Antibody-antigen interaction: idiotype, paratope, affinity, and immunoglobulin biosynthesis

Domain structure of immunoglobulins

An immunoglobulin molecule (using IgG as an example) is built on a domain principle: heavy (H) and light (L) chains consist of several compact tertiary structures—domains—linked together. Each chain contains two types of domains: variable and constant.

• V_H is the variable domain of the heavy chain;
• V_L is the variable domain of the light chain;
• C_H are the constant domains of the heavy chain (several, depending on the isotype);
• C_L is the constant domain of the light chain.

Despite the name, constant domains can vary among different individuals due to allelic gene variants. These individual differences in C_H form the allotype, which is a heritable allelic variant of the heavy chain.

Idiotype, idiotope and paratope

The set of V_H and V_L variable domains of a single antibody molecule forms the idiotype. The idiotype is composed of multiple idiotopes—individual antigenic determinants of the antibody itself. Functionally, idiotopes are divided into two groups:

• Idiotopes not associated with the antigen-recognizing site—located outside the binding zone, capable of binding metals and possessing enzymatic activity;
• Idiotopes associated with the antigen-recognizing site—directly contact the antigen epitope; their combination forms the paratope.

Thus, a paratope is the active center of an antibody, represented by a group of associated idiotopes. The area of the paratope exceeds the area of the epitope: such "slack" is necessary for subsequent conformational adjustment, since the body cannot know the exact structure of the epitope in advance.

Hypervariable regions and affinity maturation

Within the paratope, three hypervariable regions are distinguished—CDR1, CDR2, and CDR3 (complementarity-determining regions). It is these regions that interact complementarily with the antigen epitope. Changes in the CDR structure directly alter the specificity of the antibody: specificity for the antigen is entirely determined by the structure of the hypervariable regions.

Following the initial contact of the epitope with the V_H and V_L idiotopes:

• the conformation of the antigen-recognizing site changes;
• the paratope becomes resistant to proteolysis;
• the mechanism of somatic hypermutation of variable region genes is triggered in the B lymphocyte with the participation of cytokines (including interleukins).

As a result, the paratope adapts to the epitope—affinity maturation occurs.

Affinity and avidity

The binding of an antibody to an antigen is carried out by numerous non-covalent interactions: hydrogen bonds, hydrophobic, van der Waals, and electrostatic interactions.

• Affinity is the binding strength of a single paratope (a single idiotope) to a single epitope; this is a "specific" concept.
• Avidity is the total binding strength of the entire antibody molecule with all available antigen epitopes; this is a "general" concept, especially significant for polymeric immunoglobulins (IgM, secretory IgA).

Localization of antibodies in the body

Antibodies are found in several functional forms:

• in dissolved form—in blood plasma and other biological fluids;
• as part of circulating immune complexes (CIC)—antigen–antibody conjugates;
• as part of the BCR (B-cell receptor)—the membrane-bound form of IgM on the surface of B lymphocytes;
• on the surface of innate immune cells (macrophages, neutrophils, etc.) carrying Fc receptors for immunoglobulins.

Biosynthesis of immunoglobulins

Immunoglobulins are proteins, so their synthesis occurs on the ribosomes of the rough endoplasmic reticulum (RER) of a plasma cell. The translation rate is high:

• the light chain is synthesized in 30–45 seconds;
• the heavy chain takes about 90 seconds.

Linear polypeptide chains undergo folding in the lumen of the RER under the action of chaperones, forming multidomain structures. Disulfide bonds are formed between the chains, catalyzed by the enzyme protein disulfide isomerase. Next, post-translational modifications occur, primarily N-glycosylation.

The finished molecules are packaged into transport vesicles. For IgM and secretory IgA, a J-chain (joining chain) is attached inside the vesicle, which is necessary for monomer polymerization. After this, immunoglobulins are secreted via the merocrine pathway. The full cycle from translation to secretion takes about 30 minutes; a single plasma cell releases about 200 immunoglobulin molecules per round.

Key points

• Immunoglobulins have a domain structure: V_H, V_L, C_H, C_L.
• Allotype is determined by allelic variants of the heavy chain constant domains.
• Idiotype = V_H + V_L; consists of idiotopes, some of which form the paratope.
• Antibody specificity is determined by the CDR1, CDR2, CDR3 hypervariable regions.
• Somatic hypermutation with the participation of cytokines ensures the adaptation of the paratope to the epitope.
• Affinity is the binding strength of one paratope to one epitope; avidity is the total strength of all interactions.
• Antibodies are present as soluble molecules, CICs, BCRs, and on Fc receptors of effector cells.
• Biosynthesis on the rough ER takes ~30 minutes; the J-chain attaches to IgM and IgA in vesicles.