Immunoglobulin G (IgG Antibody)- Definition, Structure, Subclasses, Functions

Immunoglobulin G (IgG) is the most abundant antibody present in human blood and tissue fluid. It is a Y-shaped glycoprotein produced by plasma cells. It gives long term protection by neutralizing toxins and microbes, opsonization and complement activation.

Immunoglobulin G (IgG) is the most abundant antibody present in human blood. It forms about 10-20% of all plasma proteins. It is also the main antibody which is found in serum and tissue fluid.

IgG is a Y-shaped immunoglobulin molecule. It has molecular weight about 146 kDa. It is made up of two identical heavy chains and two identical light chains. These chains are joined together by disulphide bonds.

The structure of IgG gives two same antigen-binding sites. Due to this, it can bind with antigen in effective manner. These antigen binding regions help in attachment with foreign particles like bacteria, virus and toxins.

IgG is mainly produced by plasma cells. It is produced during the secondary immune response. In this response antibody production is more rapid and more specific than primary response.

The main function of IgG is protection of body from bacterial and viral infections. It neutralizes toxins and virus particles. It also helps in opsonization, where microbes are marked for destruction by phagocytic cells.

IgG can also activate the complement system. By this process, microbial cells are damaged and removed from the body. So, it has important role in humoral immunity.

There are four subclasses of IgG. These are IgG1, IgG2, IgG3 and IgG4. Each subclass has some structural difference and different immune function.

IgG is the only immunoglobulin which can cross the placenta. It passes from mother to fetus and gives passive immunity to the growing fetus. For this reason, IgG is the most abundant antibody in newborn baby.

Normal Serum Levels of IgG

Note: mg/mL and g/L are used as equivalent units for these values.

Discovery and Historical Background of IgG

• The study of Immunoglobulin G (IgG) started from the early concept of passive immunity. This was related with how young offspring get protection from infection. The early works of Paul Ehrlich and F.W. Rogers Brambell helped to develop this idea.
• F.W. Rogers Brambell first suggested that there may be a special Fc receptor system for IgG. This idea came from his study on transfer of maternal antibodies to fetus and newborn animal.
• In the 1960s, detailed studies were done on human IgG myeloma proteins. Specific polyclonal rabbit antisera were used in these studies. From these works, it was found that IgG is not a single type antibody.
• After this, four subclasses of IgG were discovered. These are IgG1, IgG2, IgG3 and IgG4. These subclasses showed some structural and functional differences.
• During the 1960s, scientists also described the transfer of IgG during perinatal period. They also observed that IgG is protected from degradation inside the body. At first these two processes were thought to be controlled by two different receptors.
• One receptor was called neonatal transport receptor (FcRn). Another one was called IgG protection receptor (FcRp). Later this concept was changed after molecular studies.
• More than 40 years ago, researchers like Jones and Rodewald studied the transfer of IgG in rodents. They showed that IgG transfer depends on age and tissue type. This helped to understand maternal antibody transport more clearly.
• In the 1980s, the use of monoclonal antibodies against human IgG and its subclasses improved the study of IgG. It allowed more accurate and reproducible measurement of IgG level in different diseases.
• The exact receptor proposed by Brambell remained unknown for nearly 30 years. In 1996, molecular characterization showed that transport and protection of IgG are done by the same receptor. This receptor is now known as neonatal Fc receptor (FcRn).
• The gene which encodes the heavy chain of FcRn is called FCGRT gene. Evolutionary studies suggested that this gene separated from classical MHC-I lineage about 163 million years ago. This happened before the divergence of mammals and monotremes.

Structure of IgG

• Immunoglobulin G (IgG) is a Y-shaped monomeric antibody. It has molecular weight about 146 kDa. It is the smallest major antibody which can easily move in blood and tissue fluid.
• IgG is made up of four polypeptide chains. These chains are arranged as light-heavy-heavy-light form. It contains two identical heavy chains and two identical light chains.
• The two heavy chains are joined with each other by disulphide bonds. The light chains are also attached with heavy chains by disulphide bonds. These bonds give stability to whole antibody structure.
• Each heavy chain has one variable domain (VH) and three constant domains. These constant domains are CH1, CH2 and CH3. These domains are folded region of the antibody chain.
• Each light chain has two domains. One is variable domain (VL) and another is constant domain (CL). The variable domain takes part in antigen binding with the heavy chain variable domain.
• The two upper arms of IgG are called Fab region or Fragment antigen-binding region. It is formed by variable domains of both heavy and light chains. This region contains hypervariable regions.
• The Fab region gives two identical antigen-binding sites. These sites bind with specific antigen. So, IgG can attach to same antigenic determinants by its two arms.
• The lower stem part of IgG is called Fc region or Fragment crystallizable region. It is mainly formed by CH2 and CH3 domains of heavy chains. This region does not bind antigen directly.
• The Fc region is responsible for biological functions of IgG. It binds with Fc receptors present on immune cells. It also helps in activation of complement system.
• A flexible hinge region is present between CH1 and CH2 domains of heavy chain. It joins the Fab arms with the Fc region. This region gives flexibility to the antibody molecule.
• Due to the hinge region, the Fab arms can move and adjust their angle. This helps IgG to bind antigen more properly. It also helps in rotation of antigen binding arms.
• The CH2 domain of the Fc region contains a conserved N-linked glycosylation site. It is present at Asn297 amino acid. This carbohydrate chain helps to maintain correct Fc structure.
• This glycosylation acts like a structural support in IgG. It keeps the receptor-binding pocket open. It is also important for immune effector functions of antibody.

Molecular Characteristics of IgG

• Immunoglobulin G (IgG) is a monomeric protein. Its molecular weight is about 146 kDa. It is present as single antibody unit in serum and body fluid.
• IgG is made up of four polypeptide chains. It contains two identical heavy chains and two identical light chains. These chains are arranged in L-H-H-L manner.
• The chains are connected with each other by covalent disulphide bonds. The two heavy chains are joined together. Each light chain is also attached with one heavy chain.
• Each heavy chain contains one variable domain (VH) and three constant domains. These constant domains are CH1, CH2 and CH3. These domains form the main molecular framework of IgG.
• Each light chain contains one variable domain (VL) and one constant domain (CL). The VL region works together with VH region for antigen binding.
• The upper two arms of IgG are called Fab region or Fragment antigen-binding region. It is formed by variable domains of heavy and light chains. This region gives specificity to the antibody.
• IgG is a divalent antibody. It has two identical antigen-binding sites. So, one IgG molecule can bind with two same antigenic determinants.
• The lower stem part is called Fc region or Fragment crystallizable region. It is formed by CH2 and CH3 domains of heavy chains. This region is not used for direct antigen binding.
• The Fc region performs the biological activities of IgG. It binds with Fc receptors on immune cells. It also activates the complement system.
• A flexible hinge region is present between CH1 and CH2 domains. It gives angular and rotational movement to the Fab arms. Due to this, the antibody can adjust with antigen surface.
• The CH2 domain has important N-linked glycosylation site. This site is present at Asn297 amino acid. The attached sugar chains help in maintaining the proper structure of Fc region.
• The carbohydrate chain in Fc region acts as a structural lock. It keeps the receptor-binding region open. So, receptor binding and immune effector function can occur properly.
• Human IgG has four subclasses. These are IgG1, IgG2, IgG3 and IgG4. They have more than 95% amino acid sequence similarity.
• The subclasses are different mainly in their hinge region. They vary in hinge length, flexibility and number of inter-heavy chain disulphide bonds. Due to this, each subclass shows some different immune function.

Subclasses of IgG

Human Immunoglobulin G (IgG) is divided into four subclasses. These are IgG1, IgG2, IgG3 and IgG4. They are named according to their decreasing amount in blood.

These subclasses are highly conserved. They share more than 90% amino acid sequence. But they are different in hinge region, structural flexibility and immune functions.

The following are the four subclasses of IgG–

1. IgG1-
   • Abundance- IgG1 is the most common subclass of IgG. It forms about 65% of total serum IgG.
   • Structure- It has highly flexible 15 amino acid hinge region. It contains 2 inter-heavy chain disulphide bonds.
   • Function- It is a strong activator of cellular immune response. It binds strongly with Fc receptors and activates the complement system. It has normal half-life about 21 days.
2. IgG2-
   • Abundance- IgG2 is the second most common subclass. It forms about 25% of total serum IgG.
   • Structure- It has short and rigid 12 amino acid hinge region. It contains poly-proline double helix and 4 disulphide bonds. So, its flexibility is less.
   • Function- It is highly resistant to degradation by enzymes. It is mainly important in defence against encapsulated bacteria having polysaccharide antigens. It is poor activator of complement system. It has half-life about 21 days.
3. IgG3-
   • Abundance- IgG3 forms about 5% of total serum IgG.
   • Structure- It has very long 62 amino acid hinge region. It contains 11 disulphide bonds. This gives very high flexibility to the molecule.
   • Function- It is the strongest activator of complement pathway. It also binds strongly with cellular immune receptors. But its long hinge region is easily cleaved by enzymes. It has short half-life about 7 days, due to variation in FcRn binding site.
4. IgG4-
   • Abundance- IgG4 is the least common subclass. It forms about 5% of serum IgG.
   • Structure- It has short 12 amino acid hinge region. It contains only 2 disulphide bonds.
   • Function- It generally does not activate the complement system. It has intermediate receptor binding. Its special character is Fab-arm exchange (FAE). In this process, half of IgG4 molecule exchange with another IgG4 molecule and forms bispecific antibody. It acts as anti-inflammatory blocking antibody. It helps in stopping allergic reaction, but sometimes it may help tumour cells to escape from immune system. It has half-life about 21 days.

Distribution of IgG in the Body

Immunoglobulin G (IgG) is widely distributed in body. It is present in blood, tissue fluid and some secretion. It is the main antibody of serum and extracellular fluid.

The following are the distribution sites of IgG–

• Blood and plasma- IgG is the most abundant antibody in human blood. It forms about 10-20% of all plasma proteins. Its average serum concentration is about 9.0 mg/mL.
• Extravascular fluid- Large amount of IgG is also present outside the blood vessels. About half of total body IgG is found in extravascular compartment and extracellular fluid. So, it gives protection in tissues also.
• Mucosal secretion- IgG is present in mucosal secretions of respiratory tract, gastrointestinal tract and genital tract. In these places it works with IgA and IgM. It helps in defence against pathogens entering through body surfaces.
• Fetal circulation- IgG is the only antibody which can cross the placenta. It is actively transported from mother to fetus. Due to this, IgG is present in fetal blood and it becomes the most abundant antibody in newborn baby.
• Central nervous system- IgG is very less in brain and spinal cord. The blood-brain barrier restricts the entry of IgG. Some receptors also remove IgG from central nervous system (CNS) to peripheral blood. Less than 0.01% of circulating IgG normally enters the brain.

Synthesis and Production of IgG

Immunoglobulin G (IgG) is produced by plasma cells. These cells are derived from B lymphocytes. It is mainly produced during secondary immune response.

The following are the synthesis and production of IgG–

• IgG is a glycoprotein antibody produced by plasma cells. Plasma cells are specialized protein producing cells formed from activated B cells.
• The production starts when a specific antigen or immunogen binds with B-cell receptor (BCR) on the surface of B lymphocyte. This antigen may be from bacteria, virus or other foreign substance.
• After binding of antigen, signal is passed inside the B cell. This signal activates some transcription factors. Then the B cell becomes activated for antibody production.
• The activated B cell differentiates into plasma cell. Plasma cell synthesizes and secretes large amount of antibody. In this condition IgG is formed and released into blood and tissue fluid.
• One clone of B cell produces one specific immunoglobulin. The formed IgG is specific for the same antigen which stimulated that B cell.
• IgM is produced first during primary immune response. IgG is mainly produced during secondary immune response. In this response, antibody production is faster and stronger.
• The heavy chain and light chain of IgG are encoded by V, D and J gene segments. These gene segments recombine with each other and produce different antibody specificity.
• Antibody diversity is formed by gene recombination, somatic mutation and gene conversion. Due to this, body can produce antibodies against many different antigens.
• Different subclasses of IgG are formed by class switch recombination. This process is controlled by cytokines and interaction with T cells.
• The switching occurs in one-way direction on chromosome 14. It may proceed from IgG3 to IgG1, then IgG2 and finally IgG4. The type of antigen and immune signal decides the subclass of IgG.

Mechanism of IgG Production

Immunoglobulin G (IgG) is produced by plasma cells. These cells are formed from B lymphocytes. It is a glycoprotein antibody and it is mainly formed during secondary immune response.

The following are the mechanism of IgG production-

• IgG production starts when a specific antigen or immunogen enters the body. This antigen may be viral protein, bacterial protein or any foreign molecule.
• The antigen binds with B-cell receptor (BCR) present on the surface of B lymphocyte. This binding is specific. Only the suitable B cell can bind with that antigen.
• After antigen binding, signal is produced inside the B cell. This signal activates different transcription factors. These factors help the B cell to start antibody forming process.
• The activated B cell then differentiates into plasma cell. Plasma cell is a protein making cell. It produces and secretes large amount of IgG antibody.
• The formed plasma cell clone produces antibody against the same antigen which first stimulated the B cell. So, the produced IgG is highly specific in nature.
• IgG is mainly synthesized during secondary immune response. In this response antibody production is faster and greater. It gives long term protection against the pathogen.
• The light chain of antibody is encoded by V and J gene segments. The heavy chain is encoded by V, D and J gene segments.
• These gene segments recombine with each other. This recombination forms different antibody specificities. So, many types of IgG can be formed against different antigens.
• More diversity is produced by somatic mutation, gene conversion and nucleotide addition. These changes help in formation of more specific antibody.
• The production of IgG1, IgG2, IgG3 and IgG4 occurs by class switch recombination. This is controlled by cytokines and interaction with T cells.
• The switching occurs in one-way direction on chromosome 14. It can move from IgG3 to IgG1, then IgG2 and finally IgG4.
• The type of IgG subclass depends on the nature of antigen and immune signal. Helper T cell signal through MHC class II can help in switching to IgG1 or IgG3 for protein antigens.
• IL-10 and IL-4 mediated modified T-helper 2 response helps in selection of IgG4. So, cytokine condition decides the type of subclass formed.
• During this process, memory B cells are also formed. These cells remember the same antigen. On next exposure, they quickly change into plasma cells and rapidly produce IgG.

Functions of IgG

Immunoglobulin G (IgG) is the main antibody present in blood and tissue fluid. It protects the body from bacteria, virus and toxins. It is important in both direct and indirect immune defence.

The following are the functions of IgG–

• IgG binds directly with viruses, toxins and some bacteria. It neutralizes them and prevents their attachment with host cells. So, infection of the cells is reduced.
• IgG helps in opsonization. In this process IgG coats the surface of microbes. The coated microbes are easily recognized by macrophages and neutrophils.
• During opsonization, the Fc region of IgG binds with Fc receptors on phagocytic cells. Then the pathogen is engulfed and destroyed inside the phagocyte.
• IgG can activate the classical complement pathway. This occurs when IgG binds with antigen on microbial surface. The complement cascade then causes destruction of pathogen.
• IgG takes part in cellular effector mechanism. It binds with Fc gamma receptors (FcγRs) present on white blood cells. This binding activates different immune cell response.
• IgG helps in antibody-dependent cellular cytotoxicity (ADCC). In this process, infected cells or tumour cells coated with IgG are destroyed by immune cells.
• IgG also helps in antibody-dependent cellular phagocytosis (ADCP). In this process, IgG coated particles are taken up by phagocytic cells and digested.
• IgG is the only antibody which can cross the placenta. It is transported from mother to fetus through neonatal Fc receptor (FcRn). This gives passive immunity to the fetus.
• In newborn baby, maternal IgG gives protection during first weeks of life. It protects the baby from many infections before its own immune system becomes fully active.
• IgG helps in formation of immune complexes. It binds with multiple antigens and forms larger complexes. These complexes are then removed from blood.
• The formed immune complexes are filtered and cleared mainly by liver, spleen and sometimes kidney. This prevents accumulation of antigen in circulation.
• Different subclasses of IgG have different defence role. IgG1 and IgG3 mainly act against viral and bacterial protein antigens. IgG2 is important against encapsulated bacteria having polysaccharide antigens.

Antigen Binding by IgG

Immunoglobulin G (IgG) binds with antigen by its upper arm region. This binding is specific. It depends on the shape of antigen and the shape of antigen-binding site of antibody.

The following are the antigen binding by IgG–

• Antigen binds with IgG at the Fab region. Fab means Fragment antigen-binding. These regions are present at the two tips of the Y-shaped antibody.
• The antigen-binding site is formed by variable domains of both heavy chain and light chain. These are VH and VL regions.
• In the variable domains, there are hypervariable regions. Three hypervariable regions are present in heavy chain and three are present in light chain.
• These hypervariable regions fold together and form the exact antigen-binding pocket. This pocket is present at the tip of Fab arm.
• One IgG molecule has two identical antigen-binding sites. So, IgG is called divalent antibody.
• The two antigen-binding sites bind with same type of antigenic determinant. This helps in stronger attachment with antigen surface.
• Antigen binding by IgG is highly specific. One clone of B cell produces one type of IgG. This IgG binds with the same antigen which first stimulated that B cell.
• The antigen may be bacterial protein, viral protein, toxin or other foreign molecule. IgG recognizes particular part of antigen called epitope.
• The hinge region of IgG gives flexibility to the molecule. It allows movement of Fab arms in different angles.
• Due to this flexibility, two Fab arms can adjust their position separately. This helps IgG to bind antigens which are present apart from each other or on uneven microbial surface.
• The movement of Fab-Fab and Fab-Fc region helps in better antigen attachment. After binding, IgG can neutralize antigen or start other immune functions.

Neutralization of Pathogens and Toxins by IgG

Immunoglobulin G (IgG) neutralizes many pathogens and toxins. It binds with them by its Fab region. This prevents their attachment with host cells.

The following are the neutralization of pathogens and toxins by IgG–

• IgG binds directly with antigen present on the surface of virus and bacteria. It can also bind with free toxin present in body fluid.
• The binding is done by variable region of Fab arms. This binding is specific for the antigen or toxin.
• When IgG binds with pathogen surface, it blocks the attachment site of the pathogen. So, the pathogen cannot bind properly with host cell receptors.
• IgG also prevents attachment of microbes with mucosal surfaces. Due to this, entry and infection of host cells is reduced.
• In viral infection, IgG can bind with viral surface protein. This stops the virus from entering into host cell.
• In bacterial infection, IgG can bind with bacterial surface antigen. This reduces bacterial attachment and spreading in tissue.
• IgG neutralizes toxin by binding with its active region. It may cover the active site of toxin. So, toxin cannot interact with vulnerable host cell.
• After toxin binding, the toxin becomes harmless or less active. Then it can be removed by immune cells and other clearance mechanism.
• IgG4 has special blocking function in allergy. It can bind with allergen before allergen binds with IgE on mast cells.
• Due to this, IgG4 can prevent mast cell activation and allergic reaction. So, it acts as anti-inflammatory blocking antibody.
• Neutralization by IgG is an important part of host defence. It is mainly effective during secondary immune response, when same pathogen enters again.

Immunological Significance of IgG

Immunoglobulin G (IgG) is the most important antibody in secondary immune response. It gives long term protection against bacteria, virus and fungi. It is the main antibody present in blood and tissue fluid.

The following are the immunological significance of IgG–

• IgG is mainly produced during secondary immune response. When same pathogen enters again, IgG is produced rapidly and in large amount.
• It gives long term defence against repeated infection. So, it is important in immunological memory and protection of body.
• IgG neutralizes viruses, toxins and bacterial antigens. It blocks their attachment with host cell. Thus, entry of pathogen into cell is prevented.
• IgG helps in opsonization. It coats the microbial surface and makes the pathogen easy for phagocytosis by macrophages and neutrophils.
• It activates the classical complement pathway. This produces a series of immune reactions which help in destruction of microbial cells.
• IgG binds with Fc gamma receptors (FcγRs) present on white blood cells. This binding starts cellular immune reactions.
• It helps in antibody-dependent cellular cytotoxicity (ADCC). In this process infected cells, tumour cells or foreign cells are destroyed by immune cells.
• It also helps in antibody-dependent cellular phagocytosis (ADCP). In this process IgG coated particles are engulfed and digested by phagocytic cells.
• IgG is the only antibody which can cross the placenta. It is transported from mother to fetus by neonatal Fc receptor (FcRn).
• Maternal IgG gives passive immunity to fetus and newborn baby. It protects the newborn during first few weeks of life.
• IgG has long half-life in serum. Most subclasses remain about 21 days in circulation. This is due to recycling by FcRn, which protects IgG from lysosomal degradation.
• Different subclasses of IgG give defence against different antigen. IgG1 and IgG3 mainly act against protein antigens of virus and bacteria.
• IgG2 is important against encapsulated bacteria having polysaccharide antigens. IgG4 acts as blocking antibody and helps in reducing allergic reaction.
• Maternal IgG immune complexes may also help in immune tolerance. They can support formation of regulatory T cells and reduce allergy against harmless antigens.
• IgG is also important in modern treatment. Most therapeutic monoclonal antibodies are made based on human IgG structure. They are used in cancer, autoimmune disease and infectious disease treatment.

Laboratory Detection and Measurement of IgG

Immunoglobulin G (IgG) can be detected and measured in laboratory by different immunological methods. These tests are used for total IgG, specific IgG antibody, subclasses and abnormal antibody production.

The following are the laboratory detection and measurement of IgG–

• Quantitative serum immunoglobulin assay- This test measures total concentration of IgG and also its subclasses in blood. It is used to diagnose immunodeficiency disorders, where IgG is absent or low, and also overproduction of IgG.
• Post-immunization IgG testing- This assay measures specific IgG after vaccination. It is used for vaccines like tetanus, diphtheria, pneumococcal polysaccharide and polio. It shows how well immune system has responded to vaccine.
• Post-exposure IgG testing- This test detects specific IgG antibodies against known pathogens like measles and varicella-zoster virus. It is used to confirm past exposure, past infection and present immunity.
• Serum protein electrophoresis- This is a qualitative laboratory test which checks overall antibody level in serum. It can show monoclonal peak in the gamma region, which is an important sign of multiple myeloma.
• Rheumatoid factor assay- This test mainly detects IgM antibody directed against the Fc region of IgG. It is used as important serological marker for diagnosis of rheumatoid arthritis.
• IgG allotyping- This method is used for typing IgG molecule for genetic markers called Gm allotypes. These markers are present on heavy chain of IgG and can be useful in family and parenthood investigation.
• Affinity chromatography- In research and biotechnology laboratory, IgG is isolated from biological mixture by using Protein A and Protein G. These bacterial proteins bind with high, pH-dependent affinity to the Fc region of IgG, so they are used for capturing and purifying IgG.
• Monoclonal reagents- Modern measurement of IgG and its four subclasses depends on monoclonal antibodies against human IgG. These reagents give more specific and reproducible result, and improved IgG measurement from the 1980s.

Clinical Significance of IgG Testing

Immunoglobulin G (IgG) testing is used to know the immune status of patient. It helps in diagnosis of low antibody level, vaccine response, past infection and abnormal antibody production.

The following are the clinical significance of IgG testing-

• Immunodeficiency disorder- Quantitative measurement of total serum IgG and IgG subclasses is used to detect immune deficiency. Low IgG may be seen in X-linked agammaglobulinemia, transient hypogammaglobulinemia of infancy and common variable immunodeficiency (CVID). It explains recurrent pyogenic bacterial infections in patient.
• Vaccine response- Post-immunization IgG testing is used to check antibody response after vaccination. It is done for vaccines like tetanus, diphtheria, pneumococcal polysaccharide and polio. It shows whether protective antibody titre is produced or not.
• Past infection and immunity- Post-exposure IgG assay detects antibody against known pathogens. It is used for infections like measles and varicella-zoster virus. Presence of specific IgG indicates past exposure, previous infection and long term immunity.
• Subclass deficiency- Testing of individual IgG subclasses helps to detect isolated immune defect. IgG2 deficiency may be present even when total IgG is normal. It causes repeated respiratory and digestive tract infections, mainly due to encapsulated bacteria.
• Replacement therapy decision- Severe IgG subclass deficiency is important clinically. It helps to decide whether patient may need gammaglobulin replacement therapy or not.
• Monoclonal gammopathy- Serum protein electrophoresis is used to detect abnormal antibody production. It can show monoclonal peak in gamma region. This finding is important in plasma cell disorders like multiple myeloma.
• Autoimmune disease- IgG testing has role in autoimmune and rheumatologic condition. In rheumatoid factor test, IgM antibody is detected which reacts against Fc region of IgG. This is used as a serological marker for rheumatoid arthritis.
• Allergy and autoimmune association- Deficiency of IgG subclasses may be associated with allergic and autoimmune diseases. So, subclass testing is sometimes done in patients having repeated infection with allergy or autoimmune feature.
• Post-viral syndrome risk- Specific IgG subclass measurement may help to predict outcome after viral infection. Decreased IgG3 with low IgM is reported as a risk sign for post-acute COVID-19 syndrome (PACS).
• Genetic investigation- IgG allotyping is used to detect genetic markers called Gm allotypes on the heavy chain of IgG. This can be useful in family study and parenthood investigation.

Diseases Associated with Elevated IgG Levels

Elevated Immunoglobulin G (IgG) level is found in different disease. It may be due to infection, autoimmune disease, cancer of plasma cell or IgG4 related disease. This increase of IgG is also called hypergammaglobulinemia.

The following are the diseases associated with elevated IgG levels-

• Chronic and transient infections- In infections, IgG production may be increased. Transient increase is seen in Epstein-Barr virus infection and Plasmodium falciparum malaria. Chronic increase is seen in long lasting infections like HIV and cytomegalovirus (CMV).
• Autoimmune diseases- In autoimmune diseases, immune system reacts against own body tissue. So, high IgG or pathogenic IgG may be formed. It is seen in systemic lupus erythematosus (SLE), rheumatoid arthritis and antiphospholipid syndrome (APS).
• Neoplastic diseases- In some cancers, abnormal IgG is produced. In multiple myeloma, malignant plasma cells produce monoclonal IgG. It may also be associated with Rosai-Dorfman disease and angioimmunoblastic T-cell lymphoma.
• IgG4-related disease- IgG4-related disease is an immune-mediated inflammatory condition. In this disease, IgG4 level is increased in blood. Tissue fibrosis and chronic inflammatory swelling may be present.

Diseases Associated with Reduced IgG Levels

Reduced Immunoglobulin G (IgG) level is seen when antibody production is low or when IgG is destroyed very fast. It causes repeated bacterial infection, mainly in respiratory and digestive tract.

The following are the diseases associated with reduced IgG levels-

• Primary immunodeficiencies- These are genetic disorders where immune system cannot produce sufficient antibody. Low IgG is seen in X-linked agammaglobulinemia or Bruton agammaglobulinemia, common variable immunodeficiency (CVID) and immunodeficiency with increased IgM.
• Transient hypogammaglobulinemia of infancy- It is temporary low immunoglobulin condition in early months of life. It occurs because infant immune system is not producing enough antibody at that time. Later it decreases when baby starts making its own antibodies properly.
• IgG subclass deficiencies- In this condition total IgG may be normal but one subclass is low. Commonly IgG2 deficiency is seen. It is often associated with IgA deficiency and causes recurrent bacterial infection of respiratory tract and digestive tract.
• Familial hypercatabolic hypoproteinemia- It is a rare genetic syndrome. It occurs due to mutation which prevents expression of neonatal Fc receptor (FcRn). Without FcRn, IgG is not recycled properly and it is degraded rapidly. So, half-life of IgG becomes short and serum IgG level becomes low.

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