Immunoglobulin A (IgA) is an antibody which plays a critical role in mucosal immunity. More IgA is produced in mucosal linings than all other types of antibody combined;[1] between 3 and 5g is secreted into the intestinal lumen each day.[2]. 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 genito-urinary 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 the 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.[3]
IgA is a poor activator of the complement system, and opsonises only weakly. Its heavy chains are of the type α.
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It exists in two isotypes, IgA1 (90%) and IgA2 (10%):
It is also possible to distinguish forms of IgA based upon their location - serum IgA vs. secretory IgA.
IgA is found in secretions in a specific form called secretory IgA, polymers of 2-4 IgA monomers linked by two additional chains. 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.
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.[4]
agar In the blood, IgA interacts with an Fc receptor called FcαRI (or CD89), which is expressed on immune effector cells, to initiate inflammatory reactions.[4] 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.[4]
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.[5] 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.
Decreased or absent IgA, termed selective IgA deficiency, can be a clinically significant immunodeficiency.
Neisseria gonorrhœae (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 it is an abnormality of immune system that results in these deposits.
ar:غلوبيولين مناعي A ca:Immunoglobulina A da:Immunoglobulin A de:Immunglobulin A es:Inmunoglobulina A fr:Superfamille des immunoglobulines it:IgA ja:免疫グロブリンA pl:Immunoglobuliny A pt:Imunoglobulina A fi:IgA
IgD's function has always been a puzzle in immunology since its discovery in 1964. IgD was recently found to be present in species from cartilaginous fish to human (probably with the exception of birds)[1]. This nearly ubiquitous appearance in species with an adaptive immune system demonstrates that IgD is as ancient as IgM and suggests the notion that IgD has important immunological functions.
In B cells, IgD's function is to signal the B cells to be activated. By being activated, they are ready to take part in the defense of the body in the immune system. During B-cell differentiation, IgM is the exclusive isotype expressed by immature B cells. IgD starts to be expressed when the B-cell exits the bone marrow to populate peripheral lymphoid tissues. When a B-cell reaches its mature state, it co-expresses both IgM and IgD. It is not well understood whether IgM and IgD antibodies are functionally different on B cells. Cδ Knockout mice have no major B-cell intrinsic defects.
Recently, IgD was found to bind to basophils and mast cells and activate these cells to produce antimicrobial factors to participate in respiratory immune defense in human[2]. It also stimulates basophils to release B-cell homeostatic factors. This is consistent with the reduction in the number of peripheral B cells, reduced serum IgE level and defective primary IgG1 response in IgD knockout mice.
In the human Heavy-Chain Locus, 3' of the V-D-J cassette is a series of C (for constant) genes, each conferring to an Ig isotype. The Cμ [IgM]gene is 3' and closest to the V-D-J cassette, with the Cδ gene appearing 3' to Cμ.
A Primary mRNA transcript will contain the transcripted V-D-J cassette, and the Cμ and Cδ genes, with introns in between them.
Alternative splicing can then occur, causing a selection of either Cμ or Cδ to appear on the functional mRNA (μ mRNA and δ mRNA respectively). Alternative splicing is thought to be possible due to two Polyadenylation sites, one appearing between the Cμ and Cδ, and the other 3' of Cδ (polyadenylation in the latter site would cause Cμ to be spliced away along with the intron). The precise mechanism of how the polyadenylation site is chosen remains unclear.
The resulting functional mRNA will have the V-D-J and C regions contiguous, and its translation will generate either a μ heavy chain or δ heavy chain. the heavy chains then couple with either κ or λ light chains to create the final IgM or IgD antibody.
Although IgE is typically the least abundant isotype - blood serum IgE levels in a normal ("non-atopic") individual are only 0.05% of the IgG concentration[7], compared to 10 mg/ml for the IgGs (the isotypes responsible for most of the classical adaptive immune response) - it is capable of triggering the most powerful immune reactions.
IgE was discovered in 1966 by the Japanese scientist couple Teruka and Kimishige Ishizaka.[8]
IgE elicits an immune response by binding to Fc receptors found on the surface of mast cells and basophils, and are also found on eosinophils, monocytes, macrophages and platelets in humans. Fc has two types:
IgE can upregulate the expression of both Fcε receptors. FcεRI is expressed only on mast cells and/or basophils in both mice and humans. Aggregation of antigens and binding of IgE to the FcεRI on mast cells causes degranulation and the release of mediators from the cells, while basophils cross-linked with IgE release type 2 cytokines like interleukin-4 (IL-4) and interleukin-13 (IL-13) and other inflammatory mediators. The low affinity receptor (FcεRII) is always expressed on B cells, but its expression can be induced on the surfaces of macrophages, eosinophils, platelets and some T cells by IL-4.
There is much speculation into what physiological benefits IgE contributes, and so far, circumstantial evidence in animal models and statistical population trends have hinted that IgE may be beneficial in fighting gut parasites such as Schistosoma mansoni, but this has not been conclusively proven in humans.
Although it is not yet well understood, IgE may play an important role in the immune system’s recognition of cancer[9], in which the stimulation of a strong cytotoxic response against cells displaying only small amounts of early cancer markers would be beneficial. Of course, if this were the case, anti-IgE treatments such as omalizumab might have some undesirable side effects.
Atopic individuals can have up to 10 times the normal level of IgE in their blood (as do sufferers of hyper-IgE syndrome). However, this may not be a requirement for symptoms to occur as has been seen in asthmatics with normal IgE levels in their blood - recent research has shown that IgE production can occur locally in the nasal mucosa[10].
IgE that can specifically recognise an "allergen" (typically this is a protein, such as dust mite DerP1, cat FelD1, grass or ragweed pollen, etc.) has a unique long-lived interaction with its high affinity receptor, FcεRI, so that basophils and mast cells, capable of mediating inflammatory reactions, become "primed", ready to release chemicals like histamine, leukotrienes and certain interleukins, which cause many of the symptoms we associate with allergy, such as airway constriction in asthma, local inflammation in eczema, increased mucus secretion in allergic rhinitis and increased vascular permeability, ostensibly to allow other immune cells to gain access to tissues, but which can lead to a potentially fatal drop in blood pressure as in anaphylaxis. Although the mechanisms of each response are fairly well understood, why some allergics develop such drastic sensitivities when others merely get a runny nose is still one of science's hot topics. Regulation of IgE levels through control of B cell differentiation to antibody-secreting plasma cells is thought to involve the "low affinity" receptor, FcεRII or CD23. CD23 may also allow facilitated antigen presentation, an IgE-dependent mechanism whereby B cells expressing CD23 are able to present allergen to (and stimulate) specific T helper cells, causing the perpetuation of a Th2 response, one of the hallmarks of which is the production of more antibodies.
IgE may be an important target in treatments for allergy and asthma.
Currently, severe allergy and asthma is usually treated with drugs (like anti-histamines) that damp down the late stages of inflammation and relax airway smooth muscle. Unfortunately, these treatments are fairly broad in their action, and so many have unpleasant side effects; they may also inhibit important protective responses.
In 2002, researchers at The Randall Division of Cell and Molecular Biophysics determined the structure of IgE[11]. Understanding of this structure (which is atypical of other isotypes in that it is highly bent and asymmetric), and of the interaction of IgE with receptor FcεRI will enable development of a new generation of allergy drugs that seek to interfere with the IgE-receptor interaction. A new treatment, omalizumab, a monoclonal antibody, recognises IgE not bound to its receptor and is used to neutralise or mop-up existing IgE and prevent it from binding to cells. It may be possible to design treatments cheaper than monoclonal antibodies (for instance, small molecule drugs) that use a similar approach to inhibit IgE binding to its receptor.
In 1975 Robert N. Hamburger, M.D. published "Peptide Inhibition of the P-K Reaction" based on blocking up to 89% of the IgE receptors on mast cells by the pentapeptide representing amino acids 320 to 324 on the epsilon chain of IgE.[12]
ar:غلوبيولين مناعي E ca:Immunoglobulina E cs:Imunoglobulin E da:Immunoglobulin E de:Immunglobulin E es:Inmunoglobulina E fr:Immunoglobuline E it:IgE ja:免疫グロブリンE pl:Immunoglobuliny E pt:Imunoglobulina E fi:IgE sv:Immunoglobulin E