Immunoglobulins and Their Production by B Cells

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Chapter 3

Immunoglobulins and Their Production by B Cells

Immunoglobulin Structure and Functions

• Immunoglobulins, synthesized by B cells, are antigen-binding glycoproteins (antibodies) that function in the recognition of and defense against antigens (Table 3-1).

TABLE 3-1

Antigen and Antibody Terminology

Term Definition
Adjuvant Substance that enhances immune response to an antigen when administered with it; used to improve response to vaccines
Affinity Binding strength of a single variable region of an antibody for a corresponding epitope on the larger antigen structure
Antigen Substance that binds to antibodies and T cell receptors. Although most antigens are also immunogens, some small molecules are antigenic but not immunogenic.
Avidity Combined binding strength of the multiple interactions between a multivalent antibody molecule and all the corresponding epitopes on an antigen
Epitope (antigenic determinant) Region on an antigen molecule to which a single antibody molecule or T cell receptor binds. An antigen usually has multiple epitopes and thus can react with antibodies of different specificities.
Fab fragment Portion of antibody molecule, produced by papain digestion, that contains a single antigen-binding site. All antibodies have two or more Fab regions and thus are bivalent or multivalent.
Fc fragment Portion of antibody molecule, produced by papain digestion, that fixes complement and binds to Fc receptors; varies among immunoglobulin isotypes
Hinge region Flexible portion of antibody heavy chains located between the Fab and Fc regions and containing intrachain disulfide bonds; present in IgG, IgA, and IgD
Immunogen Substance capable of eliciting a specific immune response
Monoclonal antibody Homogeneous antibody that recognizes only one epitope; produced by a single clone of plasma cells
Polyclonal antibody Mixture of antibodies that recognize different epitopes on an antigen; produced by multiple clones of plasma cells in response to an antigen containing different epitopes. Natural antiserum to a microbial antigen is polyclonal.
Thymus-dependent antigens Antigens that require helper T cells to induce antibody production (humoral response); most protein antigens
Thymus-independent antigens Antigens possessing many repetitive structures (e.g., flagellin, polysaccharide, and LPS) that can induce antibody production (humoral response) without helper T cells

Chain structure of immunoglobulins (Fig. 3-1A)

1. Each monomeric antibody molecule comprises two identical heavy (H) chains and two identical light (L) chains (κ or λ).

2. Antigenic specificity is determined by the amino acid sequence of the variable domains near the amino-terminal end of each chain.

Functional regions of antibody molecules

1. Papain digestion cleaves the antibody molecule into two Fab fragments and one Fc fragment (Fig. 3-1B).

2. The Fab portion contains variable region (VL/VH) domains, which bind antigen.

3. The Fc portion mediates antigen clearance by binding to complement and to Fc receptors on immune system cells (Table 3-2).

TABLE 3-2

Functions Mediated by Interactions with Antibody Fc Region

Function Fc Region Interacts with
Opsonization Fc receptors on macrophages and neutrophils
Killing by means of ADCC Fc receptors on neutrophils, macrophages, NK cells, eosinophils
Degranulation leading to allergic and antiparasitic responses Fc receptors for IgE on mast cells
Activation of cells Fc receptors on lymphocytes
Transmucosal movement Fc receptors for dimeric IgA on epithelial cells
Activation of classical complement pathway leading to cell lysis (especially of bacteria), opsonization, and inflammatory response Initial component of pathway (C1)

ADCC, antibody-dependent cellular cytotoxicity; NK, natural killer.

4. Membrane-spanning region is a heavy-chain carboxyl-terminal domain present only in immunoglobulins expressed on the surface of B cells.

Properties of immunoglobulin isotypes

• The five major immunoglobulin classes, or isotypes, exhibit different functions and roles in immunity (Table 3-3; Fig. 3-2).

1. IgM

2. IgD

3. IgG

4. IgA

5. IgE

Antigenic determinants on antibodies

1. Immunoglobulins, like other proteins, can induce an immune response.

2. Three major groups of immunoglobulin epitopes—isotypic, allotypic, and idiotypic—differ in their location within antibody molecules and/or distribution among individuals (Table 3-4).

TABLE 3-4

Antigenic Determinants on Antibodies

Epitope Class Location Comment
Isotype Constant region These epitopes, which define each class of Ig heavy chains, are identical in all members of a species. The five human isotypes are IgA, IgD, IgE, IgG, and IgM. (Iso = same.)
Allotype Constant region These epitopes vary among individuals. IgG exhibits the most allotypic differences. (Allo = different.)
Idiotype Variable region These epitopes differ among antibodies because of different antigen-binding specificities. Monoclonal antibodies have the same idiotype. (There are many “idiot” types.)

II Development and Activation of B Cells

Antigen-independent maturation of B cells

1. Germline Ig DNA consists of multiple coding segments separated by noncoding regions.

2. Random recombination of gene segments forms VLJ (light chain) or VHDJ (heavy chain) units, which encode the variable region of each chain and determine the antigenic specificity of mature B cells (Fig. 3-4).

3. Splicing of primary RNA transcripts formed by mature B cells yields messenger RNAs (mRNAs) with a single variable region and single constant region.

Stimulation by T-independent (TI) antigens

Stimulation by T-dependent (TD) antigens (Box 3-1)

1. Three types of signals are required for response to TD antigens.

2. Affinity maturation (clonal expansion) results from selective expansion of B cell clones that make the best antibody.

3. Class (isotype) switching occurs as the immune response progresses.

III Antibody Effector Mechanisms

Neutralization of viruses and toxins

Opsonization (IgG)

Complement activation (IgG and IgM)

Antibody-mediated agglutination (IgM) of bacteria

Antibody-dependent cellular cytotoxicity

Binding of secretory IgA to microbes at mucosal surfaces

Hypersensitivity reactions

IV Antigen-Antibody Reactions

• Antigen-antibody reactions provide the basis for qualitative and quantitative tests for both antigen (Ag) and antibody (Ab) (see Chapter 5).

Precipitation-based assays

Agglutination-based assays