Antibody Subtype and Isotype
Antibodies, called immunoglobulins, are usually "Y" shaped, and they are molecules secreted by b cells. The primary function of antibodies is to control and prevent pathogens and assist the immune response. Antibody isotype: Ig antigen-specific structure shared by all individuals in the same species. In mammals, there are five heavy chain isotypes: IgA (α), IgD (δ), IgE (ε), IgG (γ) and IgM (μ) Antibody Subtype: Based on the size of the hinge region, the position and molecular weight of the sulfur bonds between chains, human and mouse IgG can be further subdivided into four subtypes, IgG1 (γ1), IgG2 (γ2), IgG3 (γ3), and IgG4 (γ4)
Antibodies, called immunoglobulins, are usually "Y" shaped, and they are molecules secreted by b cells. The essential function of antibodies is to control and prevent pathogens and assist the immune response. Human antibodies can be divided into five classes: IgA, IgD, IgE, IgG, and IgM. For example, an IgG antibody is a four-peptide chain structure composed of two identical heavy chains (H) and light chains (L)assembled through disulfide bonds. Each chain has a constant region (C) and a variable region (V). The tail of"Y" is responsible for biological activity, such as binding to cells. The antigen-binding area is also called a paratope, which is the part that recognizes and binds antigen.
The heavy and light chains of different antibodies vary significantly in the sequence of about 110 amino acids near theN-terminus, called variable regions (V regions). The variable regions of the heavy and light chains are called VH and VL, respectively. The amino acid sequence near the C-terminus of the heavy chain and delicate chain is relatively stable and is called the constant region (C region). The constant regions of the heavy and light chains are called CH and CL, respectively. The variable regions of antibodies are used to recognize and bind antigens, while the constant regions initiate downstream effects, such as antibody-dependent cell-mediated cytotoxicity (ADCC). According to the different amino acid compositions and arrangement of the C region of the Ig light chain, the light chain can be divided into kappa and lambda. There are slight differences in the amino acid composition in the C region of the λ-type light chain, which divides the λ chain into four subtypes (λ1-λ4). The V region of an antibody can be subdivided into CDR (complementarity determining region) and FR (framework region, FR1-FR4). The CDR region sequence is highly variable, while the FR region sequence is relatively constant.
Based on the size of the hinge region, the position and molecular weight of the sulfur bonds between chains, human and mouse IgG can be further subdivided into four subtypes. Human IgG can be divided into IgG1 (γ1), IgG2 (γ2), IgG3 (γ3), and IgG4 (γ4), named in the order of their abundance in serum (IgG1 is the most abundant). Mouse IgG can be divided into IgG1, IgG2a, IgG2b, and IgG3. After the hybridoma monoclonal antibody preparation is completed, the antibody subtype needs to be identified.
IgG1 accounts for about 60-65% of the total IgG content. It is mainly responsible for the thymus-mediated immune response against protein and polypeptide antigens. It is also involved in the conditioning and activation of the complement cascade. Lack of IgG1 isotype is usually a sign of hypogammaglobulinemia.
IgG2 accounts for about 20-25% of the total IgG content. It mainly targets the immune response of carbohydrate/polysaccharide antigens. Among all IgG isotype defects, IgG2 deficiency is the most common cause of recurrent airway/respiratory infections in infants.
IgG3 accounts for 5-10% of the total IgG content and plays a significant role in the immune response against protein or polypeptide antigens.
IgG4 usually accounts for less than 4% of the total IgG content and does not bind to polysaccharides. The latest research shows that serum IgG4 levels are elevated in patients with sclerosing pancreatitis, cholangitis, and interstitial pneumonia. Other effects of IgG4 are still unknown.
The subtle differences in the amino acid sequence between IgG subclasses also affect their biological functions:
l IgG1, IgG3, and IgG4 cross the placenta readily, but IgG2 crosses the placenta with very low efficiency.
l IgG3 is the most effective complement activator, followed by IgG1; IgG2 is less efficient, and IgG4cannot activate complement.
IgG1 and IgG3 bind to Fc receptors on phagocytes with high affinity, thereby mediating opsonization.IgG4 has a medium affinity for Fc receptors, and IgG2 has a shallow relationship.
All individuals share Ig antigen-specific structures in the same species. In mammals, there are five heavychain isotypes: IgA (α), IgD (δ), IgE (ε), IgG (γ) and IgM (μ)
IgA is secreted in the respiratory tract or intestinal tract, acting as the primary mediator of mucosal immunity and the first line of defense against infection. They are monomeric in serum but appear as dimers on the mucosal surface. IgA antibodies are divided into two subclasses with different hinge regions. IgA1 has a more extended hinge region, which increases its sensitivity to bacterial proteases. Therefore, this subclass dominates serum IgA, andIgA2 is mainly present in mucosal secretions. IgA's complement fixation is not the primary effect mechanism of the mucosal surface. IgA receptors are expressed on neutrophils, which can activate to mediate antibody-dependent cellular cytotoxicity.
IgD accounts for less than 1% of the immunoglobulin library and is usually found on the cell membrane of B cells, and its molecular mass is 150kDa. The expression level of IgD isoforms is related to the activation state of B cells. There are few studies on IgD, and little is known about its role in serum.
IgE is usually found in basophils and mast cells, and its molecular mass is about 190kDa. Similar to the structure of IgM, IgE does not contain a hinge region but has two additional constant domains instead of the hinge region. IgE antibody is related to type I immediate hypersensitivity.
IgG is the most abundant antibody in serum, accounting for 70-85% of the total immunoglobulin library, with a molecular weight of about 150kDa, and usually exists as a monomer. Based on the structural differences of constant region genes and their ability to trigger different effector functions, they are divided into four subclasses, IgG1, IgG2, IgG3, and IgG4. They have a high degree of sequence similarity (about 90% identical) but have different half-lives, antigen-binding characteristics, and complement activation capabilities. IgG1 is the most abundant IgG subclass, dominating the response to protein antigens. The reaction to bacterial capsular polysaccharide antigen is mainly mediated by IgG2, the primary antibody subclass that reacts with glycan antigen. IgG3 is an effective activator of pro-inflammatory response, and it has the shortest half-life compared with other IgG subclasses. IgG4 is the least abundant IgG subclass in serum and is usually produced after repeated exposure to the same antigen or persistent infection. The IgG1, IgG3, and IgG4 subclasses of IgG can cross the placental barrier, are the only immunoglobulin capable of placental transport, and play an essential role in neonatal anti-infection immunity.
IgM is the first immunoglobulin expressed during the development of B cells. It is the primary antibody in the initial immune response, with a molecular weight of approximately 900kDa. IgM can exist in the form of monomers or pentamers. It binds to the surface of B cells in the monomeric form, and in the secreted form, it is in the form of pentamers (connected by the J chain). The pentameric structure allows them to bind to epitopes effectively. Since IgM antibodies are expressed in the early stages of B cell response, they are rarely highly mutated and have broad antigen reactivity, so they provide an early response to multiple antigens without the help of T cells.
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