ResourcesBlogAntibody Isotypes: Structure and Function
Antibody Isotypes: Structure and Function
Biointron2024-09-04Read time: 6 mins
In mammals, antibodies are classified into five major isotypes: IgA, IgD, IgE, IgG, and IgM. Each isotype is defined by the heavy chain it contains: alpha (IgA), delta (IgD), epsilon (IgE), gamma (IgG), or mu (IgM). These structural differences in the heavy chains determine the antibody's function, tissue localization, and role in the immune response. Furthermore, antibody light chains fall into two classes—kappa and lambda—with kappa being more common, though both exhibit similar functions despite differences in sequence.
Understanding the structural variations across antibody isotypes is crucial in therapeutic antibody development, where specific isotypes can be leveraged to elicit desired immune responses, enhance bioavailability, or improve stability in various clinical applications.
DOI:10.3389/fimmu.2021.753294
IgG: The Dominant Antibody in the Immune System
IgG is the most abundant antibody in human serum, accounting for 70-85% of the total immunoglobulin pool. It is monomeric, with a molecular weight of approximately 150 kDa, and is the principal antibody of the secondary immune response. IgG is critical in long-term immunity due to its prolonged half-life of 20-24 days, making it a valuable candidate for therapeutic antibody engineering.
The human IgG class consists of four subclasses: IgG1, IgG2, IgG3, and IgG4. These subclasses differ primarily in the hinge region and their ability to activate various immune responses. For instance, IgG1 and IgG3 are highly effective at initiating complement activation and binding to Fc receptors, making them important in antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). In contrast, IgG4 has a more limited capacity to activate immune responses, making it useful for therapies requiring reduced immune activation, such as in certain autoimmune diseases.
Subclasses of IgG vary between species. In humans, there are four subclasses, while in mice there are five (IgG1, IgG2A, IgG2B, IgG2C, IgG3), and in rats, four. These variations underscore the importance of species-specific considerations in preclinical models when developing therapeutic antibodies.
IgM is the first antibody produced during the primary immune response and constitutes 5-10% of the total immunoglobulin pool. Unlike IgG, IgM lacks a hinge region and instead contains an additional constant domain and an 18-amino acid tailpiece at the carboxy terminus, which plays a crucial role in its multimerization. Typically, IgM exists as a pentamer held together by a J chain, but it can also form a hexamer lacking the J chain. The pentameric form of IgM gives it a high molecular weight of over 1 MDa, which restricts it to the intravascular space.
IgM's large size and multivalency enable it to bind antigens with high avidity and efficiently activate the complement system. This makes IgM particularly valuable during early immune responses, where rapid neutralization of pathogens is critical. Its presence on B cells as a monomer further supports its role in immune surveillance and activation of the adaptive immune system.
IgA represents 5-15% of the immunoglobulin pool and is the predominant antibody in mucosal secretions, such as saliva, tears, and intestinal fluids. It exists in both monomeric and dimeric forms, with the dimeric form being most common in secretions. Like IgM, dimeric IgA contains a J chain, and it is associated with a secretory component—a polypeptide chain produced by epithelial cells. This secretory component not only facilitates IgA transport across epithelial barriers but also protects it from proteolytic degradation in the gut.
The role of IgA in protecting mucosal surfaces from pathogens is critical, as it prevents microbial invasion by neutralizing pathogens at the entry points. This makes IgA particularly important in vaccines designed for mucosal immunity, as well as in therapeutic strategies aimed at bolstering immune responses in the respiratory or gastrointestinal tracts.
IgD is the least understood of the antibody isotypes, making up less than 1% of plasma immunoglobulins. It shares a similar basic structure with IgG but features an extended hinge region, rendering it highly susceptible to proteolytic degradation. While its precise role remains unclear, IgD is known to be present in large amounts on the surface of B cells, where it is thought to play a role in B cell activation and differentiation.
Despite its enigmatic function, the presence of IgD on B cells suggests that it may be involved in immune surveillance or regulation of immune responses. As research continues, it is possible that IgD may present novel opportunities in therapeutic antibody research, particularly in the modulation of B cell activity in autoimmune diseases or cancers.
IgE is the least abundant antibody in serum but plays a significant role in allergic reactions and immune responses to parasites. Structurally, IgE is similar to IgM, with two additional constant domains that replace the hinge region, allowing it to bind with high affinity to Fc receptors on mast cells and basophils. Upon antigen binding, IgE triggers the release of histamine and other inflammatory mediators, which leads to the symptoms of allergic reactions such as asthma, hay fever, and anaphylaxis.
Due to its role in allergic diseases, IgE is a target for therapeutic interventions aimed at reducing or neutralizing its activity. Monoclonal antibodies that block IgE binding to its receptors are already in use to treat severe allergic conditions, and further research into IgE's role in immunity could reveal additional therapeutic targets, particularly in the context of parasitic infections.
Antibodies are versatile molecules that perform a range of effector functions, many of which engage different arms of the immune system. Their modes of action extend beyond simple antigen binding, enabling the activation of various immune mechanisms that lead to pathogen neutralization and clearance. These functions include blocking molecular interactions, activating the complement system, and linking the humoral immune response to cellular immune responses via Fc receptor engagement.
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In addition to isotypes and subtypes, antibodies exhibit genetic variation known as allotypes, which are polymorphic epitopes on immunoglobulins. These allotypic differences arise from allelic variations in immunoglobulin genes, causing certain antibody subtypes to differ between individuals or ethnic groups. The presence of these polymorphic forms can influence immune responses, particularly when an individual is exposed to a non-self allotype, potentially triggering an anti-allotype immune reaction.
