Transcript B Cell Activation and Antibody Production

Chapter 12
B Cell Activation
and
Antibody Production
•
Humoral immunity is mediated by secreted antibodies, which are produced by
cells of the B lymphocyte lineage
•
Two types of microbial antigens can induce robust antibody responses:
– First, multivalent antigens of microbial origin can activate B cells through the B cell
receptor (BCR), often accompanied by signals provided by engagement of pattern
recognition receptors (PRR) on B cells by microbial products, but without T cell help (T
independent antigen)
– Second, microbial protein antigens can be presented by B cells to helper T cells,
resulting in T-dependent responses in which helper T cells drive B cell activation (T
dependent antigen)
Phases of the humoral immune response
General Feature of Humoral Immune Responses
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The type and amount of antibodies produced vary according to the: type of
antigen driving the immune response, the involvement of T cells, a prior history
of antigen exposure, and the anatomic site at which activation occurs
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Antibody responses to protein antigens require that the antigen be specifically
recognized and internalized by B cells and that a peptide fragment of the
internalized protein be presented to CD4+ helper T lymphocytes that then
activate these B cells
•
Antibody responses to multivalent non-protein antigens with repeating
determinants, such as polysaccharides, some lipids, and nucleic acids, do not
require antigen specific helper T lymphocytes (thymus independent or Tindependent antigens)
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Some of the progeny of activated B cells are long-lived antibody-secreting plasma
cells, which continue to produce antibodies for months or years, and others are
long-lived memory cells
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Heavy chain isotype switching and affinity maturation are typically seen in helper
T cell–dependent humoral immune responses to protein antigens (CD40 ligand
(CD40L) on the surface of activated helper T cells and cytokines Secreted and
CD40 on B cells
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Primary and secondary antibody responses to protein antigens differ
qualitatively and quantitatively
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Distinct subsets of B cells respond preferentially to different types of antigens
• ANTIGEN RECOGNITION AND ANTIGEN-INDUCED B CELL ACTIVATION
Antigen Recognition and Antigen-induced B Cell Activation
• Step 1. Antigen Capture and Delivery to B Cells:
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Mature B lymphocytes (Naive B cells) migrate from one secondary lymphoid
organ to the next in search of antigen
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Entry into the follicles is guided by the chemokine CXCL13 (binds to the CXCR5 on
naïve B cell) secreted by follicular dendritic cells (FDC) and other stromal cells in
the follicle
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Antigen may be delivered to naive B cells in lymphoid organs in different forms
and by multiple routes
Pathways of antigen delivery to follicular B cells
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Most antigens from tissue sites are transported to lymph nodes by afferent
lymphatic vessels that drain into the subcapsular sinus of the nodes. Soluble
antigens, generally smaller than 70 kD, may reach the B cell zone through
conduits that extend between the subcapsular sinus and the follicle and interact
directly with specific B cells
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Subcapsular sinus macrophages capture large microbes and antigen-antibody
complexes and deliver these to follicles, which lie under the sinus
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Many relatively large antigens that enter the node through afferent lymphatic
vessels are not captured by subcapsular sinus macrophages but are too large to
enter the conduits
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Antigens in immune complexes may bind to complement receptors (in particular
the complement receptor type 2 or CR2) on marginal zone B cells, and these cells
can transfer the immune complex–containing antigens to follicular B cells
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Antigen in immune complexes may also bind to CR2 on the surface of follicular
dendritic cells (FDC) and be presented to antigen-specific B cells
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Blood-borne pathogens may be captured by plasmacytoid dendritic cells in the
blood and transported to the spleen, where they may be delivered to marginal
zone B cells
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Polysaccharide antigens can be captured by macrophages in the marginal zone of
splenic lymphoid follicles and displayed or transferred to B cells in this area
Step 2. Activation of B Cells by Antigens and Other Signals
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The activation of antigen-specific B lymphocytes is initiated by the binding of
antigen to membrane Ig molecules, which, in conjunction with the associated Igα
and Igβ proteins, make up the antigen receptor complex of mature B cells
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B cell activation is facilitated by the CR2/CD21 coreceptor on B cells, which
recognizes complement fragments covalently attached to the antigen or that are
part of immune complexes containing the antigen
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Microbial products engage Toll-like receptors (TLR 5, 7) on B cells, which also
enhances B cell activation
Functional Responses of B Cells to Antigens
HELPER T CELL–DEPENDENT ANTIBODY RESPONSES
TO PROTEIN ANTIGENS
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Antibody responses to protein antigens require recognition and processing of the
antigen by B cells, followed by presentation of a peptide fragment of the antigen
to helper T cells, leading to cooperation between the antigen specific B and T
lymphocytes
Initial Activation and Migration of
Helper T Cells and B Cells
Role of CD40L:CD40 Interaction in T-Dependent B Cell Activation
Extrafollicular B Cell Activation
The Germinal Center B Cell Reaction and the Function of
Follicular Helper T Cells
Molecular events in follicular helper T cell generation
T follicular helper cell
Follicular Dendritic Cells (FDCs)
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FDCs are found only in lymphoid follicles and express complement receptors
(CR1, CR2, and CR3) and Fc receptors, are involved in displaying antigens for the
selection of germinal center B cells
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FDCs do not express class II MHC molecules and are not derived from progenitors
in the bone marrow
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The rim of naive B cells in the follicle, surrounding the germinal center, is called
the mantle zone
Heavy Chain Isotype (Class) Switching
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The key enzyme required for isotype switching (and somatic mutation) is activationinduced deaminase (AID). Humans and knockout mice lacking this enzyme have profound
defects in isotype switching and affinity maturation. AID expression is activated mainly by
CD40 signals. The enzyme deaminates cytosines in single-stranded DNA templates,
converting cytosine (C) residues to uracil (U) residues
Affinity Maturation: Somatic Mutation of Ig Genes
and Selection of High-Affinity B Cells
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Helper T cells and CD40:CD40L interactions are required for somatic mutation to be
initiated
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In proliferating germinal center B cells in the dark zone, Ig V genes undergo point mutations
at an extremely high rate. This rate is estimated to be 1 in 103 V gene base pairs per cell
division, which is about a thousand times higher than the spontaneous rate of mutation in
other mammalian genes. (For this reason, mutation in Ig V genes is also called
hypermutation)
B Cell Differentiation into Antibody-Secreting Plasma Cells
Generation of Memory B Cells and Secondary
Humoral Immune Responses
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Such vaccines, which are called conjugate vaccines, more readily induce highaffinity antibodies and memory than do polysaccharide vaccines without linked
proteins
Antigen Presentation by B Cells and the Hapten-Carrier Effect
ANTIBODY RESPONSES TO T CELL–INDEPENDENT
ANTIGENS
Nature of B Cells That Respond to
T-Independent Antigens
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The marginal zone and B-1 subsets of B cells are especially important for
antibody responses to TI antigens
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Marginal zone B cells are a distinct population of B cells that mainly respond to
polysaccharides. After activation, these cells differentiate into short-lived plasma
cells that produce mainly IgM. In humans these cells are also called IgM memory
cells
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B-1 cells represent another lineage of B cells that responds readily to TI antigens
mainly in the peritoneum and in mucosal sites
Functions of T-Independent Antibody Responses
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The practical significance of TI antigens is that many bacterial cell wall
polysaccharides belong to this category, and humoral immunity is the major
mechanism of host defense against infections by such encapsulated bacteria
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TI antigens contribute to the generation of natural antibodies, which are present
in the circulation of normal individuals and are apparently produced without
overt exposure to pathogens. Most natural antibodies are low-affinity
anticarbohydrate antibodies, postulated to be produced by B-1 peritoneal B cells
stimulated by bacteria that colonize the gastrointestinal tract and by marginal
zone B cells in the spleen. Antibodies to the A and B glycolipid blood group
antigens are examples of these natural antibodies
ANTIBODY FEEDBACK: REGULATION OF HUMORAL
IMMUNE RESPONSES BY Fc RECEPTORS