Immunoglobulin G Subclasses

Structures and Physical Properties of IgG Subclasses

The four IgG subclasses exist as monomers in serum. While their tertiary structures are similar, they differ in the number and location of interchain disulfide bonds. The variation in heavy chain constant (CH) regions allows for the determination of class and subclass. The Fc regions of each subclass have different affinities for Fc-gamma-receptors (FcγR) on phagocytes, which are crucial for initiating phagocytosis. IgG1 and IgG3 bind to FcγRI, FcγRII, and FcγRIII; IgG2 binds to FcγRII; and IgG4 binds to FcγRI and FcγRII.

In an IgG molecule, two identical heavy chains and two identical light chains make up the structure, typically resulting in two identical antigen-binding sites on the Fab arms. However, IgG4 antibodies have a unique property called "half antibody exchange." This means that a significant portion of IgG4 molecules can exchange their H-L dimer partners, resulting in hybrid antibodies with two different Fab arms that have different antigen specificities. Although these antibodies can only bind to antigens in a monovalent manner, they are capable of cross-linking two different antigens.

The hinge regions of antibodies allow for rotation and flexion of the Fab arms, and the flexibility of the hinge depends on the number of inter-heavy chain disulfide bonds present. The relative flexibility of the hinge regions in decreasing order among the IgG subclasses is IgG3, IgG1, IgG4, and IgG2. Additionally, the number of amino acids in the hinge region varies among the subclasses. This increased flexibility in the hinge region may contribute to enhanced complement activation and Fc receptor (FcR) binding affinity.

Characteristics and Functions of IgG Subclasses

• Opsonization
  IgG1, IgG2, and IgG3 play a crucial role in opsonization, which involves binding antibodies to microbes and facilitating their phagocytosis by immune cells through Fc-gamma-receptors. Opsonins can be antibodies or complement proteins. IgG antibodies interact with microbes through their Fab portions and bind to phagocytes through the Fc portion. However, IgG4 has a low affinity for Fc-gamma-receptors and C1q, resulting in minimal cell activation and complement activation. IgG4 antibodies can undergo Fab arm exchange, leading to the loss of their ability to cross-link antigens and form immune complexes.
• Complement Activation
  The various IgG subclasses have varying abilities to bind C1q and activate the classical complement pathway. IgG1 and IgG3 are the most effective at binding C1q and initiating complement activation. IgG2 exhibits weak binding to C1q, while IgG4 does not bind complement at all.
• Antibody-dependent Cellular Cytotoxicity
  Antibody-dependent cellular cytotoxicity (ADCC) is a process where immune cells with Fc-gamma receptors, like NK cells, bind to target cells using IgG antibodies that recognize specific antigens. Among the IgG subclasses, IgG1 is the most effective in mediating ADCC.
• Half-Life
  IgG subclasses have different half-lives, indicating how long they persist in circulation. This characteristic influences the duration and efficacy of their protective effects.