IgG1IgG4

IgG1 and IgG4 are two of the four human immunoglobulin G (IgG) subclasses. They make up a major portion of circulating IgG, with IgG1 typically the most abundant and IgG4 representing a smaller but clinically significant fraction. Both share the standard IgG structure of two heavy chains and two light chains, featuring Fc and Fab regions that govern effector functions and antigen recognition. A key difference is the hinge region: IgG4 has a more flexible hinge and can undergo Fab-arm exchange, a process in which half-molecules swap with other IgG4 molecules to form bispecific, functionally monovalent antibodies. This exchange reduces the ability to cross-link antigens and dampens inflammatory responses.

IgG1 is a pro-inflammatory, high-affinity subclass with strong binding to Fc gamma receptors and C1q, enabling potent effector functions such as antibody-dependent cellular cytotoxicity (ADCC), phagocytosis, and complement activation. IgG4, by contrast, exhibits relatively low Fc receptor binding and poor C1q activation, contributing to a more anti-inflammatory profile. The two subclasses also differ in their interactions with the neonatal Fc receptor (FcRn), which governs serum half-life; both IgG1 and IgG4 have similar extended half-lives of about 21 days, though their effector profiles diverge.

Clinically, IgG4 is associated with IgG4-related disease, a condition marked by tissue infiltration with IgG4-positive plasma cells and elevated serum IgG4. IgG4 is also leveraged in therapeutics: many monoclonal antibodies are engineered as IgG1 to maximize effector functions, while IgG4 variants (often with mutations such as S228P to prevent Fab-arm exchange) are used when reduced effector activity is desired, as in anti-inflammatory therapies such as certain PD-1 inhibitors.