What are Antibodies?
Antibodies, also known as immunoglobulins (Ig), are Y-shaped proteins produced by specialized white blood cells called B lymphocytes (B cells) in response to the presence of foreign substances known as antigens. Antibodies are an essential component of the immune system and play a crucial role in recognizing, binding to, and neutralizing antigens.
The structure of an antibody consists of four polypeptide chains: two identical heavy chains and two identical light chains. Each chain has a constant region and a variable region. The variable regions, located at the tips of the Y shape, are highly diverse and specific to different antigens. This diversity allows antibodies to recognize and bind to a wide range of antigens.
When an antigen enters the body, B cells are activated and undergo a process called clonal selection and expansion. During this process, B cells with receptors (antibodies) that can bind to the specific antigen are selected for proliferation. The activated B cells then differentiate into plasma cells, which are antibody-producing factories. Plasma cells secrete large amounts of antibodies into the bloodstream and other body fluids.
Antibodies function in several ways to defend against foreign invaders:
- Neutralization: Antibodies can bind to antigens, preventing them from interacting with host cells or tissues. This neutralization inhibits the harmful effects of antigens and prevents them from causing infection or damage.
- Opsonization: Antibodies can act as opsonins by binding to antigens on the surface of pathogens, marking them for recognition and ingestion by immune cells such as macrophages and neutrophils. This enhances the efficiency of phagocytosis and clearance of pathogens.
- Activation of complement system: Antibodies can activate the complement system, a group of proteins that work together to eliminate pathogens. Activation of complement can lead to the formation of membrane attack complexes that directly lyse target cells or enhance phagocytosis by immune cells.
- Antibody-dependent cell-mediated cytotoxicity (ADCC): Antibodies can bind to antigens on the surface of infected or abnormal cells, signaling natural killer (NK) cells and other immune effector cells to destroy the target cells.
- Immunological memory: After an initial exposure to an antigen, B cells can differentiate into memory B cells, which have a long lifespan and “remember” the antigen. In subsequent encounters with the same antigen, memory B cells can quickly mount a more rapid and robust immune response, leading to faster clearance of the pathogen.
Antibodies are diverse and can be classified into different classes (IgM, IgG, IgA, IgE, IgD), each with distinct properties and functions. Their ability to specifically recognize and target antigens is fundamental to the adaptive immune response and provides a crucial defense mechanism against infections and other foreign substances in the body.
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Immunoglobulin A (IgA)
- Immunoglobulin A (IgA) is an essential antibody that plays a crucial role in the immune system’s defense mechanisms, particularly in protecting mucous membranes. In fact, the amount of IgA produced in association with mucosal membranes surpasses the combined production of all other types of antibodies . To put it into perspective, around three to five grams of IgA are secreted into the intestinal lumen each day, constituting up to 15% of the total immunoglobulins produced in the body  .
- IgA has two subclasses known as IgA1 and IgA2, and it can exist in two different forms: monomeric and dimeric. The dimeric form, also referred to as secretory IgA (sIgA), is the most prevalent form of IgA. sIgA is primarily found in various mucous secretions, including tears, saliva, sweat, colostrum, and secretions from the genitourinary tract, gastrointestinal tract, prostate, and respiratory epithelium. Although present in smaller amounts, it can also be found in the bloodstream.
- One key feature of sIgA is the presence of a secretory component that protects the immunoglobulin from degradation by proteolytic enzymes. This protection enables sIgA to withstand the harsh environment of the gastrointestinal tract and effectively defend against microbes that thrive in body secretions . Additionally, sIgA possesses the ability to inhibit the inflammatory effects caused by other immunoglobulins .
- Unlike some other immunoglobulins, IgA exhibits poor activation of the complement system and demonstrates weak opsonization capabilities. Nonetheless, its primary function lies in providing defense at mucosal surfaces, contributing to the immune response against pathogens that attempt to invade the body through these routes.
- In summary, Immunoglobulin
Function of Immunoglobulin A (IgA)
- Immunoglobulin A (IgA) performs various crucial functions in the immune system, particularly through its secretory form, secretory IgA (SIgA). SIgA acts as the first line of defense in the mucosal surfaces, acting as a barrier against pathogens and other irritants. It binds to antigens, preventing their access to the submucosa and circulation, thus impeding their ability to cause infections or inflammation.
- SIgA interacts with several receptors, including the IgA transmembrane receptor (FcαRI), transferrin receptor, and Galectin-1, which plays a role in regulating intestinal immunity. FcαRI, found on myeloid cells such as eosinophils, neutrophils, macrophages, and Kupffer cells, is the primary receptor responsible for IgA mucosal immunity. When IgA immune complexes or IgA-bound pathogens cross-link with FcαRI, it triggers a series of physiological responses. These responses include phagocytosis, antibody-dependent cellular cytotoxicity, release of cytokines and other mediators of inflammation, and antigen presentation. Cross-linking with FcαRI also leads to the release of leukotriene B4 by neutrophils, a potent chemoattractant that promotes increased migration, reinforcing the containment of irritants or pathogens in the mucosa.
- Aside from its role in immune protection, IgA has significant anti-inflammatory functions mediated through interactions with FcαRI, dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN), and specific ICAM-3 grabbing nonintegrin-related 1 (SIGNR1) receptors. SIgA interacts with SIGNR1 in a sugar-dependent manner, inducing immune tolerance through regulatory T cells on dendritic cells. DC-SIGN interacts with sub-epithelial dendritic cells, facilitating the uptake of SIgA immune complexes in the lamina propria. Additionally, monomeric IgA interacts with FcαRI to phosphorylate Fc receptor gamma-identical activatory motifs (FcRy-ITAM), which recruits the tyrosine phosphatase SHP-1, leading to cellular inhibition through the formation of inhibisomes.
- Due to the pivotal roles of FcαRI and IgA in inflammation and immunity, researchers are exploring the potential of FcαRI inhibitors as treatments for allergies and immune complex conditions. These potential therapies are currently being tested in mouse models.
- In summary, Immunoglobulin A (IgA), especially in its secretory form (SIgA), fulfills critical functions in the immune system. It acts as a protective barrier against pathogens and irritants by binding to antigens and preventing their access to deeper tissues. Additionally, IgA exhibits anti-inflammatory effects mediated by specific receptors, promoting immune tolerance and cellular inhibition. Understanding the functions of IgA provides valuable insights into its role in immune responses and its potential applications in therapeutic interventions.
Mechanism of Immunoglobulin A (IgA)
- The mechanism of Immunoglobulin A (IgA) involves its secretion by plasma cells throughout the body into internal fluids or external secretions. In internal fluids like plasma and cerebrospinal fluid, IgA remains in its monomeric form. However, in external secretions, where it contributes to mucosal immunity, IgA is primarily released as a dimer held together by a joining (J) chain.
- Plasma cells located in the subepithelium of mucosal tissues secrete monomeric IgA. Subsequently, these monomers form complexes through covalent bonding with J chains, resulting in the formation of dimeric IgA. The next step involves the binding of dimeric IgA to the polymeric Ig receptor (pIgR) on the basolateral surface of intestinal epithelial cells. This binding enables the internalization of IgA through a process known as transcytosis.
- During transcytosis, the epithelial cell transports the IgA-bound pIgR across its cytoplasm and ultimately reaches the apical surface. At this point, the pIgR that is still attached to IgA is cleaved, resulting in the release of the secretory component. The secretory component is derived from pIgR and remains associated with the dimeric IgA. This process ultimately leads to the formation of secretory IgA (SIgA), which consists of dimeric IgA, the J chain, and the secretory component derived from pIgR.
- The secretory component of SIgA plays a crucial role in protecting IgA antibodies from proteolytic degradation. It also prevents the attachment of IgA to the epithelial surface within the mucosal lumen, allowing for effective interaction with pathogens. SIgA functions by preventing the adhesion and penetration of antigens, neutralizing viruses, and opsonizing antigens. In this way, SIgA provides a defense mechanism to prevent the invasion of pathogens and maintain the integrity of mucosal surfaces.
- In summary, the mechanism of Immunoglobulin A (IgA) involves its secretion as a dimeric form in external secretions through the action of plasma cells in mucosal tissues. The binding of dimeric IgA to the polymeric Ig receptor (pIgR) facilitates its transcytosis across epithelial cells. The cleavage of pIgR at the apical surface releases the secretory component, resulting in the formation of secretory IgA (SIgA). The secretory component protects IgA from degradation and prevents its attachment to the mucosal surface, enabling SIgA to fulfill its functions in neutralizing pathogens and maintaining mucosal defense.
Immunoglobulin G (IgG)
- Immunoglobulin G (IgG) is a type of antibody that plays a vital role in the immune system. It is the most common antibody found in blood circulation, accounting for approximately 75% of serum antibodies in humans. IgG antibodies are produced and released by plasma B cells and have two paratopes, which enable them to bind to specific antigens.
- There are four subclasses of IgG: IgG1, IgG2, IgG3, and IgG4. These subclasses have different functional properties and distribution within the body. One notable characteristic of IgG1, IgG3, and IgG4 is their ability to cross the placental barrier, providing protection to the developing fetus against infections.
- IgG antibodies serve various functions in the immune response. They can activate the complement system, particularly IgG3, IgG1, and IgG2 subclasses, which play a role in triggering an immune response against pathogens. Additionally, IgG antibodies mediate opsonization, a process in which they bind to pathogens and enhance their recognition and phagocytosis by immune cells. IgG1 and IgG3 exhibit high affinity for Fc receptors on phagocytic cells, IgG4 has intermediate affinity, and IgG2 has low affinity.
- Furthermore, IgG antibodies bind to microorganisms and facilitate their phagocytosis, contributing to the clearance of infections. They also participate in processes such as precipitation, complement fixation, and neutralization of toxins and viruses. IgG antibodies confer protection against microorganisms present in the blood and tissues, playing a crucial role in immune defense.
- In summary, Immunoglobulin G (IgG) is the most common type of antibody found in blood circulation. It comprises four subclasses and is produced by plasma B cells. IgG antibodies play a significant role in immune protection by activating the complement system, mediating opsonization, facilitating phagocytosis, and participating in processes such as precipitation, complement fixation, and neutralization. They also confer protection against microorganisms present in the blood and tissues, contributing to overall immune defense in the body.
Functions of Immunoglobulin G (IgG)
Immunoglobulin G (IgG) is a type of antibody that plays a crucial role in humoral immunity. It is the most abundant antibody in the extracellular fluid and blood, accounting for approximately 75% to 80% of the total antibodies in the human body. IgG is primarily responsible for defending against various pathogens, including viruses, bacteria, and fungi, thereby protecting us from infections. Here are some of the key functions of IgG:
- Pathogen Immobilization: When IgG encounters a pathogen, it binds to specific antigens present on the surface of the pathogen. This binding process leads to the coating or opsonization of the pathogen, making it more recognizable to phagocytic immune cells such as macrophages and neutrophils. These immune cells can then easily recognize, engulf, and destroy the antibody-coated pathogen through a process known as phagocytosis.
- Activation of Complement Pathway: IgG can activate the classical complement pathway, which is a cascade of immune proteins that work together to eliminate pathogens. Once IgG binds to a pathogen, it can trigger the activation of complement proteins, leading to the formation of membrane attack complexes that directly damage the pathogen’s membrane, resulting in its destruction.
- Toxin Neutralization: IgG antibodies can also bind to and neutralize toxins produced by certain bacteria or other microorganisms. By binding to the toxins, IgG prevents them from exerting their harmful effects on the body’s cells and tissues.
- Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC): IgG participates in antibody-dependent cell-mediated cytotoxicity, a process in which natural killer (NK) cells, macrophages, and other immune cells recognize and destroy cells that are coated with IgG antibodies. This mechanism is particularly important in the immune response against infected cells or cells that have become cancerous.
- Intracellular Antibody-Mediated Proteolysis: IgG can also enter cells and target intracellular pathogens, such as viruses that have already infected host cells. Once inside the cell, IgG can bind to viral antigens and mark them for destruction by proteolytic enzymes, effectively limiting the spread of the infection.
- Role in Hypersensitivity Reactions: IgG is involved in both type I and type II hypersensitivity reactions. In type I hypersensitivity, IgG antibodies bind to allergens and trigger the release of inflammatory mediators, leading to immediate allergic responses. In type II hypersensitivity, IgG antibodies recognize and bind to antigens on the surface of cells, triggering immune responses that can lead to cell destruction or damage.
- Maternal-Fetal Immunity: During pregnancy, IgG is released as a small molecule that can easily cross the placenta. This unique feature allows IgG to provide passive immunity to the developing fetus, offering protection against various infections that the mother has encountered throughout her life. Additionally, IgG present in breast milk provides humoral immunity to the infant before their own immune system fully develops, helping them fight infections early in life.
- Prevention of Allergic Reactions: IgG antibodies also play a role in preventing allergic reactions. By binding to allergens and neutralizing them, IgG can reduce the immune system’s response to these allergens, thereby minimizing the severity of allergic reactions.
Immunoglobulin M (IgM)
Immunoglobulin M (IgM) is a type of antibody that is produced by vertebrates, including humans. It is the largest antibody in size and is the first antibody to be produced in response to initial exposure to an antigen. IgM plays a crucial role in the early stages of the immune response. Here are some key features and characteristics of IgM:
- Source of IgM Production: In humans and other mammals, plasmablasts residing in the spleen are the primary source for specific IgM production. These cells produce and release IgM antibodies into the bloodstream in response to an antigenic stimulus.
- Structure of IgM: Immunoglobulins, including IgM, are composed of light chains and heavy chains. The µ heavy chain of IgM is a protein consisting of approximately 576 amino acids. It includes a variable domain (VH) and four distinct constant region domains (Cµ1, Cµ2, Cµ3, Cµ4). The light chain (λ or κ) is composed of a variable domain (VL) and a constant domain (CL). IgM also has a “tailpiece” of approximately 20 amino acids. The heavy and light chains are held together by disulfide bonds and non-covalent interactions.
- Multimeric Structure: IgM has a unique multimeric structure. It can exist as a pentamer, which is a polymer composed of five “monomers” [(µL)2]. Each monomer is formed by the association of one light chain and one heavy chain. The pentameric IgM structure includes disulfide bonds between the Cµ3 domains and between the tailpieces. Additionally, a third protein called the J chain is involved in joining two µ chains via disulfide bonds in the tailpieces.
- Function in the Immune Response: IgM plays a crucial role in the early stages of the immune response, particularly during the primary immune response to an antigen. It helps in the neutralization of pathogens, activation of complement proteins, and opsonization for phagocytosis. IgM antibodies have a high binding avidity, allowing them to effectively capture antigens.
- Activation of Complement Pathway: IgM is highly efficient at activating the classical complement pathway. When IgM antibodies bind to antigens on the surface of pathogens, they can trigger the activation of complement proteins, leading to the formation of membrane attack complexes that directly damage the pathogens.
- Role in Blood Group Antibodies: IgM antibodies are involved in the immune response against blood group antigens. For example, natural IgM antibodies can recognize and bind to ABO blood group antigens, leading to agglutination of incompatible blood types.
In summary, Immunoglobulin M (IgM) is the first antibody to be produced in response to an antigen. It has a unique pentameric structure and plays a crucial role in the early stages of the immune response. IgM is involved in neutralizing pathogens, activating the complement pathway, and contributing to the immune response against blood group antigens.
Functions of Immunoglobulin M (IgM)
Immunoglobulin M (IgM) has several important functions in the immune response. Here are the key functions of IgM based on the provided information:
- Activation of the Classical Complement Pathway: IgM can bind to complement component C1 and activate the classical complement pathway. This activation leads to opsonization of antigens, making them more recognizable and easily ingested by phagocytic cells. Additionally, it can result in the cytolysis of cells targeted by the immune system.
- Binding to Polyimmunoglobulin Receptor (pIgR): IgM interacts with the polyimmunoglobulin receptor (pIgR) via the J chain. This binding facilitates the transport of IgM to mucosal surfaces, such as the gut lumen and breast milk. This mechanism is important for providing local immune protection at mucosal sites.
- Interaction with Fc Receptors: IgM can also bind to Fc receptors, specifically Fcα/µ-R and Fcµ-R. Fcα/µ-R can bind both polymeric IgM and IgA and is involved in mucosal immunity. Fcµ-R exclusively binds IgM and can mediate the cellular uptake of IgM-conjugated antigens. The precise physiological functions of these receptors are still being studied.
- Regulation of the Immune Response: IgM plays a role in regulating the immune response. Injected specific immunoglobulins, including IgM, can influence the antibody response to the same antigen. The regulatory effects can be both positive and negative, depending on the antigen and the isotype of the antibody. For example, IgG administered with foreign erythrocytes suppresses the erythrocyte-specific antibody response, while IgM specific to erythrocytes can enhance the antibody response. The enhancing effect of IgM is thought to be dependent on its ability to activate complement, suggesting that B lymphocytes capture IgM-antigen-complement complexes and transport them to sites where efficient immune responses are generated.
In summary, Immunoglobulin M (IgM) has functions that include activating the classical complement pathway, binding to the polyimmunoglobulin receptor (pIgR) for transport to mucosal surfaces, interacting with Fc receptors, and regulating the immune response by enhancing or suppressing antibody responses to specific antigens.
Immunoglobulin E (IgE)
- Immunoglobulin E (IgE) is a specific type of antibody found in mammals. It plays a crucial role in the immune response against certain parasitic worms and protozoan parasites, as well as in allergic diseases and hypersensitivity reactions.
- The structure of IgE consists of two heavy chains (ε chain) and two light chains, with the ε chain containing four Ig-like constant domains (Cε1–Cε4). IgE is synthesized by plasma cells and is primarily associated with allergic responses and hypersensitivity reactions.
- In the immune response against parasitic infections, IgE is thought to provide defense against parasites such as Schistosoma mansoni, Trichinella spiralis, Fasciola hepatica, and Plasmodium falciparum. It may have evolved as a defense mechanism against venoms as well.
- In type I hypersensitivity reactions, IgE plays a pivotal role. It is involved in various allergic diseases including allergic asthma, sinusitis, allergic rhinitis, food allergies, chronic urticaria, and atopic dermatitis. It is also critical in responses to allergens, such as anaphylactic reactions to drugs, bee stings, and allergenic preparations used in desensitization immunotherapy.
- Despite being the least abundant isotype, with serum levels typically around 0.05% of total Ig concentration in non-atopic individuals, IgE can trigger rapid and severe immunological reactions, including anaphylaxis.
- IgE exerts its effects by binding to two types of Fc receptors: FcεRI (high-affinity IgE receptor) and FcεRII (low-affinity IgE receptor or CD23). FcεRI is found on mast cells, basophils, dendritic cells, eosinophils, monocytes, macrophages, and platelets. FcεRII is expressed on B cells and can be induced on the surfaces of macrophages, eosinophils, platelets, and certain T cells in the presence of IL-4.
- When antigens bind to IgE antibodies already bound by FcεRI on mast cells and basophils, it causes cross-linking of IgE and aggregation of FcεRI. This triggers degranulation, leading to the release of mediators and type 2 cytokines such as IL-3, stem cell factor (SCF), IL-4, IL-5, IL-13, and IL-33. These mediators and cytokines play roles in mast cell survival, accumulation in tissues, activation of group 2 innate lymphoid cells (ILC2 or natural helper cells), and the release of inflammatory mediators.
- In summary, IgE is a specialized antibody that participates in immune responses against parasitic infections and plays a central role in type I hypersensitivity reactions and allergic diseases. Its binding to Fc receptors triggers the release of mediators and cytokines involved in allergic and inflammatory responses.
Functions of Immunoglobulin E (IgE)
Immunoglobulin E (IgE) serves various functions in the immune system. Here are some key roles and observations associated with IgE:
- Defense against parasites: IgE has co-evolved with basophils and mast cells to protect against parasitic infections, particularly helminths such as Schistosoma mansoni and nematodes. Increased levels of IgE have been observed in humans infected with these parasites, suggesting a beneficial role in their removal, such as hookworms from the lung.
- Allergic response and toxin defense: The “toxin hypothesis” proposes that allergic reactions, including IgE-mediated responses, have evolved as a defense mechanism against venoms and other noxious toxins. Recent studies have shown that IgE antibodies play a vital role in acquired resistance to honey bee and viper venoms. IgE-mediated immune responses confer immunity and protect against potentially lethal doses of venom.
- Potential role in cancer recognition: Although not yet fully understood, IgE may play a role in the immune system’s recognition of cancer. It is believed that IgE could stimulate a strong cytotoxic response against cells displaying early cancer markers, which could be beneficial. However, further research is needed to fully understand this potential role.
- Implications in disease: Elevated levels of IgE are observed in atopic individuals and those with hyper-IgE syndrome. However, recent research suggests that symptoms can occur even in individuals with normal IgE levels, as IgE production can occur locally in the nasal mucosa. IgE is also implicated in autoimmune disorders like systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and psoriasis, where it may elicit hypersensitivity reactions.
- Regulation and diagnosis: The regulation of IgE levels and B cell differentiation to antibody-secreting plasma cells involve the low-affinity receptor FcεRII or CD23. IgE testing, specifically measuring allergen-specific IgE, is commonly used for diagnosing allergies by reviewing medical history and conducting skin or blood tests. The presence of allergen-specific IgE is a reliable indicator of allergic sensitization.
In summary, IgE plays a significant role in defense against parasites, allergic responses, potential toxin defense, and may have implications in cancer recognition and autoimmune disorders. Its regulation and measurement of allergen-specific IgE are crucial in diagnosing allergies.
Immunoglobulin D (IgD)
- Immunoglobulin D (IgD) is an antibody isotype primarily found on the surface of immature B-lymphocytes. It is often co-expressed with another antibody called IgM. IgD is also secreted in small amounts in the bloodstream. In serum, it constitutes approximately 0.25% of the total immunoglobulins. The secreted form of IgD is a monomeric antibody composed of two delta (δ) heavy chains and two light chains.
- IgD exhibits structural diversity across vertebrate species, serving as a flexible locus to complement the functions of IgM. It can compensate for defects in IgM function when necessary. The expression of IgD by B cells is regulated through alternative RNA splicing and class switch recombination. While alternative splicing is prevalent in all jawed vertebrates, class switch recombination occurs only in higher vertebrates, contributing to the diversification of IgD.
- In jawed fishes, the constant region of IgD displays high diversity, featuring amplifications of Cδ exons. Different splice variants of IgD exist due to alternative splicing. In humans and primates, IgD consists of three Cδ domains and a long H region. The amino-terminal region of the H region is rich in alanine and threonine residues, while the C-terminal region contains lysine, glutamate, and arginine residues that undergo O-glycosylation. This modification allows for binding to a putative IgD receptor on the surface of activated T cells. In humans, IgD with its H region interacts with heparin and heparan sulphate proteoglycans found on basophils and mast cells. In mice, IgD has a shorter H region with a distinct amino acid composition modified by N-glycosylation.
Functions of Immunoglobulin D (IgD)
- The precise functions of Immunoglobulin D (IgD) have been a subject of inquiry in immunology since its discovery. Although its exact role is not fully understood, studies indicate that IgD plays important immunological functions across various species with adaptive immune systems.
- In B cells, IgD serves as a signaling molecule that activates the B cells. This activation enables the B cells to participate in the body’s defense as part of the immune system. During the maturation of B cells, IgM is the primary antibody isotype expressed by immature B cells. However, as the B cells exit the bone marrow and populate peripheral lymphoid tissues, IgD starts to be expressed. In their mature state, B cells co-express both IgM and IgD on their surface. A study conducted in 2016 demonstrated that IgD signaling is specifically triggered by repetitive multivalent immunogens, while IgM can be triggered by soluble monomeric or multivalent immunogens. Knockout mice lacking the Cδ gene, which prevents the production of IgD, do not exhibit major intrinsic defects in B cells. However, IgD may have a role in allergic reactions, although further research is needed to clarify this connection.
- IgD has been found to bind to basophils and mast cells, activating these cells to produce antimicrobial factors. This suggests a role for IgD in respiratory immune defense in humans. Additionally, IgD stimulates basophils to release B cell homeostatic factors. The absence of IgD in knockout mice leads to reduced peripheral B cell numbers, decreased serum IgE levels, and impaired primary IgG1 responses.
- While the full extent of IgD’s functions is still being explored, its presence and activity in various immune processes highlight its significance in the immune system’s defense mechanisms. Further research is necessary to fully elucidate the specific roles and mechanisms of IgD in immune responses and disease conditions.