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PHASES AND TYPES OF HUMORAL IMMUNE RESPONSES

The activation of B lymphocytes results in the proliferation of antigen-specifc cells, leading to clonal expansion, and in their differentiation into plasma cells, which actively secrete antibodies and are thus the effector cells of humoral immunity

One activated B cell may generate a few thousand plasma cells, each of which can produce copious amounts of antibody molecules, in the range of several thousand per hour.

Class switching Affinity Maturation T-dependent Vs T-independent response Primary Vs Secondary response

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Phases of humoral immune responses

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T-dependent and T-independent antibody responses. 4

Different subsets of B cells

Follicular B cells make the bulk of T-dependent, class-switched, and high-affinity antibody responses to protein antigens; give rise to long-lived plasma cells.

Marginal-zone B cells respond largely to blood-borne polysaccharide and lipid antigens

B-1 cells respond to nonprotein antigens in the mucosal tissues and peritoneum.

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STIMULATION OF B LYMPHOCYTES BY ANTIGEN

Humoral immune responses are initiated when antigen-specific B lymphocytes in the spleen, lymph nodes, and mucosal lymphoid tissues recognize antigens.

B lymphocytes specific for an antigen use their membrane-bound immunoglobulin (Ig) as receptors that recognize the antigen directly, without any need for processing.

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Antigen-Induced Signaling in B Cells Antigen-induced clustering of membrane Ig receptors

triggers biochemical signals that are transduced by receptor-associated signaling molecules

Signals initiated by antigen receptor crosslinking are transduced by receptor-associated proteins. Membrane IgM and IgD, the antigen receptors of naive B lymphocytes, are membrane bound antibodies.

The receptors are noncovalently associated with two proteins, called Igα and Igβ, to form the B cell receptor (BCR) complex

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Role of Innate Immune Signals in B Cell Activation

B lymphocytes express a receptor for a protein of the complement system that provides signals for the activation of these cells

When the complement system is activated by a microbe, the microbe becomes coated with proteolytic fragments of the most abundant complement protein, C3.

One of these fragments is called C3d. B lymphocytes express a receptor for C3d called complement receptor type 2 (CR2, or CD21).

Engagement of CR2 greatly enhances antigen-dependent activation responses of B cells.

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Microbial products also directly activate B cells by engaging innate pattern recognition receptors (PAMP; pathogen associated molecular patterns)

B Cells express numerous Toll-like receptors. TLR engagement on the B cells by microbial products triggers activating signals that work in concert with signals from the antigen receptor.

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Role of innate immune signals in B cell activation 10

Functional Consequences of B Cell Activation by Antigen

B cell activation by antigen (and other signals) initiates the proliferation and differentiation of the cells and prepares them to interact with helper T lymphocytes if the antigen is a protein

Activated B cells endocytose protein antigen that binds specifcally to the B cell receptor, resulting in degradation of the antigen and display of peptides bound to class II MHC molecules, which can be recognized by helper T cells.

Activated B cells migrate out of the follicles and toward the anatomic compartment where helper T cells are concentrated.

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Functional consequences of antigen receptor-mediated B cell activation. 12

FUNCTIONS OF HELPER T LYMPHOCYTES IN HUMORAL IMMUNE RESPONSES

For a protein antigen to stimulate an antibody response, B lymphocytes and helper T lymphocytes specific for that antigen must come together in lymphoid organs and interact in a way that stimulates B cell proliferation and differentiation.

The process of T-B cell interaction and T cell– dependent antibody responses is initiated by recognition of the same protein antigen by both cell types and occurs in a series of sequential steps

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Sequence of events in helper T cell–dependent antibody responses 14

Naive CD4+ T cells are activated in the T cell zones by antigen (in the form of processed peptides bound to class II MHC molecules) presented by dendritic cells, and differentiate into functional (cytokine-producing) helper T cells.

Naive B cells are activated in the follicles by an exposed epitope on the same protein that is transported there.

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The antigen-activated helper T cells and B cells migrate toward one another and interact at the edges of the follicles, where the initial antibody response develops.

Some of the cells migrate back into follicles to form germinal centers, where the more specialized antibody responses are induced.

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Heavy-Chain Isotype (Class) Switching

Helper T cells stimulate the progeny of IgM– and IgD–expressing B lymphocytes to produce antibodies of different heavy chain isotypes (classes)

The molecular mechanism of isotype switching, called switch recombination, takes the previously formed VDJ exon encoding the V domain of an Ig µ heavy chain and moves it adjacent to a downstream C region

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Class Switching 18

*Activation-induced deaminase (AID)

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Affinity Maturation Affinity maturation is the process by which the affinity

of antibodies produced in response to a protein antigen increases with prolonged or repeated exposure to that antigen

Affinity maturation occurs in the germinal centers of lymphoid follicles and is the result of somatic hypermutation of Ig genes in dividing B cells, followed by the selection of high-affinity B cells by antigen

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ANTIBODY RESPONSES TO T-INDEPENDENT ANTIGENS

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REGULATION OF HUMORAL IMMUNE RESPONSES: ANTIBODY FEEDBACK

After B lymphocytes differentiate into antibody secreting cells and memory cells, a fraction of these cells survive for long periods, but most of the activated B cells probably die by apoptosis.

This gradual loss of the activated B cells contributes to the physiologic decline of the humoral immune response.

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As IgG antibody is produced and circulates throughout the body, the antibody binds to antigen that is still available in the blood and tissues, forming immune complexes.

B cells specific for the antigen may bind the antigen part of the immune complex by their Ig receptors. At the same time, the Fc tail of the attached IgG antibody may be recognized by a special type of Fc receptor expressed on B cells (as well as on many myeloid cells) called FcγRIIB

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This Fc receptor delivers inhibitory signals that shut off antigen receptor–induced signals, thereby terminating B cell responses. This process, in which antibody bound to antigen inhibits further antibody production, is called antibody feedback.

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