Immunoglobulin A (Ig A, also referred to as sIgA in its secretory form) is an
antibody
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of t ...
that plays a role in the
immune function
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splin ...
of
mucous membrane
A mucous membrane or mucosa is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It i ...
s. 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.
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 is also called ''secretory IgA'' (sIgA). sIgA is the main
immunoglobulin
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of th ...
found in
mucous secretions, including
tears
Tears are a clear liquid secreted by the lacrimal glands (tear gland) found in the eyes of all land mammals. Tears are made up of water, electrolytes, proteins, lipids, and mucins that form layers on the surface of eyes. The different types of ...
,
saliva
Saliva (commonly referred to as spit) is an extracellular fluid produced and secreted by salivary glands in the mouth. In humans, saliva is around 99% water, plus electrolytes, mucus, white blood cells, epithelial cells (from which DNA can ...
,
sweat
Perspiration, also known as sweating, is the production of fluids secreted by the sweat glands in the skin of mammals.
Two types of sweat glands can be found in humans: eccrine glands and apocrine glands. The eccrine sweat glands are distrib ...
,
colostrum and secretions from the
genitourinary tract,
gastrointestinal tract
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...
,
prostate
The prostate is both an accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found only in some mammals. It differs between species anatomically, chemically, and phys ...
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
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...
environment and provide protection against
microbe
A microorganism, or microbe,, ''mikros'', "small") and ''organism'' from the el, ὀργανισμός, ''organismós'', "organism"). It is usually written as a single word but is sometimes hyphenated (''micro-organism''), especially in olde ...
s that multiply in body secretions. sIgA can also inhibit inflammatory effects of other immunoglobulins.
IgA is a poor activator of the
complement system
The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and ...
, and
opsonizes only weakly.
Forms
IgA1 vs. IgA2
IgA exists in two
isotypes, IgA1 and IgA2. They are both heavily
glycosylated
Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...
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
In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...
, but with
non-covalent
In chemistry, a non-covalent interaction differs from a covalent bond in that it does not involve the sharing of electrons, but rather involves more dispersed variations of electromagnetic interactions between molecules or within a molecule. Th ...
bonds. In secretory lymphoid tissues (e.g.,
gut-associated lymphoid tissue
Gut-associated lymphoid tissue (GALT) is a component of the mucosa-associated lymphoid tissue (MALT) which works in the immune system to protect the body from invasion in the gut.
Owing to its physiological function in food absorption, the mucosa ...
, 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
Tears are a clear liquid secreted by the lacrimal glands (tear gland) found in the eyes of all land mammals. Tears are made up of water, electrolytes, proteins, lipids, and mucins that form layers on the surface of eyes. The different types of ...
and
saliva
Saliva (commonly referred to as spit) is an extracellular fluid produced and secreted by salivary glands in the mouth. In humans, saliva is around 99% water, plus electrolytes, mucus, white blood cells, epithelial cells (from which DNA can ...
, where IgA2 is more prominent than in the blood.
Polysaccharide antigens tend to induce more IgA2 than protein antigens.
Both IgA1 and IgA2 can be in membrane-bound form. (''see
B-cell receptor'')
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
A polymer (; Greek '' poly-'', "many" + '' -mer'', "part")
is a substance or material consisting of very large molecules called macromolecules, composed of many repeating subunits. Due to their broad spectrum of properties, both synthetic a ...
of 2–4 IgA
monomers
In chemistry, a monomer ( ; ''mono-'', "one" + '' -mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or three-dimensional network in a process called polymerization.
Classification
Mo ...
are linked by two additional chains; as such, the
molecular weight
A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and bio ...
of slgA is 385,000D. One of these is the
J chain
A J chain is a protein component of the antibodies IgM and IgA. It is a 137 residue polypeptide, encoded by the ''IGJ'' gene.
Structure
The J Chain's molecular weight is approximately 15 kDa. It exhibits a standard immunoglobulin folding ...
(joining chain), which is a
polypeptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
...
of molecular mass 15kD, rich with
cysteine
Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile.
When present as a deprotonated catalytic residue, some ...
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
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellu ...
. 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.
Physiology
Serum IgA
In the blood, IgA interacts with an
Fc receptor called FcαRI (or
CD89
Fc fragment of IgA receptor (''FCAR'') is a human gene that codes for the transmembrane receptor FcαRI, also known as CD89 (Cluster of Differentiation 89). FcαRI binds the heavy-chain constant region of Immunoglobulin A (IgA) antibodies. FcαRI ...
), 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
Antibody-dependent cellular cytotoxicity (ADCC), also referred to as antibody-dependent cell-mediated cytotoxicity, is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system actively lyses a target cell, whose ...
(ADCC), degranulation of
eosinophil
Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells (WBCs) and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. A ...
s and
basophil
Basophils are a type of white blood cell. Basophils are the least common type of granulocyte, representing about 0.5% to 1% of circulating white blood cells. However, they are the largest type of granulocyte. They are responsible for inflammator ...
s,
phagocytosis
Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is ...
by
monocyte
Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also ...
s,
macrophage
Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
s, and
neutrophil
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...
s, and triggering of respiratory burst activity by
polymorphonuclear leukocytes.
Secretory IgA
The high prevalence of IgA in mucosal areas is a result of a cooperation between
plasma cell
Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B lymphocytes and secrete large quantities of proteins called antibodies in response to being presented specific subs ...
s that produce polymeric IgA (pIgA), and mucosal epithelial cells that express
polymeric immunoglobulin receptor
Polymeric immunoglobulin receptor (pIgR) is a transmembrane protein that in humans is encoded by the ''PIGR'' gene. It is an Fc receptor which facilitates the transcytosis of the soluble polymeric isoforms of immunoglobulin A and immunoglobulin M ...
(pIgR).
Polymeric IgA (mainly the secretory dimer) is produced by
plasma cell
Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B lymphocytes and secrete large quantities of proteins called antibodies in response to being presented specific subs ...
s in the
lamina propria
The lamina propria is a thin layer of connective tissue that forms part of the moist linings known as mucous membranes or mucosae, which line various tubes in the body, such as the respiratory tract, the gastrointestinal tract, and the urogenit ...
adjacent to mucosal surfaces. It binds to the pIgR on the
basolateral surface of epithelial cells, and is taken up into the cell via
endocytosis
Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested material. ...
. 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
Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called protease ...
of the receptor occurs, and the dimeric IgA molecule, along with a portion of the receptor known as the
secretory component – known as sIgA, are free to diffuse throughout the
lumen.
In the gut, IgA can bind to the mucus layer covering the epithelial cells. In this way, a barrier capable of neutralizing threats before they reach the epithelial cells is formed.
Production of sIgA against specific antigens depends on sampling of
M cells and underlying
dendritic cell
Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. Th ...
s, T cell activation, and B cell
class switching
Immunoglobulin class switching, also known as isotype switching, isotypic commutation or class-switch recombination (CSR), is a biological mechanism that changes a B cell's production of immunoglobulin from one type to another, such as from the ...
in GALT,
mesenteric lymph nodes
The superior mesenteric lymph nodes may be divided into three principal groups:
* mesenteric lymph nodes
* ileocolic lymph nodes
* mesocolic lymph nodes
Structure
Mesenteric lymph nodes
The mesenteric lymph nodes or mesenteric glands are one of ...
, and isolated lymphoid follicles in the small intestine.
sIgA primarily acts by blockading
epithelial
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellu ...
receptors (e.g. by binding their ligands on pathogens), by sterically hindering attachment to epithelial cells, and by immune exclusion.
Immune exclusion is a process of agglutinating
polyvalent antigens or pathogens by crosslinking them with antibody, trapping them in the mucus layer, and/or clearing them
peristaltically. The oligosaccharide chains of the component of IgA can associate with the mucus layer that sits atop epithelial cells.
[ Since sIgA is a poor opsonin and activator of complement, simply binding a pathogen isn't necessarily enough to contain it—specific epitopes may have to be bound to sterically hinder access to the epithelium.][
Clearance of IgA is mediated at least in part by asialoglycoprotein receptors, which recognizes ]galactose
Galactose (, '' galacto-'' + ''-ose'', "milk sugar"), sometimes abbreviated Gal, is a monosaccharide sugar that is about as sweet as glucose, and about 65% as sweet as sucrose. It is an aldohexose and a C-4 epimer of glucose. A galactose molecu ...
-terminating IgA N-glycan
The terms glycans and polysaccharides are defined by IUPAC as synonyms meaning "compounds consisting of a large number of monosaccharides linked glycosidically". However, in practice the term glycan may also be used to refer to the carbohydrate ...
s.[
]
Pathology
Genetic
Decreased or absent IgA due to an inherited inability to produce IgA is termed selective IgA deficiency
Selective immunoglobulin A (IgA) deficiency (SIgAD) is a genetic immunodeficiency, a type of hypogammaglobulinemia. People with this deficiency lack immunoglobulin A (IgA), a type of antibody that protects against infections of the mucous membrane ...
and can produce a clinically significant immunodeficiency
Immunodeficiency, also known as immunocompromisation, is a state in which the immune system's ability to fight infectious diseases and cancer is compromised or entirely absent. Most cases are acquired ("secondary") due to extrinsic factors that a ...
.
Anti-IgA antibodies, sometimes present in individuals with low or absent IgA, can result in serious anaphylactic reactions when transfused with blood products that incidentally contain IgA. However, most persons with suspected IgA anaphylactic reactions had experienced acute generalized reactions that were from causes other than anti-IgA transfusion.
Microbial
'' Neisseria'' species including ''Neisseria gonorrhoeae
''Neisseria gonorrhoeae'', also known as ''gonococcus'' (singular), or ''gonococci'' (plural), is a species of Gram-negative diplococci bacteria isolated by Albert Neisser in 1879. It causes the sexually transmitted genitourinary infection gon ...
'' (which causes gonorrhea
Gonorrhea, colloquially known as the clap, is a sexually transmitted infection (STI) caused by the bacterium ''Neisseria gonorrhoeae''. Infection may involve the genitals, mouth, or rectum. Infected men may experience pain or burning with u ...
), ''Streptococcus pneumoniae
''Streptococcus pneumoniae'', or pneumococcus, is a Gram-positive, spherical bacteria, alpha-hemolytic (under aerobic conditions) or beta-hemolytic (under anaerobic conditions), aerotolerant anaerobic member of the genus Streptococcus. They ar ...
'', and ''Haemophilus influenzae
''Haemophilus influenzae'' (formerly called Pfeiffer's bacillus or ''Bacillus influenzae'') is a Gram-negative, non-motile, coccobacillary, facultatively anaerobic, capnophilic pathogenic bacterium of the family Pasteurellaceae. The bact ...
'' type B all release a protease that destroys IgA. Additionally, ''Blastocystis
''Blastocystis'' is a genus of single-celled heterokont parasites belonging to a group of organisms that are known as the Stramenopiles (also called Heterokonts) that includes algae, diatoms, and water molds. Blastocystis consists of several ...
'' species have been shown to have several subtypes that generate cysteine
Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile.
When present as a deprotonated catalytic residue, some ...
and aspartic protease
Aspartic proteases are a catalytic type of protease enzymes that use an activated water molecule bound to one or more aspartate residues for catalysis of their peptide substrates. In general, they have two highly conserved aspartates in the activ ...
enzymes which degrade human IgA.
Autoimmune and immune-mediated
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
Coeliac disease (British English) or celiac disease (American English) is a long-term autoimmune disorder, primarily affecting the small intestine, where individuals develop intolerance to gluten, present in foods such as wheat, rye and barle ...
involves IgA pathology due to the presence of IgA antiendomysial antibodies. Additional testing has been conducted using IgA trans-glutaminase autoantibodies which has been identified as a specific and sensitive for the detection of celiac disease.
Henoch–Schönlein purpura
Henoch–Schönlein purpura (HSP), also known as IgA vasculitis, is a disease of the skin, mucous membranes, and sometimes other organs that most commonly affects children. In the skin, the disease causes palpable purpura (small, raised areas of b ...
(HSP) is a systemic vasculitis caused by deposits of IgA and complement component 3
Complement component 3, often simply called C3, is a protein of the immune system. It plays a central role in the complement system and contributes to innate immunity. In humans it is encoded on chromosome 19 by a gene called ''C3''.
Function
C ...
(C3) in small blood vessels. HSP occurs usually in small children and involves the skin and connective tissues, scrotum, joints, gastrointestinal tract and kidneys. It usually follows an upper respiratory infection and resolves within a couple weeks as the liver clears out the IgA aggregates.
Linear IgA bullous dermatosis and IgA pemphigus are two examples of IgA-mediated immunobullous diseases. IgA-mediated immunobullous diseases can often be difficult to treat even with usually effective medications such as rituximab.
Drug-induced
Vancomycin
Vancomycin is a glycopeptide antibiotic medication used to treat a number of bacterial infections. It is recommended intravenously as a treatment for complicated skin infections, bloodstream infections, endocarditis, bone and joint infection ...
can induce a linear IgA bullous dermatosis in some patients.
See also
* List of target antigens in pemphigus
*TGF beta
Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other ...
References
External links
*
*
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Antibodies
Glycoproteins