Immunoglobulin A (IgA)- Structure, Subclasses and Functions

Immunoglobulin A (IgA) is one of the five major classes of antibodies that play a vital role in the immune system. IgA is mainly found in mucosal secretions, such as saliva, tears, breast milk, and intestinal fluids, where it protects the body from pathogens and toxins. IgA is also present in the blood serum, but at lower levels than other immunoglobulins.

IgA can exist in two subclasses: IgA1 and IgA2. These subclasses differ in their structure, distribution, and function. The subclasses are defined by the type of heavy chain they have: IgA1 has an alpha 1 (α1) heavy chain, while IgA2 has an alpha 2 (α2) heavy chain. The heavy chains are composed of four domains: variable (V), constant 1 (C1), hinge (H), and constant 2 (C2). The hinge region is a flexible segment that connects the C1 and C2 domains and allows the antibody to bend and bind to antigens.

• Molecular mass: IgA1 has a higher molecular mass than IgA2 because it has a longer hinge region with more amino acids and more disulfide bonds. The molecular mass of IgA1 is about 170 kDa, while that of IgA2 is about 160 kDa.
• Serum concentration: IgA1 is the predominant circulating IgA subclass, comprising about 85% of the total IgA concentration in serum. IgA2 represents only up to 15% of the total IgA in serum, but its percentage is higher in secretions.
• Protease susceptibility: IgA1 is more vulnerable to cleavage by bacterial proteases than IgA2 because its hinge region contains more potential cleavage sites. Proteases are enzymes that break down proteins and can be secreted by some bacteria as a way of evading the immune system. Cleavage of IgA1 can impair its ability to bind to antigens and activate the complement system.
• Allotypic forms: IgA2 can exist in two allotypic forms, IgA2 (m1) and IgA2 (m2), which differ by a single amino acid substitution in the C2 domain. The allotypic forms have different affinities for certain receptors and antigens. IgA1 does not have allotypic forms.
• Antigen specificity: IgA1 shows a better immune response to protein antigens than IgA2, while IgA2 plays a more important role in fighting against polysaccharide and lipopolysaccharide antigens. Polysaccharides and lipopolysaccharides are complex carbohydrates that are found on the surface of some bacteria and can trigger inflammation.

• IgA2 is the second subtype of IgA and represents only up to 15% of total IgA in serum, but IgA2 percentages are higher in secretions.
• IgA2 has a shorter hinge region than IgA1 and is more resistant to cleavage by bacterial proteases. This makes IgA2 more suitable for mucosal immunity, especially in the respiratory and gastrointestinal tracts where proteolytic enzymes are abundant.
• IgA2 can bind to both FcαRI (CD89) and FcαRII (CD40L) receptors on immune cells, whereas IgA1 can only bind to FcαRI. This may enhance the effector functions of IgA2, such as antibody-dependent cellular cytotoxicity (ADCC), phagocytosis and cytokine production.
• IgA2 occurs in two allotypic forms, IgA2 (m1) and IgA2 (m2), which differ by a single amino acid in the constant region of the heavy chain. The two allotypes have different antigenic and functional properties, such as binding affinity to Fc receptors, complement activation and susceptibility to bacterial degradation.
• IgA2 shows a better immune response to polysaccharide and lipopolysaccharide antigens than IgA1. This may reflect the different types of antigens encountered at mucosal surfaces, where bacteria and viruses often have polysaccharide or lipopolysaccharide components on their surface.

Immunoglobulin A (IgA) is a type of antibody that is found in both serum and secretions. IgA has a complex structure that varies depending on its location and function. In this section, we will describe the main features of IgA structure and how they relate to its role in immunity.

Monomeric IgA

Monomeric IgA is the predominant form of IgA in serum, accounting for about 85% of total IgA concentration. Monomeric IgA consists of four polypeptide chains: two identical light chains (κ or λ) and two identical heavy chains (α). The light and heavy chains are linked by disulfide bonds, forming a basic Y-shaped structure. Each arm of the Y has a variable region (V) that binds to a specific antigen, and a constant region (C) that determines the isotype and subclass of the antibody. The stem of the Y has a hinge region that allows flexibility and movement of the arms.

Monomeric IgA has two subclasses: IgA1 and IgA2. They differ in the length and composition of their hinge regions, which affects their susceptibility to proteolytic cleavage by bacterial enzymes. IgA1 has a longer hinge region with more proline residues, making it more vulnerable to degradation. IgA2 has a shorter hinge region with fewer proline residues, making it more resistant to degradation. IgA2 also has two allotypes: IgA2(m1) and IgA2(m2), which differ in the amino acid sequence of their Cα2 domains.

Dimeric IgA

Dimeric IgA is the main form of IgA in secretions, such as saliva, tears, milk, and mucous. Dimeric IgA consists of two monomeric IgA units joined by a J-chain (joining chain), which is a small polypeptide that facilitates polymerization and secretion of IgA. The J-chain is attached to the C-terminal end of the Cα3 domains of the two monomers by disulfide bonds. The resulting dimer has four antigen-binding sites and can bind to multiple antigens at once.

Dimeric IgA also contains a secretory component (SC), which is a glycoprotein derived from the epithelial cells that transport IgA across the mucosal barrier. The SC binds to the C-terminal end of the J-chain and covers part of the hinge regions of the two monomers, protecting them from proteolytic cleavage. The SC also helps in transcytosis of IgA from the basolateral to the apical side of the epithelial cells, where it is released into the secretions.

Other forms of IgA

In addition to monomeric and dimeric forms, IgA can also exist as trimeric or tetrameric forms in serum or secretions. These forms are less common and less well-studied than monomeric and dimeric forms. They are thought to have higher avidity and potency than monomeric or dimeric forms, but their exact structure and function are not fully understood.

Immunoglobulin A (IgA) is the most abundant antibody in the body, especially in mucosal secretions such as saliva, tears, breast milk, and intestinal fluids. IgA plays a crucial role in protecting the mucous membranes from pathogens and toxins by preventing their attachment and invasion. IgA also helps to maintain the balance of the microbiota in the gut and other mucosal surfaces by modulating their growth and activity.

• Neutralization: IgA can bind to viruses, bacteria, and toxins and prevent them from infecting or harming the cells. For example, IgA can neutralize influenza virus, rotavirus, cholera toxin, and staphylococcal enterotoxin. IgA can also block the receptors that some pathogens use to enter the cells, such as HIV and poliovirus.
• Immune exclusion: IgA can form a protective layer on the mucosal surface and prevent the penetration of foreign antigens into the underlying tissues. This reduces the risk of inflammation and tissue damage. IgA can also facilitate the clearance of pathogens and antigens by enhancing their transport across the epithelium and into the lumen.
• Immune regulation: IgA can modulate the immune response by interacting with various immune cells and molecules. For example, IgA can inhibit the activation of mast cells and basophils, which are involved in allergic reactions. IgA can also suppress the production of pro-inflammatory cytokines by macrophages and dendritic cells. IgA can also regulate the differentiation and function of B cells and T cells, which are responsible for antibody production and cellular immunity.
• Complement activation: IgA can activate the complement system, which is a group of proteins that enhance the immune response by opsonizing pathogens, triggering inflammation, and inducing cell lysis. However, IgA is a poor activator of complement compared to other immunoglobulins, such as IgG and IgM. IgA mainly activates the alternative pathway of complement, which does not require antibodies or antigen-antibody complexes. IgA also activates a specific form of complement called secretory component (SC), which is attached to IgA in mucosal secretions. SC can bind to complement receptors on epithelial cells and enhance their barrier function.

• IgA plays an important role in the immune system, especially in the mucosal surfaces and secretions. However, some disorders can affect the production, function, or regulation of IgA, leading to various clinical conditions.
• One of the most common immunodeficiency disorders is selective IgA deficiency (SIgAD), which is characterized by low or undetectable levels of serum and secretory IgA. SIgAD can increase the risk of infections, allergies, autoimmune diseases, and malignancies. The symptoms and severity of SIgAD vary widely among individuals, and some may remain asymptomatic throughout their lives. The exact cause of SIgAD is unknown, but genetic and environmental factors may be involved. There is no specific treatment for SIgAD, but supportive care and prophylactic antibiotics may be used to prevent or treat infections.
• Another disorder related to IgA is IgA nephropathy (IgAN), which is a type of glomerulonephritis that affects the kidneys. IgAN is caused by the deposition of IgA immune complexes in the glomeruli, which triggers inflammation and damage to the kidney tissues. IgAN can cause hematuria (blood in urine), proteinuria (protein in urine), hypertension (high blood pressure), and renal failure. The exact cause of IgAN is unclear, but genetic predisposition, infections, diet, and other factors may play a role. There is no cure for IgAN, but treatments such as corticosteroids, immunosuppressants, and angiotensin-converting enzyme inhibitors may help to slow down the progression of the disease and reduce the risk of complications.
• A third disorder associated with IgA is IgA vasculitis (IgAV), which is a type of vasculitis that affects the small blood vessels. IgAV is also known as Henoch-Schönlein purpura (HSP) or anaphylactoid purpura. IgAV is caused by the deposition of IgA immune complexes in the blood vessel walls, which leads to inflammation and bleeding. IgAV can affect various organs, such as the skin, joints, kidneys, and gastrointestinal tract. The most common symptom of IgAV is a purpuric rash (purple spots) on the lower limbs and buttocks. Other symptoms may include abdominal pain, bloody stools, arthritis, nephritis, and neuropathy. The exact cause of IgAV is unknown, but infections, drugs, vaccines, and food allergens may trigger or exacerbate the condition. Most cases of IgAV are self-limited and resolve within weeks or months, but some may require treatment with corticosteroids, immunosuppressants, or plasmapheresis to prevent or manage complications.

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