Immunoglobulin A
Encyclopedia
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
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
Mucous membrane
The mucous membranes are linings of mostly endodermal origin, covered in epithelium, which are involved in absorption and secretion. They line cavities that are exposed to the external environment and internal organs...
, including tears
Tears
Tears are secretions that clean and lubricate the eyes. Lacrimation or lachrymation is the production or shedding of tears....
, saliva
Saliva
Saliva , referred to in various contexts as spit, spittle, drivel, drool, or slobber, is the watery substance produced in the mouths of humans and most other animals. Saliva is a component of oral fluid. In mammals, saliva is produced in and secreted from the three pairs of major salivary glands,...
, colostrum
Colostrum
Colostrum is a form of milk produced by the mammary glands of mammals in late pregnancy. Most species will generate colostrum just prior to giving birth...
and secretions from the genitourinary tract, gastrointestinal tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
, prostate
Prostate
The prostate is a compound tubuloalveolar exocrine gland of the male reproductive system in most mammals....
and respiratory epithelium
Respiratory epithelium
Respiratory epithelium is a type of epithelium found lining the respiratory tract, where it serves to moisten and protect the airways. It also functions as a barrier to potential pathogens and foreign particles, preventing infection and tissue injury by action of the mucociliary escalator.-...
. 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
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
environment and provide protection against microbes that multiply in body secretions.
IgA is a poor activator of the complement system
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
, and opsonise
Opsonin
An opsonin is any molecule that targets an antigen for an immune response. However, the term is usually used in reference to molecules that act as a binding enhancer for the process of phagocytosis, especially antibodies, which coat the negatively-charged molecules on the membrane. Molecules that...
s only weakly. Its heavy chain
Heavy chain
]The immunoglobulin heavy chain is the large polypeptide subunit of an antibody .A typical antibody is composed of two immunoglobulin heavy chains and two Ig light chains. Several different types of heavy chain exist that define the class or isotype of an antibody. These heavy chain types vary...
s are of the type α.
IgA1 vs. IgA2
IgA exists in two isotypesIsotype (immunology)
An isotype usually refers to any related proteins/genes from a particular gene family. In immunology, the "immunoglobulin isotype" refers to the genetic variations or differences in the constant regions of the heavy and light chains...
, 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}:
- 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 disulfideDisulfideIn chemistry, a disulfide usually refers to the structural unit composed of a linked pair of sulfur atoms. Disulfide usually refer to a chemical compound that contains a disulfide bond, such as diphenyl disulfide, C6H5S-SC6H5....
, but with noncovalent bonds. In secretory lymphoid tissues (e.g. gut associated lymphoid tissue, GALTGalt-Biology and biochemistry:*Galactose-1-phosphate uridylyltransferase, an enzyme*Gut-associated lymphoid tissue-People:*Sir Alexander Tilloch Galt, a major figure in Canadian Confederation*James Galt, Scottish footballer*Galt MacDermot, musician...
), 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
Colostrum
Colostrum is a form of milk produced by the mammary glands of mammals in late pregnancy. Most species will generate colostrum just prior to giving birth...
, maternal milk, tears
Tears
Tears are secretions that clean and lubricate the eyes. Lacrimation or lachrymation is the production or shedding of tears....
and saliva
Saliva
Saliva , referred to in various contexts as spit, spittle, drivel, drool, or slobber, is the watery substance produced in the mouths of humans and most other animals. Saliva is a component of oral fluid. In mammals, saliva is produced in and secreted from the three pairs of major salivary glands,...
, 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}
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
J chain
A J chain is a protein component of the antibodies IgM and IgA. It is a 137 residue polypeptide.-Structure:The J Chain's molecular weight is approximately 15 kDa. It exhibits a standard immunoglobulin folding structure of two β-pleated sheets of four ribbons folded against one another. It has 8...
(joining chain), which is a polypeptide of molecular mass 15kD, rich with cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
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
Secretory component
The secretory component is a component of immunoglobulin A which consists of a portion of the polymeric immunoglobulin receptor. Polymeric IgA binds to the polymeric immunoglobulin receptor on the basolateral surface of epithelial cells and is taken up into the cell via transcytosis...
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 cellPlasma cell
Plasma cells, also called plasma B cells, plasmocytes, and effector B cells, are white blood cells which produce large volumes of antibodies. They are transported by the blood plasma and the lymphatic system...
s 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
Fc receptor
An Fc receptor is a protein found on the surface of certain cells - including natural killer cells, macrophages, neutrophils, and mast cells - that contribute to the protective functions of the immune system....
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 monocyte
Monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...
s, macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s, neutrophils and eosinophils, and triggering of respiratory burst activity by polymorphonuclear leukocytes.
Transport
Polymeric IgA (mainly the secretory dimer) is produced by plasma cellPlasma cell
Plasma cells, also called plasma B cells, plasmocytes, and effector B cells, are white blood cells which produce large volumes of antibodies. They are transported by the blood plasma and the lymphatic system...
s in the lamina propria
Lamina propria
The lamina propria is a constituent of the moist linings known as mucous membranes or mucosa, which line various tubes in the body ....
adjacent to mucosal surfaces. It binds to the polymeric immunoglobulin receptor
Polymeric immunoglobulin receptor
Polymeric immunoglobulin receptor is a protein that in humans is encoded by the PIGR gene.It is a Fc receptor which facilitates the secretion of immunoglobulin A and immunoglobulin M.-Further reading:-External links:...
on the basolateral surface of epithelial cells, and is taken up into the cell via endocytosis
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
. The receptor-IgA complex passes through the cellular compartments before being secreted on the luminal surface
Lumen (anatomy)
A lumen in biology is the inside space of a tubular structure, such as an artery or intestine...
of the epithelial cells, still attached to the receptor. Proteolysis
Proteolysis
Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...
of the receptor occurs, and the dimeric IgA molecule, along with a portion of the receptor known as the secretory component
Secretory component
The secretory component is a component of immunoglobulin A which consists of a portion of the polymeric immunoglobulin receptor. Polymeric IgA binds to the polymeric immunoglobulin receptor on the basolateral surface of epithelial cells and is taken up into the cell via transcytosis...
, 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 immunodeficiencyImmunodeficiency
Immunodeficiency is a state in which the immune system's ability to fight infectious disease is compromised or entirely absent. Immunodeficiency may also decrease cancer immunosurveillance. Most cases of immunodeficiency are acquired but some people are born with defects in their immune system,...
.
Neisseria gonorrhœae (which causes gonorrhea
Gonorrhea
Gonorrhea is a common sexually transmitted infection caused by the bacterium Neisseria gonorrhoeae. The usual symptoms in men are burning with urination and penile discharge. Women, on the other hand, are asymptomatic half the time or have vaginal discharge and pelvic pain...
) releases a protease which destroys IgA.
IgA nephropathy
IgA nephropathy
IgA nephropathy is a form of glomerulonephritis...
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.