Immunoglobulins and Their Production by B Cells

I 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

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

3-1 Structure of IgG, the most abundant class of antibody in serum. A, Chain and domain structure of IgG. Variable domains of light and heavy chains (V_L and V_H) contribute to the antigen-binding sites. Only the heavy chain constant domains C_H2 and C_H3 contribute to effector functions. B, Products of papain digestion of IgG. Fab fragments have one antigen-binding site (monovalent), whereas F(ab′)₂ fragments have two antigen-binding sites (bivalent). Fc fragments interact with C1 complement and cellular Fc receptors.

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.

• Light chains contain one variable domain (V_L) and one constant domain (C_L).

a. Sequence differences in the constant-region domain define two types of light chains: κ and λ.

• Heavy chains contain one variable domain (V_H) and three or four constant domains (C_H1, C_H2, etc.).

a. Sequence differences in the constant-region domains define five major types of heavy chains: μ, γ, δ, α, and ε.

Heavy chains define the specificity of the immunoglobulin.

b. Each type of heavy chain can be expressed as a membrane-bound or membrane-soluble (secreted) form.

Papain cleaves immunoglobulin G (IgG) into two monovalent Fab and one Fc fragment.

Pepsin cleaves IgG into one divalent F(ab′)₂ and one Fc fragment.

Fab interacts with antigen, and Fc interacts with complement and immune cells.

B Functional regions of antibody molecules

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

• Pepsin digestion cleaves the antibody molecule into one F(ab′)₂ and one Fc fragment.

2. The Fab portion contains variable region (V_L/V_H) 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)