Structure and function of immunoglobulins

Abstract

Immunoglobulins are heterodimeric proteins composed of 2 heavy and 2 light chains. They can be separated functionally into variable domains that bind antigens and constant domains that specify effector functions, such as activation of complement or binding to Fc receptors. The variable domains are created by means of a complex series of gene rearrangement events and can then be subjected to somatic hypermutation after exposure to antigen to allow affinity maturation. Each variable domain can be split into 3 regions of sequence variability termed the complementarity-determining regions (CDRs) and 4 regions of relatively constant sequence termed the framework regions. The 3 CDRs of the heavy chain are paired with the 3 CDRs of the light chain to form the antigen-binding site, as classically defined. The constant domains of the heavy chain can be switched to allow altered effector function while maintaining antigen specificity. There are 5 main classes of heavy chain constant domains. Each class defines the IgM, IgG, IgA, IgD, and IgE isotypes. IgG can be split into 4 subclasses, IgG1, IgG2, IgG3, and IgG4, each with its own biologic properties, and IgA can similarly be split into IgA1 and IgA2.

Figure 1. Two-dimensional model of an IgG molecule

The H and L chains at the top deconstruct the antibody at a nucleotide level. The chains at the bottom deconstruct the protein sequence. See text for further details.

Figure 2. Rearrangement events in the human κ locus

See text for further details.

Figure 3. Representation of the chromosomal organization of the Ig H, κ, and λ gene clusters

The typical numbers of functional gene segments are shown. The κ gene cluster includes a κ deleting element that can rearrange to sequences upstream of Ck in cells that express λ chains, reducing the likelihood of dual κ and λ light chain expression.

Figure 4. The antigen binding site is the product of a nested gradient of diversity

(A) H chain rearrangement can yield as many as 38,000 different VDJ combinations. The addition of nine N nucleotides on either side of the D gene segment yields can yield up to 64,000,000 different CDR-H3 junctional sequences. (B) The view is looking into the binding site as an antigen would see the antigen binding site. This site is created by the juxtaposition of the three CDRs of the H chain and the three CDRs of the light chain. The V_H domain is on the right side. The central location of CDR-H3, which due to N addition is the focus for repertoire diversity, is readily apparent.

Figure 5. Immunoglobulin diversification and B cell development

Cartoon illustrating B cell development as a function of immunoglobulin rearrangement and modification. After birth, B cell development begins in the bone marrow and is independent of antigen stimulation. The pre-B cell is defined by the presence of cytoplasmic μ protein (Cμ⁺). With development, the fate of the B cell becomes increasingly dependent on its response to antigen. Immature B cells leave the bone marrow and begin to express IgD. They recirculate through the blood, the secondary lylmphoid organs and the bone marrow. Encounter with cognate antigen can cause the cell to become a memory B cell or a plasma cell. Patients with X-linked agammaglobulinemia (XLA) lack BTK function and have difficulty making immature B cells and IgM. Patients with hyper IgM syndrome (Hyper IgM) are unable to class switch. Patients with selective IgA deficiency (IgAD) or common variable immune deficiency (CVID) can class switch, but have difficulty becoming plasma cells or memory B cells.

Figure 6. Structural and glycosylation properties of immunoglobulins

Depiction of the structure and glycosylation sites (indicated by amino acid location) for human IgM, IgG, IgD, IgE and IgA2 and IgA2. Adapted from.(28)