Elitedocs
Elitedocs
, Cellular Molecular
and
Immunology
SEVENTH EDITION
Abul K. Abbas, MBBS
Elitedocs
Distinguished Professor in Pathology
Chair, Department of Pathology
University of California San Francisco
San Francisco, California
Andrew H. Lichtman, MD, PhD
Professor of Pathology
Harvard Medical School
Brigham and Women’s Hospital
Boston, Massachusetts
Shiv Pillai, MBBS, PhD
Professor of Medicine and Health Sciences and Technology
Harvard Medical School
Massachusetts General Hospital
Boston, Massachusetts
Illustrations by
David L. Baker, MA
Alexandra Baker, MS, CMI
DNA Illustrations, Inc.
Elitedocs
, CHAPTER
11
B Cell Activation and Antibody Production
Humoral immunity is mediated by secreted antibodies,
GENERAL FEATURES OF HUMORAL IMMUNE RESPONSES, 243 which are produced by cells of the B lymphocyte lineage.
Two types of microbial antigens can induce robust anti-
ANTIGEN RECOGNITION AND ANTIGEN-INDUCED B CELL body responses. First, multivalent antigens of microbial
ACTIVATION, 245 origin can activate B cells through the B cell receptor
Elitedocs
Antigen Capture and Delivery to B Cells, 245 (BCR), often accompanied by signals provided by engage-
ment of pattern recognition receptors on B cells by
Activation of B Cells by Antigens and Other Signals, 247
microbial products, but without T cell help. Second,
Functional Responses of B Cells to Antigens, 248 microbial protein antigens can be presented by B cells to
HELPER T CELL–DEPENDENT ANTIBODY RESPONSES TO helper T cells, resulting in T-dependent responses in
PROTEIN ANTIGENS, 250 which helper T cells drive B cell activation. In both cases,
antibodies are secreted and bind to the antigens of extra-
The Sequence of Events During T Cell–Dependent Antibody cellular bacteria, viruses, and other microbes and func-
Responses, 250 tion to neutralize and eliminate these pathogens. The
Initial Activation and Migration of Helper T Cells and B Cells, 251 elimination of different types of microbes requires several
Antigen Presentation by B Cells and the Hapten-Carrier effector mechanisms that are mediated by distinct anti-
Effect, 251 body isotypes. In general, antibodies produced with help
Role of CD40L:CD40 Interaction in T-Dependent B Cell from T cells bind more tightly to antigens and serve more
Activation, 252 diverse functions than antibodies produced without T cell
Extrafollicular B Cell Activation, 254 help, and this is why antibodies against protein antigens
(the stimulators of T cells) are the most effective media-
The Germinal Center B Cell Reaction and the Function of Follicular
tors of humoral immunity. This chapter describes the
Helper T Cells, 254
molecular and cellular events of the humoral immune
Heavy Chain Isotype (Class) Switching, 256 response, in particular the stimuli that induce B cell
Affinity Maturation: Somatic Mutation of Ig Genes and Selection of proliferation and differentiation and how these stimuli
High-Affinity B Cells, 259 influence the type of antibody that is produced. The
B Cell Differentiation into Antibody-Secreting Plasma Cells, 263 mechanisms by which antibodies eliminate microbes are
Generation of Memory B Cells and Secondary Humoral Immune described in Chapter 12.
Responses, 264
Role of Transcriptional Regulators in Determining the Fate of GENERAL FEATURES OF HUMORAL
Activated B Cells, 264
IMMUNE RESPONSES
ANTIBODY RESPONSES TO T CELL–INDEPENDENT
ANTIGENS, 265 The earliest studies of adaptive immunity were devoted
to analyses of serum antibodies produced in response to
Nature of B Cells That Respond to T-Independent Antigens, 265
microbes, toxins, and model antigens. Much of our
Mechanisms of T-Independent Antibody Responses, 265 current understanding of adaptive immune responses
Functions of T-Independent Antibody Responses, 266 and the cellular interactions that take place during such
responses has evolved from studies of antibody produc-
ANTIBODY FEEDBACK: REGULATION OF HUMORAL IMMUNE
tion. We begin with a summary of some of the key fea-
RESPONSES BY Fc RECEPTORS, 266
tures of B cell activation and antibody production.
SUMMARY, 267
l The activation of B cells results in their prolifera-
tion, leading to clonal expansion, followed by
243
Elitedocs
, 244 Chapter 11 – B Cell Activation and Antibody Production
Recognition Activation phase: B cell
phase proliferation and differentiation
Plasma IgM
cell Antibody
Helper T cells,
other stimuli
Clonal secretion
expansion
IgG-expressing IgG
B cell
+ Isotype
switching
Antigen
Resting Activated
IgM+, IgD+ B cell
mature B cell Affinity
maturation
High-affinity Ig- High-
expressing B cell affinity IgG
Memory
B cell
Elitedocs
FIGURE 11–1 Phases of the humoral immune response. The activation of B cells is initiated by specific recognition of antigens by the
surface Ig receptors of the cells. Antigen and other stimuli, including helper T cells, stimulate the proliferation and differentiation of the specific B cell
clone. Progeny of the clone may produce IgM or other Ig isotypes (e.g., IgG), may undergo affinity maturation, or may persist as memory cells.
differentiation, culminating in the generation of by B cells and that a peptide fragment of the internal-
memory B cells and antibody-secreting plasma cells ized protein be presented to CD4+ helper T lymphocytes
(Fig. 11-1). As we discussed in Chapter 8, mature that then activate these B cells. For this reason, pro-
antigen-responsive B lymphocytes develop from bone teins are classified as thymus-dependent or T-dependent
marrow precursors before antigenic stimulation and antigens. The term helper T lymphocyte arose from the
populate peripheral lymphoid tissues, which are the realization that these cells stimulate, or help, B lym-
sites where lymphocytes interact with foreign anti- phocytes to produce antibodies. A specialized type of
gens. Humoral immune responses are initiated by the helper T cell, called a follicular helper T cell, facilitates
recognition of antigens by specific B lymphocytes. the formation of germinal centers, which are special-
Antigen binds to membrane IgM and IgD on mature, ized structures in lymphoid organs generated during
naive B cells and activates these cells. Activation leads T-dependent humoral immune responses.
to proliferation of antigen-specific cells and their dif- l Antibody responses to multivalent nonprotein antigens
ferentiation, generating memory B cells and antibody- with repeating determinants, such as polysaccharides,
secreting plasma cells. A single B cell may, within a some lipids, and nucleic acids, do not require antigen-
week, give rise to as many as 5000 antibody-secreting specific helper T lymphocytes. Multivalent antigens (so
cells, which produce more than 1012 antibody mole- called because each antigen molecule contains multi-
cules per day. This tremendous expansion is needed to ple identical epitopes) are therefore called thymus-
keep pace with rapidly dividing microbes. Some acti- independent or T-independent antigens. These
vated B cells begin to produce antibodies other than responses are elicited by engagement of the BCR and
IgM and IgD; this process is called heavy chain isotype may be enhanced by the triggering of pattern recogni-
(class) switching. As a humoral immune response tion receptors on B cells and myeloid cells and by
develops, activated B cells that produce antibodies that cytokines.
bind to antigens with increasing affinity progressively l Some of the progeny of activated B cells are long-lived
dominate the response; this process is called affinity antibody-secreting plasma cells, which continue to
maturation. produce antibodies for months or years, and others
l The type and amount of antibodies produced vary are long-lived memory cells. Humoral immune
according to the type of antigen driving the immune responses are initiated in peripheral lymphoid organs,
response, the involvement of T cells, a prior history of such as the spleen for blood-borne antigens, draining
antigen exposure, and the anatomic site at which acti- lymph nodes for antigens entering through the skin
vation occurs. The influence of these factors on the and other epithelia, and mucosal lymphoid tissues for
humoral immune response is summarized later and some inhaled and ingested antigens. Antibodies pro-
discussed throughout the chapter. duced at these sites enter the circulation or are trans-
l Antibody responses to protein antigens require that ported into the lumens of mucosal organs and mediate
the antigen be specifically recognized and internalized their protective effects wherever antigens are present.
Elitedocs
Elitedocs
, Cellular Molecular
and
Immunology
SEVENTH EDITION
Abul K. Abbas, MBBS
Elitedocs
Distinguished Professor in Pathology
Chair, Department of Pathology
University of California San Francisco
San Francisco, California
Andrew H. Lichtman, MD, PhD
Professor of Pathology
Harvard Medical School
Brigham and Women’s Hospital
Boston, Massachusetts
Shiv Pillai, MBBS, PhD
Professor of Medicine and Health Sciences and Technology
Harvard Medical School
Massachusetts General Hospital
Boston, Massachusetts
Illustrations by
David L. Baker, MA
Alexandra Baker, MS, CMI
DNA Illustrations, Inc.
Elitedocs
, CHAPTER
11
B Cell Activation and Antibody Production
Humoral immunity is mediated by secreted antibodies,
GENERAL FEATURES OF HUMORAL IMMUNE RESPONSES, 243 which are produced by cells of the B lymphocyte lineage.
Two types of microbial antigens can induce robust anti-
ANTIGEN RECOGNITION AND ANTIGEN-INDUCED B CELL body responses. First, multivalent antigens of microbial
ACTIVATION, 245 origin can activate B cells through the B cell receptor
Elitedocs
Antigen Capture and Delivery to B Cells, 245 (BCR), often accompanied by signals provided by engage-
ment of pattern recognition receptors on B cells by
Activation of B Cells by Antigens and Other Signals, 247
microbial products, but without T cell help. Second,
Functional Responses of B Cells to Antigens, 248 microbial protein antigens can be presented by B cells to
HELPER T CELL–DEPENDENT ANTIBODY RESPONSES TO helper T cells, resulting in T-dependent responses in
PROTEIN ANTIGENS, 250 which helper T cells drive B cell activation. In both cases,
antibodies are secreted and bind to the antigens of extra-
The Sequence of Events During T Cell–Dependent Antibody cellular bacteria, viruses, and other microbes and func-
Responses, 250 tion to neutralize and eliminate these pathogens. The
Initial Activation and Migration of Helper T Cells and B Cells, 251 elimination of different types of microbes requires several
Antigen Presentation by B Cells and the Hapten-Carrier effector mechanisms that are mediated by distinct anti-
Effect, 251 body isotypes. In general, antibodies produced with help
Role of CD40L:CD40 Interaction in T-Dependent B Cell from T cells bind more tightly to antigens and serve more
Activation, 252 diverse functions than antibodies produced without T cell
Extrafollicular B Cell Activation, 254 help, and this is why antibodies against protein antigens
(the stimulators of T cells) are the most effective media-
The Germinal Center B Cell Reaction and the Function of Follicular
tors of humoral immunity. This chapter describes the
Helper T Cells, 254
molecular and cellular events of the humoral immune
Heavy Chain Isotype (Class) Switching, 256 response, in particular the stimuli that induce B cell
Affinity Maturation: Somatic Mutation of Ig Genes and Selection of proliferation and differentiation and how these stimuli
High-Affinity B Cells, 259 influence the type of antibody that is produced. The
B Cell Differentiation into Antibody-Secreting Plasma Cells, 263 mechanisms by which antibodies eliminate microbes are
Generation of Memory B Cells and Secondary Humoral Immune described in Chapter 12.
Responses, 264
Role of Transcriptional Regulators in Determining the Fate of GENERAL FEATURES OF HUMORAL
Activated B Cells, 264
IMMUNE RESPONSES
ANTIBODY RESPONSES TO T CELL–INDEPENDENT
ANTIGENS, 265 The earliest studies of adaptive immunity were devoted
to analyses of serum antibodies produced in response to
Nature of B Cells That Respond to T-Independent Antigens, 265
microbes, toxins, and model antigens. Much of our
Mechanisms of T-Independent Antibody Responses, 265 current understanding of adaptive immune responses
Functions of T-Independent Antibody Responses, 266 and the cellular interactions that take place during such
responses has evolved from studies of antibody produc-
ANTIBODY FEEDBACK: REGULATION OF HUMORAL IMMUNE
tion. We begin with a summary of some of the key fea-
RESPONSES BY Fc RECEPTORS, 266
tures of B cell activation and antibody production.
SUMMARY, 267
l The activation of B cells results in their prolifera-
tion, leading to clonal expansion, followed by
243
Elitedocs
, 244 Chapter 11 – B Cell Activation and Antibody Production
Recognition Activation phase: B cell
phase proliferation and differentiation
Plasma IgM
cell Antibody
Helper T cells,
other stimuli
Clonal secretion
expansion
IgG-expressing IgG
B cell
+ Isotype
switching
Antigen
Resting Activated
IgM+, IgD+ B cell
mature B cell Affinity
maturation
High-affinity Ig- High-
expressing B cell affinity IgG
Memory
B cell
Elitedocs
FIGURE 11–1 Phases of the humoral immune response. The activation of B cells is initiated by specific recognition of antigens by the
surface Ig receptors of the cells. Antigen and other stimuli, including helper T cells, stimulate the proliferation and differentiation of the specific B cell
clone. Progeny of the clone may produce IgM or other Ig isotypes (e.g., IgG), may undergo affinity maturation, or may persist as memory cells.
differentiation, culminating in the generation of by B cells and that a peptide fragment of the internal-
memory B cells and antibody-secreting plasma cells ized protein be presented to CD4+ helper T lymphocytes
(Fig. 11-1). As we discussed in Chapter 8, mature that then activate these B cells. For this reason, pro-
antigen-responsive B lymphocytes develop from bone teins are classified as thymus-dependent or T-dependent
marrow precursors before antigenic stimulation and antigens. The term helper T lymphocyte arose from the
populate peripheral lymphoid tissues, which are the realization that these cells stimulate, or help, B lym-
sites where lymphocytes interact with foreign anti- phocytes to produce antibodies. A specialized type of
gens. Humoral immune responses are initiated by the helper T cell, called a follicular helper T cell, facilitates
recognition of antigens by specific B lymphocytes. the formation of germinal centers, which are special-
Antigen binds to membrane IgM and IgD on mature, ized structures in lymphoid organs generated during
naive B cells and activates these cells. Activation leads T-dependent humoral immune responses.
to proliferation of antigen-specific cells and their dif- l Antibody responses to multivalent nonprotein antigens
ferentiation, generating memory B cells and antibody- with repeating determinants, such as polysaccharides,
secreting plasma cells. A single B cell may, within a some lipids, and nucleic acids, do not require antigen-
week, give rise to as many as 5000 antibody-secreting specific helper T lymphocytes. Multivalent antigens (so
cells, which produce more than 1012 antibody mole- called because each antigen molecule contains multi-
cules per day. This tremendous expansion is needed to ple identical epitopes) are therefore called thymus-
keep pace with rapidly dividing microbes. Some acti- independent or T-independent antigens. These
vated B cells begin to produce antibodies other than responses are elicited by engagement of the BCR and
IgM and IgD; this process is called heavy chain isotype may be enhanced by the triggering of pattern recogni-
(class) switching. As a humoral immune response tion receptors on B cells and myeloid cells and by
develops, activated B cells that produce antibodies that cytokines.
bind to antigens with increasing affinity progressively l Some of the progeny of activated B cells are long-lived
dominate the response; this process is called affinity antibody-secreting plasma cells, which continue to
maturation. produce antibodies for months or years, and others
l The type and amount of antibodies produced vary are long-lived memory cells. Humoral immune
according to the type of antigen driving the immune responses are initiated in peripheral lymphoid organs,
response, the involvement of T cells, a prior history of such as the spleen for blood-borne antigens, draining
antigen exposure, and the anatomic site at which acti- lymph nodes for antigens entering through the skin
vation occurs. The influence of these factors on the and other epithelia, and mucosal lymphoid tissues for
humoral immune response is summarized later and some inhaled and ingested antigens. Antibodies pro-
discussed throughout the chapter. duced at these sites enter the circulation or are trans-
l Antibody responses to protein antigens require that ported into the lumens of mucosal organs and mediate
the antigen be specifically recognized and internalized their protective effects wherever antigens are present.
Elitedocs
