Immunoglobulin A

Immunoglobulin A (IgA, also referred to as sIgA in its secretory form) is an antibody that plays a role in the immune function of mucous membranes. The amount of IgA produced in association with mucosal membranes is greater than all other types of antibody combined. In absolute terms, between three and five grams are secreted into the intestinal lumen each day. This represents up to 15% of total immunoglobulins produced throughout the body. Primate IgA has two subclasses (IgA1 and IgA2) and can be produced as a monomeric as well as a dimeric form. The IgA dimeric form is the most prevalent and, when it has bound the Secretory component, is also called secretory IgA (sIgA). sIgA is the main immunoglobulin found in mucous secretions, including tears, saliva, sweat, colostrum and secretions from the genitourinary tract, gastrointestinal tract, prostate and respiratory epithelium. It is also found in small amounts in blood. The secretory component of sIgA protects the immunoglobulin from being degraded by proteolytic enzymes; thus, sIgA can survive in the harsh gastrointestinal tract environment and provide protection against microbes that multiply in body secretions. sIgA can also inhibit inflammatory effects of other immunoglobulins. IgA is a poor activator of the complement system, and opsonizes only weakly.

Forms

IgA1 vs. IgA2 Primate IgA exists in two isotypes, IgA1 and IgA2. They are both heavily glycosylated proteins. While IgA1 predominates in serum (~80%), IgA2 percentages are higher in secretions than in serum (~35% in secretions); the ratio of IgA1 and IgA2 secreting cells varies in the different lymphoid tissues of the human body:

IgA1 is the predominant IgA subclass found in serum. Most lymphoid tissues have a predominance of IgA1-producing cells. In IgA2, the heavy and light chains are not linked with disulfide, but with non-covalent bonds. In secretory lymphoid tissues (e.g., gut-associated lymphoid tissue, or GALT), the share of IgA2 production is larger than in the non-secretory lymphoid organs (e.g. spleen, peripheral lymph nodes). Both IgA1 and IgA2 have been found in external secretions like colostrum, maternal milk, tears and saliva, where IgA2 is more prominent than in the blood. The IgA1:A2 ratio in serum is 9:1, compared to 4:6 in secretions. Polysaccharide antigens tend to induce more IgA2 than protein antigens. The heavy chain of IgA1, in contrast to IgA2, features an extended hinge region. This is thought to allow IgA1 to adapt more effectively to varying epitope spacings on multivalent antigens, while also presenting less resistance to bacterial proteases. Both IgA1 and IgA2 can be in membrane-bound form (see B-cell receptor).

Monomeric vs. polymeric IgA IgA can be secreted by B cells either as a monomer or as a covalently-linked polymer/oligomer of multiple IgA subunits. Polymers of 2–4 IgA monomers, but most commonly 2 (dimers), are covalently linked to one molecule of the J chain (joining chain) inside the B cell prior to secretion as a J chain-coupled polymeric IgA molecule. The J chain is a polypeptide with a backbone molecular mass of 15 kDa but typically ~18 kDa when glycosylated, rich with cysteine and structurally completely different from other immunoglobulin chains. As such, the molecular weight of a J chain-coupled dimer of IgA is ~340 kDa. The oligomer forms of IgA in the external (mucosal) secretions also contain a polypeptide of a much larger molecular mass (70 kDa) called the secretory component that is produced by epithelial cells. This molecule originates from the poly-Ig receptor (130 kDa) that is responsible for the uptake and transcellular transport of J chain-containing polymeric (but not monomeric, which is devoid of J chain) IgA across the epithelial cells and into secretions such as tears, saliva, sweat and gut fluid.

Physiology

Serum IgA In the blood, IgA interacts with an Fc receptor called FcαRI (or CD89), which is expressed on immune effector cells, to initiate inflammatory reactions. Ligation of FcαRI by IgA containing immune complexes causes antibody-dependent cell-mediated cytotoxicity (ADCC), degranulation of eosinophils and basophils, phagocytosis by monocytes, macrophages, and neutrophils, and triggering of respiratory burst activity by polymorphonuclear leukocytes. Unlike IgM and IgG, which activate complement through the classical pathway, IgA can activate complement via the alternative and lectin pathways.

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