Immunoglobulin A



Immunoglobulin A (IgA) is an antibody that plays a critical role in mucosal immunity. More IgA is produced in mucosal linings than all other types of antibody combined; between three and five grams are secreted into the intestinal lumen each day. This accumulates to 75% of the total immunoglobulin produced in the entire body.

IgA has two subclasses (IgA1 and IgA2) and can exist in a dimeric form called secretory IgA (sIgA). In its secretory form, IgA is the main immunoglobulin found in mucous secretions, including tears, saliva, 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. IgA is a poor activator of the complement system, and opsonises only weakly. Its heavy chains are of the type α.

IgA1 vs. IgA2
IgA exists in two isotypes, IgA1 (~90%) and IgA2 (~10%); the ratio of IgA1 and IgA2 secreting cells varies in the different lymphoid tissues of the human body {Simell B et al. Clin Experiment Immunol 2006; 143:543-9}: 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. Polysaccharide antigens tend to induce more IgA2 than protein antigens. {Simell B et al. Clin Experiment Immunol 2006; 143:543-9}
 * IgA1 is the predominant IgA subclass found in serum. Most lymphoid tissues have a predominance of IgA-producing cells.
 * In IgA2, the heavy and light chains are not linked with disulfide, but with noncovalent bonds. In secretory lymphoid tissues (e.g. gut associated lymphoid tissue, GALT), the share of IgA2 production is larger than in the non-secretory lymphoid organs (e.g. spleen, peripheral lymph nodes).

Serum vs. secretory IgA
It is also possible to distinguish forms of IgA based upon their location - serum IgA vs. secretory IgA.

In secretory IgA, the form found in secretions, polymers of 2-4 IgA monomers are linked by two additional chains; as such slgA holds a molecular weight of 385,000. One of these is the J chain (joining chain), which is a polypeptide of molecular mass 15kD, rich with cysteine and structurally completely different from other immunoglobulin chains. This chain is formed in the IgA-secreting cells.

The oligomeric forms of IgA in the external (mucosal) secretions also contain a polypeptide of a much larger molecular mass (70 kD) called the secretory component that is produced by epithelial cells. This molecule originates from the poly-Ig receptor (130 kD) that is responsible for the uptake and transcellular transport of oligomeric (but not monomeric) IgA across the epithelial cells and into secretions such as tears, saliva, sweat and gut fluid.

IgA activity
The high prevalence of IgA in mucosal areas is a result of a cooperation between plasma cells that produce polymeric IgA (pIgA), and mucosal epithelial cells that express an immunoglobulin receptor called the polymeric Ig receptor (pIgR). pIgA is released from the nearby activated plasma cells and binds to pIgR. This results in transportation of IgA across mucosal epithelial cells and its cleavage from pIgR for release into external secretions.

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, neutrophils and eosinophils, and triggering of respiratory burst activity by polymorphonuclear leukocytes.

Transport
Polymeric IgA (mainly the secretory dimer) is produced by plasma cells in the lamina propria adjacent to mucosal surfaces. It binds to the polymeric immunoglobulin receptor on the basolateral surface of epithelial cells, and is taken up into the cell via endocytosis. The receptor-IgA complex passes through the cellular compartments before being secreted on the luminal surface of the epithelial cells, still attached to the receptor. Proteolysis of the receptor occurs, and the dimeric IgA molecule, along with a portion of the receptor known as the secretory component, are free to diffuse throughout the lumen. In the gut, it can bind to the mucus layer on top of the epithelial cells to form a barrier capable of neutralizing threats before they reach the cells.

Pathology
Decreased or absent IgA, termed selective IgA deficiency, can be a clinically significant immunodeficiency.

Neisseria gonorrhœae (which causes gonorrhea) releases a protease which destroys IgA.

IgA nephropathy is caused by IgA deposits in the kidneys. It is not yet known why IgA deposits occur in this chronic disease. Some theories suggest an abnormality of the immune system results in these deposits.

Celiac disease involves IgA pathology due to the presence of IgA antiendomysial antibodies.