IgG Antibodies: Structure, Subclasses, Functions, and Clinical Significance

If you could describe IgG in a single sentence, it would be this: IgG is the only antibody that crosses the placenta, giving a newborn its mother's protection for the first months of life. That one fact captures why IgG matters so much. But IgG does far more than that. It is the most abundant antibody in the blood, the main antibody of the second and lasting immune response, and the workhorse behind opsonization, complement activation, and antibody-based killing. This article covers its structure, its four subclasses, and the functions that make it central to immunity.

IgG is an important component of the neonatal immunological defense mechanisms against infection.

IgG is mostly found in the γ-globulin fraction (when separated into high-and low-molecular weight fractions, it is found in low-molecular-weight-fraction i.e. around 150,000 MW). Significant amounts of it and other classes of antibody molecules are found in the alpha and beta fraction of serum.

Figure: Schematic diagram of Immunoglobulin G (IgG) Source: Kuby Immunology

IgG is a monomer of about 150 kDa, built on the standard antibody plan of two heavy chains and two light chains. What makes it IgG is its gamma (γ) heavy chain, which has three constant domains and a hinge region. The general antibody structure, Fab and Fc regions, variable and constant domains, is covered in the article on immunoglobulin structure. What is specific to IgG, and the focus here, is its four subclasses and its functions.

The gamma heavy chain comes in four versions (γ1 to γ4), which is why IgG has four subclasses: IgG1, IgG2, IgG3, and IgG4, numbered by decreasing abundance in serum.

Key Points Regarding IgG Antibodies

1. Most abundant antibody class in serum, making up roughly 70 to 75% of total serum immunoglobulin.
2. There are four subclasses of IgG; IgG1, IgG2, IgG3, and IgG4
3. Activates complement
4. Crosses placenta and play an important role in protecting the developing fetus.

Functions of IgG Antibody

1. Complement activation: Most IgG subclasses can activate complement system (It’s a collection of serum glycoproteins that can perforate cell membranes of pathogens).
2. Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC): NK cells express membrane receptor (CD16) for the carboxyl-terminal end (Fc region) of the IgG molecule. When antigens/pathogens are coated with IgG antibodies, NK cells can attach to these antibodies and subsequently destroy the targeted cells.
   The general mechanisms of these functions, how opsonization, complement activation, and ADCC actually work, are covered in the article on the functions of antibodies. What matters for IgG specifically is that it is the main antibody carrying out all three in the blood and tissues.
3. Neonatal immunity: Some mammalian species, such as humans and mice, also transfer significant amounts of most subclasses of IgG from mother to fetus. The transfer of IgG from mother to fetus is a form of passive immunization (acquisition of immunity by receipt of preformed antibodies rather than by active production of antibodies after exposure to antigen).
4. Opsonization
5. Feedback inhibition of B Cells

The four subclasses of IgG

The four subclasses are more than 90% identical, but small differences in the heavy chain, especially the hinge and disulfide bonds, give each a distinct functional profile.

Figure: General Structure of Four Subclasses of IgG Antibody (Source: Kuby Immunology)

These differences are clinically important.

Several patterns are worth learning:

Complement activation: IgG3 is the strongest activator, then IgG1, then weak IgG2, and IgG4 cannot activate complement at all. A memory aid: 3 and 1 are the complement subclasses.

Opsonization: IgG1 and IgG3 bind Fc receptors on phagocytes with high affinity and are the main opsonizers. IgG2 binds very poorly.

Placental transfer: IgG1 is the principal subclass crossing the placenta, with IgG3 and IgG4 also crossing; IgG2 crosses with much lower efficiency.

Half-life: IgG1, IgG2, and IgG4 last about three weeks, but IgG3 has a notably short half-life of about one week. This is the one subclass that behaves differently, and it is a common exam point.

A notable structural feature: IgG3 has an unusually long hinge with 11 interchain disulfide bonds, which is linked to both its strong complement activation and its shorter half-life.

Clinical significance of IgG

IgG's roles show up directly in the clinic:

IgG is the marker of past or resolving infection. Because IgG rises later than IgM and persists for years, a positive IgG with negative IgM usually means past infection or immunity, while IgM points to recent or acute infection. This is the basis of many serological tests.

IgG is what vaccines aim to produce. Lasting protection from most vaccines comes from IgG and the memory to make it quickly.

Maternal IgG protects the newborn. Transferred across the placenta, it shields the infant for the first months. This is also why some maternal antibody can interfere with certain infant vaccines given too early.

IgG subclass deficiency causes recurrent infection. IgG2 deficiency is the most common and is linked to recurrent respiratory infections in children, because IgG2 carries much of the response to bacterial polysaccharide antigens.

Therapeutic antibodies are mostly IgG. Most monoclonal antibody drugs are engineered IgG, using IgG1 when strong effector function is wanted and IgG4 when it is not.

How to remember

IgG in one line: the only one that crosses the placenta. The single most memorable IgG fact, and clinically the most important.

Subclass complement: "3 beats 1, 2 is weak, 4 does none." IgG3 > IgG1 > IgG2 >> IgG4 (none). The order of complement power.

IgG3 is the odd one out: strongest complement, longest hinge, shortest half-life. Everything about IgG3 is extreme. If a subclass question asks "which is different," it is usually IgG3.

IgM first, IgG later and lasting. In a response, IgM appears first (recent infection), IgG follows and persists (past infection or immunity). This underlies serology.

GAME-D abundance, and within IgG: 1 > 2 > 3 > 4. IgG is the most abundant class, and its subclasses fall in numbered order of abundance.

Key exam facts in one table

Where students get confused

"IgG appears first in an infection." No. IgM appears first; IgG appears later and lasts. A positive IgG usually means past infection, vaccination, or a maturing response, not a brand-new one.

"All IgG subclasses activate complement equally." No. IgG3 is strongest, then IgG1, IgG2 is weak, and IgG4 does not activate complement at all. The subclass matters.

"All IgG subclasses cross the placenta equally." No. IgG1 is the main placental crosser; IgG2 crosses poorly. This affects which maternal antibodies protect the newborn.

"IgG3 lasts as long as the others." No. IgG3 is the exception, with a half-life of about 7 days versus about 21 for the rest, because of a structural difference affecting its recycling.

"IgG is only about neutralizing pathogens." No. IgG opsonizes, activates complement, mediates ADCC, crosses the placenta, and neutralizes. It is the all-round effector antibody.

References and further readings

• Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular Immunology. 10th ed. Elsevier; 2022.
• Punt J, Stranford SA, Jones PP, Owen JA. Kuby Immunology. 8th ed. W.H. Freeman; 2019.
• Vidarsson G, Dekkers G, Rispens T. IgG subclasses and allotypes: from structure to effector functions. Front Immunol. 2014;5:520. https://doi.org/10.3389/fimmu.2014.00520