IgG1 vs IgG2 vs IgG3 vs IgG4: Key Differences in Structure and Function Explained

EllieB

The human immune system’s complexity is perhaps best illustrated by immunoglobulins—particularly the IgG subclasses. While you might be familiar with antibodies in general, understanding the distinct roles of IgG1, IgG2, IgG3, and IgG4 reveals how your body mounts targeted defenses against different threats.

These four molecular variants may look similar at first glance, but they possess unique structures and functions that dramatically impact your immune response. From fighting bacterial infections to managing allergic reactions, each IgG subclass specializes in specific protective mechanisms. Their differences in half-life, complement activation, and placental transfer aren’t just academic distinctions—they’re crucial factors in how your body maintains health and fights disease.

ChatGPT: The human immune system’s complexity is perhaps best illustrated by immunoglobulins—particularly the IgG subclasses. While you might be familiar with antibodies in general, understanding the distinct roles of IgG1, IgG2, IgG3, and IgG4 reveals how your body mounts targeted defenses against different threats.

What Are Immunoglobulins?

Immunoglobulins are specialized glycoprotein molecules that function as antibodies in your immune system. These Y-shaped proteins are produced by plasma cells (mature B lymphocytes) and serve as critical components of the adaptive immune response. Each immunoglobulin consists of four polypeptide chains—two heavy chains and two light chains—connected by disulfide bonds.

Five main classes of immunoglobulins exist in humans:

IgG (Immunoglobulin G): The most abundant antibody in serum, comprising 75-80% of all antibodies
IgA (Immunoglobulin A): Found primarily in mucosal secretions
IgM (Immunoglobulin M): The first antibody produced during an immune response
IgE (Immunoglobulin E): Associated with allergic reactions and parasite defense
IgD (Immunoglobulin D): Functions mainly as an antigen receptor on B cells

Immunoglobulins bind to specific antigens through their variable regions, marking them for destruction by immune cells or neutralizing their ability to cause harm. This antigen-binding specificity is what enables your immune system to recognize and respond to millions of different potential threats.

The constant regions of immunoglobulins determine their biological functions, such as complement activation, phagocyte binding, and placental transfer. These regions also define the five distinct classes and various subclasses, including the four IgG subclasses (IgG1, IgG2, IgG3, and IgG4) that differ in their structure and functional properties.

Structure and Composition of IgG Antibodies

IgG antibodies possess distinct structural elements and compositional features that differentiate each subclass. These molecular characteristics influence how each IgG subclass functions within the immune response and interacts with pathogens.

Basic Structure of Immunoglobulin G

All IgG antibodies share a fundamental Y-shaped structure consisting of four polypeptide chains: two identical heavy chains and two identical light chains connected by disulfide bonds. Each chain contains constant and variable regions, with the variable regions forming the antigen-binding sites at the tips of the Y structure. The heavy chains in IgG molecules contain three constant domains (CH1, CH2, and CH3) and one variable domain (VH), while light chains have one constant domain (CL) and one variable domain (VL). The Fab (fragment antigen-binding) regions form the arms of the Y and contain the antigen-binding sites, while the Fc (fragment crystallizable) region forms the stem and mediates effector functions like complement activation and receptor binding.

Molecular Characteristics of IgG Subclasses

IgG subclasses exhibit notable differences in their heavy chain structure, hinge region, and glycosylation patterns. These variations contribute to their functional diversity:

IgG1 contains 2-3% carbohydrate and has a molecular weight of approximately 146 kDa. It’s hinge region is intermediate in length with 15 amino acids and includes 2 inter-heavy chain disulfide bonds. IgG1’s flexibility enables efficient crosslinking of antigens.
IgG2 has a shorter, more rigid hinge region with 12 amino acids and 4 inter-heavy chain disulfide bonds, making it less flexible than IgG1. It weighs about 146 kDa and contains 2-3% carbohydrate. This structure is optimized for binding polysaccharide antigens on bacterial cell walls.
IgG3 features an extended hinge region with 62 amino acids and 11 inter-heavy chain disulfide bonds, making it the most flexible IgG subclass. It’s molecular weight reaches 170 kDa, with 2-3% carbohydrate content. These characteristics give IgG3 enhanced complement activation capabilities.
IgG4 has a flexible hinge region similar in length to IgG1 (15 amino acids) but with 2 inter-heavy chain disulfide bonds that can form intra-chain bonds. It weighs approximately 146 kDa and contains 2-3% carbohydrate. A unique feature of IgG4 is it’s ability to undergo Fab arm exchange, where half-molecules from different IgG4 antibodies combine.

Each IgG subclass also differs in the arrangement of disulfide bonds between chains and the distribution of charged amino acids, which affects their stability and function in different biological environments. These molecular distinctions determine their binding affinity for Fc receptors on immune cells, their ability to activate complement, and their capacity to cross the placenta for maternal-fetal immunity transfer.

IgG1: The Dominant Antibody

IgG1 represents approximately 60-70% of the total IgG in human serum, making it the most abundant immunoglobulin subclass. This predominance underscores its crucial role in mediating immune responses against a wide variety of pathogens and maintaining overall immune homeostasis.

Structure and Properties of IgG1

IgG1 exhibits the classic Y-shaped antibody structure with two heavy chains and two light chains connected by disulfide bonds. Its molecular weight is approximately 146 kDa, with a half-life of 21 days in circulation – longer than IgG3 (7 days) but similar to IgG2 and IgG4. The hinge region of IgG1 is moderately flexible, containing 15 amino acids and 2 interchain disulfide bonds, providing sufficient mobility for the Fab arms to capture antigens effectively.

IgG1’s CH2 domain contains a N-linked glycosylation site at Asn297, which affects its stability and interaction with Fc receptors. This glycosylation pattern differs from other subclasses, particularly IgG4, influencing its binding affinity and effector functions. The distinctive amino acid sequence in the Fc region of IgG1 creates binding sites with high affinity for FcγRI, FcγRIIa, and FcγRIIIa receptors, enabling potent immune responses.

Biological Functions of IgG1

IgG1 functions as the primary defense against protein antigens, viruses, and gram-positive bacteria. It’s capabilities include:

Neutralizing pathogens by binding to their surface antigens, preventing cellular entry and infection
Activating complement through the classical pathway, triggering a cascade that leads to pathogen lysis
Mediating opsonization by coating foreign particles, enhancing their recognition and phagocytosis by macrophages
Facilitating antibody-dependent cellular cytotoxicity (ADCC) where natural killer cells recognize and destroy IgG1-tagged cells

IgG1 crosses the placenta more efficiently than other subclasses due to its strong affinity for the neonatal Fc receptor (FcRn), providing critical passive immunity to newborns. This placental transfer begins around week 13 of gestation and increase throughout pregnancy, reaching its peak in the third trimester.

In therapeutic applications, IgG1 serves as the backbone for many monoclonal antibody drugs, including adalimumab (Humira) for autoimmune conditions and trastuzumab (Herceptin) for certain breast cancers. These medications leverage IgG1’s potent effector functions to targets specific diseases mechanisms while maintaining favorable pharmacokinetic profiles.

IgG2: The Carbohydrate Fighter

IgG2 specializes in combating encapsulated bacteria through its unique structure and properties. This subclass makes up approximately 20-25% of total IgG in healthy adults and exhibits distinctive characteristics that make it particularly effective against carbohydrate antigens.

Structure and Properties of IgG2

IgG2 possesses a rigid hinge region with four inter-heavy chain disulfide bonds, creating a more compact structure compared to other IgG subclasses. Its molecular weight averages 146 kDa, similar to IgG1 but with notable structural differences. The shorter hinge region limits IgG2’s flexibility, resulting in reduced conformational adaptability when binding to antigens.

The heavy chains of IgG2 contain unique amino acid sequences in the constant regions that affect its biological functions. These distinctive sequences influence how IgG2 interacts with cell surface receptors and complement proteins. IgG2 antibodies feature lower levels of glycosylation at asparagine 297 compared to other subclasses, which impacts their stability and binding affinity.

IgG2 molecules exist in three structural isoforms (A, A/B, and B) based on disulfide bond arrangements between heavy and light chains. These structural variants affect antigen recognition capabilities and may influence IgG2’s effectiveness against different pathogens.

Biological Functions of IgG2

IgG2 primarily targets carbohydrate antigens found on bacterial cell surfaces, making it essential for defending against encapsulated bacteria like Streptococcus pneumoniae and Haemophilus influenzae. These pathogens, protected by polysaccharide capsules, are particularly dangerous to young children whose IgG2 production hasn’t fully developed.

Unlike IgG1 and IgG3, IgG2 demonstrates weak binding to Fc receptors on phagocytic cells, resulting in limited opsonization capabilities. This subclass activates the classical complement pathway less efficiently than IgG1 or IgG3, though it can still trigger complement-mediated bacterial lysis under certain conditions.

IgG2 crosses the placenta less efficiently than IgG1, providing limited protection to newborns against carbohydrate-rich pathogens. This reduced placental transfer explains why infants under 2 years old are more susceptible to infections caused by encapsulated bacteria.

Deficiencies in IgG2 has been linked to increased susceptibility to respiratory infections and autoimmune disorders. Studies show that patients with selective IgG2 deficiency experience recurrent sinopulmonary infections and may require immunoglobulin replacement therapy.

IgG2’s role in vaccine responses is particularly important, especially for polysaccharide vaccines like pneumococcal vaccines. The efficacy of these vaccines often depends on the individual’s ability to produce adequate IgG2 responses, which varies with age and immune status.

IgG3: The Complement Activator

IgG3 stands out among the IgG subclasses for its exceptional ability to activate the complement system. Making up about 5-10% of total IgG in healthy adults, IgG3 plays a critical role in immune defense against viral pathogens and parasitic infections.

Structure and Properties of IgG3

IgG3’s structure features the longest hinge region of all IgG subclasses, containing 62 amino acids compared to IgG1’s 15 amino acids. This extended hinge provides IgG3 with superior flexibility and reach when capturing antigens. The molecule weighs approximately 170 kDa and contains more disulfide bonds than other IgG subclasses, enhancing its structural stability even though its flexibility.

The glycosylation pattern of IgG3 differs from other subclasses, with unique oligosaccharide attachments at position Asn297 in the CH2 domain. These carbohydrate modifications influence receptor binding and complement activation capabilities. IgG3’s heavy chains contain distinctive amino acid sequences that create stronger interactions with Fc receptors on immune cells.

One notable disadvantage of IgG3 is its shorter half-life of just 7 days, compared to the 21-day half-life of other IgG subclasses. This reduced circulation time results from IgG3’s amino acid sequence at position 435, which affects its interaction with the neonatal Fc receptor responsible for recycling antibodies.

Biological Functions of IgG3

IgG3 excels at complement activation, triggering the classical pathway more efficiently than any other IgG subclass. When IgG3 binds to pathogens, it recruits C1q protein to initiate a cascade of reactions leading to the formation of membrane attack complexes that puncture bacterial cell membranes.

The antibody demonstrates powerful effector functions through high-affinity binding to all Fcγ receptors on phagocytes, natural killer cells, and neutrophils. This interaction enhances:

Phagocytosis of opsonized pathogens by macrophages and neutrophils
Antibody-dependent cellular cytotoxicity against virus-infected cells
Release of inflammatory mediators from immune cells
Clearance of immune complexes from circulation

IgG3 crosses the placental barrier effectively, though not as efficiently as IgG1. This transfer contributes significantly to maternal antibody protection for newborns. During viral infections, IgG3 is often produced early in the immune response, appearing before IgG1 in many cases, which makes it a valuable diagnostic marker for recent infections.

Research shows IgG3 plays important roles in immunity against malaria parasites, HIV, and respiratory viruses. Studies have linked abnormal IgG3 levels to autoimmune conditions like systemic lupus erythematosus and rheumatoid arthritis, where it can contribute to tissue damage through enhanced complement activation.

Unlike IgG4, IgG3 doesn’t undergo half-molecule exchange and maintains stable antigen binding, making it more reliables for long-term immune protection. But, therapeutic applications of IgG3 are limited by it’s shorter half-life, leading pharmaceutical companies to focus on engineering antibodies with IgG1 or IgG4 backbones instead.

IgG4: The Peaceful Mediator

IgG4 represents approximately 2-4% of total IgG in healthy adults, making it the least abundant IgG subclass. Even though its low concentration, IgG4 plays a unique regulatory role in the immune system, often dampening inflammatory responses rather than amplifying them.

Structure and Properties of IgG4

IgG4 displays several structural features that distinguish it from other IgG subclasses. Its molecular weight ranges between 146-170 kDa with a relatively short hinge region that limits flexibility compared to IgG1 and IgG3. The most unique structural characteristic of IgG4 is its ability to undergo “Fab arm exchange,” where half-molecules from two different IgG4 antibodies can swap, creating bispecific antibodies with dual targeting capabilities. This phenomenon occurs due to weak interactions between the heavy chains in the CH3 domain and the presence of specific amino acids at positions 409 and 368.

IgG4 molecules contain higher levels of terminal sialic acid residues in their glycan structures, contributing to their anti-inflammatory properties. These glycosylation patterns differ from other subclasses and affect receptor binding and biological functions. IgG4 also demonstrates poor complement activation and reduced binding to Fcγ receptors, which aligns with its non-inflammatory role.

Biological Functions of IgG4

IgG4 functions primarily as an anti-inflammatory mediator within the immune system. Unlike its counterparts, IgG4 doesn’t effectively activate complement or trigger antibody-dependent cellular cytotoxicity (ADCC). This subclass binds antigens with high affinity but forms small, non-precipitating immune complexes that don’t efficiently recruit inflammatory cells or activate complement.

The Fab arm exchange creates functionally monovalent antibodies that can’t crosslink antigens, preventing large immune complex formation. This exchange occurs in vivo and represents a form of post-translational modification that dampens inflammatory responses. IgG4 also competitively inhibits IgE-mediated allergic reactions by binding to allergens without triggering mast cell degranulation.

In chronic antigen exposure scenarios, the immune response often shifts toward IgG4 production, known as “IgG4 switching.” This phenomenon is observed in beekeepers, allergic individuals undergoing immunotherapy, and patients with certain parasitic infections. The shift from pro-inflammatory IgE to anti-inflammatory IgG4 helps prevent excessive tissue damage during prolonged immune responses.

But, IgG4 plays a central role in IgG4-related disease (IgG4-RD), a group of disorders characterized by tissue infiltration with IgG4-positive plasma cells and elevated serum IgG4 levels. These conditions can affect various organs, including the pancreas, salivary glands, and kidneys, highlighting the complex nature of IgG4’s involvement in immune regulation.

IgG4 also crosses the placenta less effeciently than IgG1, providing limited protection to newborns against specific pathogens. This reduced transplacental transfer reflects its evolutionary role as a regulator rather than a front-line defender in the immune system’s arsenal.

Key Differences Between IgG Subclasses

IgG subclasses exhibit distinct characteristics that influence their functionality within the immune system. These differences in structure, function, half-life, and distribution contribute to their specialized roles in immune defense against various pathogens.

Structural Differences

The four IgG subclasses differ significantly in their molecular structure, particularly in their hinge regions and disulfide bonds. IgG1 features a flexible hinge region with 15 amino acids secured by two interchain disulfide bonds, allowing for efficient antigen binding. IgG2 contains a more rigid hinge region with 12 amino acids and four disulfide bonds, limiting its flexibility but providing stability for binding to carbohydrate antigens. IgG3 possesses the longest hinge region (62 amino acids) with 11 disulfide bonds, creating exceptional flexibility for antigen capture. IgG4 has a short hinge region similar to IgG1 but with unique structural properties that enable Fab arm exchange, a process where half-molecules from different IgG4 antibodies recombine to form bispecific antibodies.

The heavy chain composition also varies among subclasses, with distinctive constant domains (CH1, CH2, CH3) that affect their biological activities. Glycosylation patterns differ as well, with IgG4 containing higher levels of terminal sialic acid residues that contribute to its anti-inflammatory properties compared to other subclasses.

Functional Differences

Each IgG subclass performs specialized functions in immune defense. IgG1 excels at neutralizing toxins and viruses while mediating powerful effector functions like complement activation and antibody-dependent cellular cytotoxicity (ADCC). IgG1 binds with high affinity to all Fcγ receptors, making it effective at triggering phagocytosis and cellular responses.

IgG2 primarily targets encapsulated bacteria with polysaccharide coats, such as Streptococcus pneumoniae and Haemophilus influenzae. It’s particularly adept at neutralizing bacterial toxins but demonstrates limited complement activation and minimal ADCC activity.

IgG3 possesses the strongest complement-activating capacity among all subclasses, binding C1q with 5-10 times higher affinity than IgG1. It shows potent effector functions through high-affinity binding to Fcγ receptors, making it especially effective against viral pathogens.

IgG4 exhibits anti-inflammatory properties and doesn’t effectively activate complement or engage in ADCC. It acts as an immune regulator, often produced during chronic antigen exposure to prevent excessive inflammation. Due to its bispecific potential through Fab arm exchange, IgG4 can simultaneously bind two different antigens, a unique characteristic among IgG subclasses.

Half-Life and Distribution

The half-life and distribution of IgG subclasses varies significantly, affecting there therapeutic potential and protective capacity. IgG1, IgG2, and IgG4 share a relatively long half-life of approximately 21 days in circulation, making them persistent defenders in the bloodstream. In contrast, IgG3 has a shorter half-life of only 7 days due to a single amino acid difference (arginine instead of histidine at position 435) that affects its interaction with the neonatal Fc receptor.

The placental transfer efficiency differs markedly among subclasses. IgG1 crosses the placenta most efficiently, providing robust passive immunity to newborns against various pathogens. IgG3 and IgG4 transfer with moderate efficiency, while IgG2 demonstrates the lowest rate of placental transfer, leaving newborns more vulnerable to encapsulated bacterial infections.

The tissue distribution patterns also vary, with IgG1 and IgG3 found predominantly in extravascular spaces, while IgG2 maintains higher serum concentrations. IgG4 is uniquely associated with specific tissues in IgG4-related diseases, where localized production can lead to fibrosis and organ dysfunction. These distribution patterns reflect the specialized roles each subclass plays in different anatomical compartments of the immune system.

Clinical Significance of IgG Subclasses

IgG subclasses play crucial roles in clinical medicine, influencing diagnostic approaches, treatment strategies, and patient outcomes. These antibody variants demonstrate distinct patterns in various disease states, providing valuable insights for healthcare professionals.

IgG Subclass Deficiencies

IgG subclass deficiencies occur when one or more IgG subclasses fall below normal levels while total IgG remains within reference ranges. Primary deficiencies stem from genetic factors, while secondary deficiencies result from medications or underlying conditions. IgG2 deficiency represents the most common single subclass deficiency, affecting approximately 1 in 10,000 individuals and causing increased susceptibility to encapsulated bacteria like Streptococcus pneumoniae and Haemophilus influenzae. Children with IgG2 deficiency experience recurrent sinopulmonary infections, otitis media, and pneumonia.

IgG1 deficiencies, though less common, lead to severe infections due to its predominant role in immunity. Patients with IgG3 deficiencies face viral infections and demonstrate poor responses to certain vaccines. IgG4 deficiencies rarely present with clinical symptoms because of this subclass’s minimal contribution to overall protection. Selective IgG subclass deficiencies often coexist with other immunological abnormalities, creating complex clinical presentations.

Diagnosis requires quantitative measurement of individual IgG subclasses using immunonephelometry or ELISA techniques. Treatment approaches include prophylactic antibiotics for patients with recurrent infections, immunoglobulin replacement therapy for severe cases, and pneumococcal vaccination to enhance protection against encapsulated bacteria. Regular monitoring of infection frequency and severity helps assess treatment efficacy and disease progression.

Role in Autoimmune Disorders

IgG subclasses contribute differently to autoimmune pathology through their distinct effector functions. IgG1 and IgG3 predominate in type II hypersensitivity reactions, where they target cell surface antigens and activate complement, causing tissue destruction. These subclasses appear elevated in conditions like rheumatoid arthritis, systemic lupus erythematosus, and myasthenia gravis. ELISA testing reveals IgG1 anti-citrullinated protein antibodies in 70-80% of rheumatoid arthritis patients, serving as both diagnostic and prognostic markers.

IgG4 exhibits a unique relationship with autoimmunity, functioning primarily as an anti-inflammatory mediator. IgG4-related disease represents a distinct entity characterized by elevated serum IgG4 levels, tissue infiltration by IgG4-positive plasma cells, and fibrosis across multiple organs. Common manifestations include autoimmune pancreatitis, sclerosing cholangitis, and retroperitoneal fibrosis. IgG4 levels above 135 mg/dL combined with tissue IgG4-positive plasma cells exceeding 40% of total IgG-positive cells support diagnosis.

IgG2 autoantibodies target predominantly carbohydrate antigens in conditions like Guillain-Barré syndrome, while IgG3 autoantibodies correlate with disease activity in multiple sclerosis. Therapeutic strategies targeting specific IgG subclasses have emerged, including rituximab for depleting B cells producing pathogenic IgG and intravenous immunoglobulin to modulate autoimmune responses. Monitoring IgG subclass distributions provides valuable information for determining treatment response and predicting disease flares in autoimmune conditions.

The balance between different IgG subclasses often determines disease severity and progression. For instance, a shift from inflammatory IgG1/IgG3 toward regulatory IgG4 responses correlate with spontaneous remission in some autoimmune disorders. Next-generation therapies aim to selectively target specific IgG subclasses or modulate their effector functions rather then depleting all antibodies, potentially improving efficacy while reducing side effects.

Conclusion

The four IgG subclasses represent nature’s specialized approach to immune defense with each playing a distinct role in your body’s protection system. While IgG1 dominates in abundance and versatility IgG2 targets encapsulated bacteria IgG3 excels at complement activation and IgG4 serves as an immune regulator.

Understanding these differences isn’t just academic—it has real implications for diagnosing immune deficiencies developing vaccines and creating targeted immunotherapies. The unique structural variations between these subclasses directly influence their biological functions from placental transfer to pathogen neutralization.

As research advances your healthcare providers can better interpret IgG subclass profiles to personalize treatment approaches for autoimmune disorders allergies and immunodeficiencies making these molecular distinctions crucial to modern medicine.