothetical transplantation

experiment. When skin from strain C mice is grafted onto

strain A mice, a primary response develops and all the grafts

are rejected in about 10–14 days. If these same mice are again

grafted with strain C skin, it is rejected much more vigor-

ously and rapidly than the first grafts. However, if animals

previously engrafted with strain C skin are next given skin

from an unrelated strain, strain B, the response to strain B is

typical of the primary response and is rejected in 10–14 days.

That is, graft rejection is a specific immune response. The

same mice that showed a secondary response to graft C will

show a primary response to graft B. The increased speed of

rejection of graft C reflects the presence of a clonally ex-

panded population of memory T

and T

cells specific for

the antigens of the foreign graft. This expanded memory

population generates more effector cells, resulting in faster

graft rejection.

The Innate and Adaptive Immune Systems

Collaborate, Increasing the Efficiency of

Immune Responsiveness

It is important to appreciate that adaptive and innate immu-

nity do not operate independently—they function as a highly

interactive and cooperative system, producing a combined

response more effective than either branch could produce by

itself. Certain immune components play important roles in

both types of immunity.

An example of cooperation is seen in the encounter

between macrophages and microbes. Interactions between

receptors on macrophages and microbial components gen-

erate soluble proteins that stimulate and direct adaptive im-

mune responses, facilitating the participation of the adap-

PART I

Introduction

Strain C

graft

repeated

Strain B

graft

Antigen A

Serum antibody level

Antigen A

+ Antigen B

Primary anti-A

response

Secondary

anti-A

response

Primary

anti-B

response

014

Time, days

(a)

140

Percentage of mice rejecting graft

Strain C

graft

Time, days

(b)

012

100

816

012816

FIGURE 1-11 Differences in the primary and secondary response

to injected antigen (humoral response) and to a skin graft (cell-me-

diated response) reflect the phenomenon of immunologic memory.

(a) When an animal is injected with an antigen, it produces a primary

serum antibody response of low magnitude and short duration,

peaking at about 10–17 days. A second immunization with the same

antigen results in a secondary response that is greater in magnitude,

peaks in less time (2–7 days), and lasts longer (months to years)

than the primary response. Compare the secondary response to anti-

gen A with the primary response to antigen B administered to the

same mice. (b) Results from a hypothetical experiment in which skin

grafts from strain C mice are transplanted to 20 mice of strain A; the

grafts are rejected in about 10–14 days. The 20 mice are rested for 2

months and then 10 are given strain C grafts and the other 10 are

given skin from strain B. Mice previously exposed to strain C skin re-

ject C grafts much more vigorously and rapidly than the grafts from

strain B. Note that the rejection of the B graft follows a time course

similar to that of the first strain C graft.

8536d_ch01_001-023 8/1/02 4:25 PM Page 16 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:

tive immune system in the elimination of the pathogen.

Stimulated macrophages also secrete cytokines that can

direct adaptive immune responses against particular intra-

cellular pathogens.

Just as important, the adaptive immune system produces

signals and components that stimulate and increase the ef-

fectiveness of innate responses. Some T cells, when they en-

counter appropriately presented antigen, synthesize and

secrete cytokines that increase the ability of macrophages to

kill the microbes they have ingested. Also, antibodies pro-

duced against an invader bind to the pathogen, marking it as

a target for attack by complement and serving as a potent ac-

tivator of the attack.

A major difference between adaptive and innate immu-

nity is the rapidity of the innate immune response, which uti-

lizes a pre-existing but limited repertoire of responding

components. Adaptive immunity compensates for its slower

onset by its ability to recognize a much wider repertoire of

foreign substances, and also by its ability to improve during a

response, whereas innate immunity remains constant. It may

also be noted that secondary adaptive responses are consid-

erably faster than primary responses. Principle characteris-

tics of the innate and adaptive immune systems are

compared in Table 1-3. With overlapping roles, the two sys-

tems together form a highly effective barrier to infection.

Comparative Immunity

The field of immunology is concerned mostly with how in-

nate and adaptive mechanisms collaborate to protect verte-

brates from infection.Although many cellular and molecular

actors have important roles, antibodies and lymphocytes are

considered to be the principal players. Yet despite their

prominence in vertebrate immune systems, it would be a

mistake to conclude that these extraordinary molecules and

versatile cells are essential for immunity. In fact, a deter-

mined search for antibodies, T cells, and B cells in organisms

of the nonvertebrate phyla has failed to find them. The inte-

rior spaces of organisms as diverse as fruit flies, cockroaches,

and plants do not contain unchecked microbial populations,

however, which implies that some sort of immunity exists in

most, possibly all, multicellular organisms, including those

with no components of adaptive immunity.

Insects and plants provide particularly clear and dramatic

examples of innate immunity that is not based on lympho-

cytes. The invasion of the interior body cavity of the fruit fly,

Drosophila melanogaster, by bacteria or molds triggers the

synthesis of small peptides that have strong antibacterial or

antifungal activity. The effectiveness of these antimicrobial

peptides is demonstrated by the fate of mutants that are un-

able to produce them. For example, a fungal infection over-

whelms a mutant fruit fly that is unable to trigger the

synthesis of drosomycin, an antifungal peptide (Figure

1-12). Further evidence for immunity in the fruit fly is given

by the recent findings that cell receptors recognizing various

classes of microbial molecules (the toll-like receptors) were

first found in Drosophila.

Plants respond to infection by producing a wide variety

of antimicrobial proteins and peptides, as well as small

Overview of the Immune System

CHAPTER

1 17

TABLE 1-3

Comparison of adaptive and

innate immunity

Innate Adaptive

Response time Hours Days

Specificity Limited and Highly diverse, improves

fixed during the course of

immune response

Response to Identical to Much more rapid than

repeat primary primary response

infection response

FIGURE 1-12 Severe fungal infection in a fruit fly (Drosophila

melanogaster) with a disabling mutation in a signal-transduction

pathway required for the synthesis of the antifungal peptide dro-

somycin. [From B. Lemaitre et al., 1996, Cell 86:973; courtesy of J. A.

Hoffman, University of Strasbourg.]

8536d_ch01_001-023 8/1/02 4:25 PM Page 17 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:

nonpeptide organic molecules that have antibiotic activity.

Among these agents are enzymes that digest microbial cell

walls, peptides and a protein that damages microbial mem-

branes, and the small organic molecules phytoalexins. The

importance of the phytoalexins is shown by the fact that mu-

tations that alter their biosynthetic pathways result in loss of

resistance to many plant pathogens. In some cases, the re-

sponse of plants to pathogens goes beyond this chemical as-

sault to include an architectural response, in which the plant

isolates cells in the infected area by strengthening the walls of

surrounding cells. Table 1-4 compares the capabilities of im-

mune systems in a wide range of multicellular organisms,

both animals and plants.

Immune Dysfunction and

Its Consequences

The above overview of innate and adaptive immunity depicts

a multicomponent interactive system that protects the host

from infectious diseases and from cancer. This overview

would not be complete without mentioning that the immune

system can function improperly. Sometimes the immune sys-

tem fails to protect the host adequately or misdirects its ac-

tivities to cause discomfort, debilitating disease, or even

death. There are several common manifestations of immune

dysfunction:

■

Allergy and asthma

■

Graft rejection and graft-versus-host disease

■

Autoimmune disease

■

Immunodeficiency

Allergy and asthma are results of inappropriate immune re-

sponses, often to common antigens such as plant pollen,

food, or animal dander. The possibility that certain sub-

stances increased sensitivity rather than protection was rec-

ognized in about 1902 by Charles Richet, who attempted to

immunize dogs against the toxins of a type of jellyfish,

Physalia. He and his colleague Paul Portier observed that

dogs exposed to sublethal doses of the toxin reacted almost

instantly, and fatally, to subsequent challenge with minute

amounts of the toxin. Richet concluded that a successful im-

munization or vaccination results in phylaxis, or protection,

and that an opposite result may occur—anaphylaxis—in

which exposure to antigen can result in a potentially lethal

sensitivity to the antigen if the exposure is repeated. Richet

received the Nobel Prize in 1913 for his discovery of the ana-

phylactic response.

Fortunately, most allergic reactions in humans are not

rapidly fatal. A specific allergic or anaphylactic response usu-

ally involves one antibody type, called IgE. Binding of IgE to

its specific antigen (allergen) releases substances that cause

irritation and inflammation. When an allergic individual is

exposed to an allergen, symptoms may include sneezing,

wheezing, and difficulty in breathing (asthma); dermatitis or

skin eruptions (hives); and, in more extreme cases, strangu-

lation due to blockage of airways by inflammation. A signifi-

cant fraction of our health resources is expended to care for

those suffering from allergy and asthma. The frequency of

allergy and asthma in the United States place these com-

plaints among the most common reasons for a visit to the

doctor’s office or to the hospital emergency room (see Clini-

cal Focus).

When the immune system encounters foreign cells or tis-

sue, it responds strongly to rid the host of the invaders. How-

ever, in some cases, the transplantation of cells or an organ

from another individual, although viewed by the immune

system as a foreign invasion, may be the only possible treat-

ment for disease. For example, it is estimated that more than

60,000 persons in the United States alone could benefit from

a kidney transplant. Because the immune system will attack

and reject any transplanted organ that it does not recognize

as self, it is a serious barrier to this potentially life-saving

treatment. An additional danger in transplantation is that

any transplanted cells with immune function may view the

new host as nonself and react against it. This reaction, which

is termed graft-versus-host disease, can be fatal. The rejec-

tion reaction and graft-versus-host disease can be suppressed

by drugs, but this type of treatment suppresses all immune

function, so that the host is no longer protected by its im-

mune system and becomes susceptible to infectious diseases.

Transplantation studies have played a major role in the de-

velopment of immunology. A Nobel prize was awarded to

Karl Landsteiner, in 1930, for the discovery of human blood

groups, a finding that allowed blood transfusions to be car-

ried out safely. In 1980, G. Snell, J. Dausset, and B. Benacerraf

were recognized for discovery of the major histocompatibil-

ity complex, and, in 1991, E. D. Thomas and J. Murray were

awarded Nobel Prizes for advances in transplantation immu-

nity. To enable a foreign organ to be accepted without sup-

pressing immunity to all antigens remains a challenge for

immunologists today.

In certain individuals, the immune system malfunctions

by losing its sense of self and nonself, which permits an im-

mune attack upon the host. This condition, autoimmunity,

can cause a number of chronic debilitating diseases. The

symptoms of autoimmunity differ depending on which

tissues and organs are under attack. For example, multiple

sclerosis is due to an autoimmune attack on the brain and

central nervous system, Crohn’s disease is an attack on the

tissues in the gut, and rheumatoid arthritis is an attack on

joints of the arms and legs. The genetic and environmental

factors that trigger and sustain autoimmune disease are very

active areas of immunologic research, as is the search for im-

proved treatments.

If any of the many components of innate or specific im-

munity is defective because of genetic abnormality, or if any

immune function is lost because of damage by chemical,

physical, or biological agents, the host suffers from immu-

nodeficiency. The severity of the immunodeficiency disease

PART I

Introduction

8536d_ch01_001-023 8/1/02 4:26 PM Page 18 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:

Overview of the Immune System

CHAPTER

1 19

TABLE 1-4 Immunity in multicellular organisms

Invasion-

induced

protective

Innate Adaptive enzymes Pattern-

immunity immunity and enzyme Antimicrobial recognition Graft T and B

Taxonomic group (nonspecific) (specific) cascades Phagocytosis peptides receptors rejection cells Antibodies

Higher plants    

Invertebrate animals

Porifera ?  ?? 

(sponges)

Annelids ?  ?? 

(earthworms)

Arthropods    ? 

(insects,

crustaceans)

Vertebrate animals

Elasmobranchs  equivalent 

(cartilaginous agents

fish; e.g.,

sharks, rays)

Teleost fish and  probable 

bony fish (e.g.,

salmon, tuna)

Amphibians    

Reptiles   ? 

Birds   ? 

Mammals    

KEY: definitive demonstration; failure to demonstrate thus far; ?  presence or absence remains to be established.

SOURCES: L. Du Pasquier and M. Flajnik, 1999, “Origin and Evolution of the Vertebrate Immune System,” in Fundamental Immunology, 4th ed.

W. E. Paul (ed.), Lippincott, Philadelphia; B. Fritig, T. Heitz, and M. Legrand, 1998, Curr. Opin. Immunol. 10:16; K. Soderhall and L. Cerenius,

1998, Curr. Opin. Immunol. 10:23.

lems. Details of the mechanisms that un-

derlie allergic and asthmatic responses

to environmental antigens (or allergens)

will be considered in Chapter 16. Simply

stated, allergic reactions are responses

to antigenic stimuli that result in immu-

nity based mainly on the IgE class of im-

munoglobulin. Exposure to the antigen

(or allergen) triggers an IgE-mediated re-

lease of molecules that cause symptoms

ranging from sneezing and dermatitis to

inflammation of the lungs in an asth-

matic attack. The sequence of events in

an allergic response is depicted in the ac-

companying figure.

The discomfort from common aller-

gies such as plant pollen allergy (often

called ragweed allergy) consists of a

week or two of sneezing and runny nose,

which may seem trivial compared with

health problems such as cancer, cardiac

arrest, or life-threatening infections. A

more serious allergic reaction is asthma,

Although the im-

mune system serves to protect the host

from infection and cancer, inappropriate

responses of this system can lead to

disease. Common among the results of

immune dysfunction are allergies and

asthma, both serious public health prob-

CLINICAL FOCUS

Allergy and Asthma as Serious

Public Health Problems

(continued)

8536d_ch01_001-023 8/1/02 4:26 PM Page 19 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e:

PART I

Introduction

a chronic disease of the lungs in which

inflammation, mediated by environmen-

tal antigens or infections, causes severe

difficulty in breathing. Approximately 15

million persons in the United States suf-

fer from asthma, and it causes about

5000 deaths per year. In the past twenty

years, the prevalence of asthma in the

Western World has doubled.*

Data on the frequency of care sought

for the most common medical com-

plaints in the United States show that

asthma and allergy together resulted in

more than 28 million visits to the doctor

in 1995. The importance of allergy as a

public health problem is underscored by

the fact that the annual number of doctor

visits for hypertension, routine medical

examinations, or normal pregnancy, are

each fewer than the number of visits for

allergic conditions. In fact, the most

common reason for a visit to a hospital

emergency room is an asthma attack, ac-

counting for one third of all visits. In ad-

dition to those treated in the ER, there

were about 160,000 hospitalizations for

asthma in the past year, with an average

stay of 3 to 4 days.

Although all ages and races are af-

fected, deaths from asthma are 3.5 times

more common among African-American

children. The reasons for the increases in

number of asthma cases and for the

higher death rate in African-American chil-

dren remain unknown, although some

clues may have been uncovered by recent

CLINICAL FOCUS (continued)

Allergy and Asthma as Serious

Public Health Problems

Sequence of events leading to an allergic

response. When the antibody produced

upon contact with an allergen is IgE, this

class of antibody reacts via its constant

region with a mast cell. Subsequent reac-

tion of the antibody binding site with the

allergen triggers the mast cell to which

the IgE is bound to secrete molecules

that cause the allergic symptoms.

Plasma cell

B cell

IgE

Production of

large amounts

of ragweed IgE

antibody

First contact

with an allergen (ragweed)

Subsequent contact

with allergen

IgE molecules

attach to mast

cells

IgE-primed mast

cell releases

molecules that

cause wheezing,

sneezing, runny nose,

watery eyes, and

other symptoms

Ragweed

pollen

Mast cell

studies of genetic factors in allergic dis-

ease (see Clinical Focus in Chapter 16).

An increasingly serious health prob-

lem is food allergy, especially to peanuts

and tree nuts (almonds, cashews, and

walnuts).

†

Approximately 3 million

Americans are allergic to these foods

and they are the leading causes of fatal

and near-fatal food allergic (anaphylac-

tic) reactions. While avoidance of these

foods can prevent harmful conse-

quences, the ubiquitous use of peanut

protein and other nut products in a vari-

ety of foods makes this very difficult for

the allergic individual. At least 50% of se-

rious reactions are caused by accidental

exposures to peanuts, tree nuts, or their

products. This has led to controversial

movements to ban peanuts from

schools and airplanes.

Anaphylaxis generally occurs within

an hour of ingesting the food allergen

and the most effective treatment is injec-

tion of the drug epinephrine. Those

prone to anaphylactic attacks often carry

injectable epinephrine to be used in case

of exposure.

In addition to the suffering and anxi-

ety caused by inappropriate immune re-

sponses or allergies to environmental

antigens, there is a staggering cost in

terms of lost work time for those affected

and for caregivers. These costs well justify

the extensive efforts by basic and clinical

immunologists and allergists to relieve

the suffering caused by these disorders.

†

Hughes, D. A., and C. Mills. 2001. Food allergy:

A problem on the rise. Biologist (London) 48:201.

depends on the number of affected components. A common

type of immunodeficiency in North America is a selective

immunodeficiency in which only one type of immunoglob-

ulin, IgA, is lacking; the symptoms may be minor or even go

unnoticed. In contrast, a rarer immunodeficiency called

severe combined immunodeficiency (SCID), which affects

both B and T cells, if untreated, results in death from infec-

tion at an early age. Since the 1980s, the most common form

of immunodeficiency has been acquired immune deficiency

syndrome, or AIDS, which results from infection with the

*Holgate, S. T. 1999. The epidemic of allergy and

asthma, Nature Supp. to vol. 402, B2.

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