Isotype (immunology)

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Some antibodies form complexes that bind to multiple antigen molecules. Mono-und-Polymere.svg
Some antibodies form complexes that bind to multiple antigen molecules.
Fab region Fc region Heavy chain (blue) with one variable (VH) domain followed by a constant domain (CH1), a hinge region, and two more constant (CH2 and CH3) domains Light chain (green) with one variable (VL) and one constant (CL) domain Antigen binding site (paratope) Hinge regions Immunoglobulin basic unit.svg
  1. Fab region
  2. Fc region
  3. Heavy chain (blue) with one variable (VH) domain followed by a constant domain (CH1), a hinge region, and two more constant (CH2 and CH3) domains
  4. Light chain (green) with one variable (VL) and one constant (CL) domain
  5. Antigen binding site (paratope)
  6. Hinge regions

In immunology, antibodies (immunoglobulins (Ig)) are classified into several types called isotypes or classes. The variable (V) regions near the tip of the antibody can differ from molecule to molecule in countless ways, allowing it to specifically target an antigen (or more exactly, an epitope). In contrast, the constant (C) regions only occur in a few variants, which define the antibody's class. Antibodies of different classes activate distinct effector mechanisms in response to an antigen (triggering different elements of the innate immune system). They appear at different stages of an immune response, differ in structural features, and in their location around the body. [1]

Contents

Isotype expression reflects the maturation stage of a B cell. Naive B cells express IgM and IgD isotypes with unmutated variable genes, which are produced from the same initial transcript following alternative splicing. Expression of other antibody isotypes (in humans: IgG, IgA, and IgE) occurs via a process of class switching after antigen exposure. [2] Class switching is mediated by the enzyme AID (activation-induced cytidine deaminase) and occurs after the B cell binds an antigen through its B cell receptor. Class-switching usually requires interaction with a T helper cell. [3] [4]

In humans, there are five heavy chain isotypes α,δ,γ,ε,μ, corresponding to five antibody isotypes:

There are also two light chain isotypes κ and λ; however, there is no significant difference in function between the two. Thus an antibody isotype is determined by the constant regions of the heavy chains only. [1]

IgM is first expressed as a monomer on the surface of immature B cells. Upon antigenic stimulation, IgM+ B cells secrete pentameric IgM antibody formed by five Ig monomers are linked via disulfide bonds. The pentamer also contains a polypeptide J-chain, which links two of the monomers and facilitates secretion at mucosal surfaces. The pentameric structure of IgM antibodies makes them efficient at binding antigens with repetitive epitopes (e.g. bacterial capsule, viral capsid) and activation of complement cascade. As IgM antibodies are expressed early in a B cell response, they are rarely highly mutated and have broad antigen reactivity thus providing an early response to a wide range of antigens without the need for T cell help. [5]

IgD isotypes are expressed on naive B cells as they leave bone marrow and populate secondary lymphoid organs. The levels of surface expression of IgD isotype has been associated with differences in B cell activation status but their role in serum is poorly understood. [6]

The IgG, IgE and IgA antibody isotypes are generated following class-switching during germinal centre reaction and provide different effector functions in response to specific antigens. IgG is the most abundant antibody class in the serum and it is divided into 4 subclasses based on differences in the structure of the constant region genes and the ability to trigger different effector functions. Despite the high sequence similarity (90% identical on the amino acid level), each subclass has a different half-life, a unique profile of antigen binding and distinct capacity for complement activation. IgG1 antibodies are the most abundant IgG class and dominate the responses to protein antigens. Impaired production of IgG1 is observed in some cases of immunodeficiency and is associated with recurrent infections. [7] The IgG responses to bacterial capsular polysaccharide antigens are mediated primarily via IgG2 subclass, and deficiencies in this subclass result in susceptibility to certain bacterial species. [8] IgG2 represents the major antibody subclass reacting to glycan antigens but IgG1 and IgG3 subclasses have also been observed in such responses, particularly in the case of protein-glycan conjugates. [9]

IgG3 is an efficient activator of pro-inflammatory responses by triggering the classical complement pathway. [10] It has the shortest half-life compared to the other IgG subclasses [11] and is frequently present together with IgG1 in response to protein antigens after viral infections. [12] IgG4 is the least abundant IgG subclass in the serum and is often generated following repeated exposure to the same antigen or during persistent infections.

IgA antibodies are secreted in the respiratory or the intestinal tract and act as the main mediators of mucosal immunity. [13] They are monomeric in the serum, but appear as a dimer termed secretory IgA (sIgA) at mucosal surfaces. The secretory IgA is associated with a J-chain and another polypeptide chain called the secretory component. [14] IgA antibodies are divided into two subclasses that differ in the size of their hinge region. [15] IgA1 has a longer hinge region which increases its sensitivity to bacterial proteases. [16] Therefore, this subclass dominates the serum IgA, while IgA2 is predominantly found in mucosal secretions. Complement fixation by IgA is not a major effector mechanism at the mucosal surface but IgA receptor is expressed on neutrophils which may be activated to mediate antibody-dependent cellular cytotoxicity. [17] sIgA has also been shown to potentiate the immune response in intestinal tissue by uptake of antigen together with the bound antibody by dendritic cells. [18]

IgE antibodies are present at lowest concentrations in peripheral blood but constitute the main antibody class in allergic responses through the engagement of mast cells, eosinophils and Langerhans cells. [19] Responses to specific helminths are also characterised with elevated levels of IgE antibodies. [20]

See also

Related Research Articles

<span class="mw-page-title-main">Antibody</span> Protein(s) forming a major part of an organisms immune system

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 the pathogen, called an antigen. Each tip of the "Y" of an antibody contains a paratope that is specific for one particular epitope on an antigen, allowing these two structures to bind together with precision. Using this binding mechanism, an antibody can tag a microbe or an infected cell for attack by other parts of the immune system, or can neutralize it directly.

<span class="mw-page-title-main">Mast cell</span> Cell found in connective tissue

A mast cell is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a part of the immune and neuroimmune systems. Mast cells were discovered by Paul Ehrlich in 1877. Although best known for their role in allergy and anaphylaxis, mast cells play an important protective role as well, being intimately involved in wound healing, angiogenesis, immune tolerance, defense against pathogens, and vascular permeability in brain tumours.

Humoral immunity is the aspect of immunity that is mediated by macromolecules - including secreted antibodies, complement proteins, and certain antimicrobial peptides - located in extracellular fluids. Humoral immunity is named so because it involves substances found in the humors, or body fluids. It contrasts with cell-mediated immunity. Humoral immunity is also referred to as antibody-mediated immunity.

Immunoglobulin G is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG antibody has two paratopes.

<span class="mw-page-title-main">Immunoglobulin A</span> Antibody that plays a crucial role in the immune function of mucous membranes

Immunoglobulin A 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.

<span class="mw-page-title-main">Immunoglobulin D</span>

Immunoglobulin D (IgD) is an antibody isotype that makes up about 1% of proteins in the plasma membranes of immature B-lymphocytes where it is usually co-expressed with another cell surface antibody called IgM. IgD is also produced in a secreted form that is found in very small amounts in blood serum, representing 0.25% of immunoglobulins in serum. The relative molecular mass and half-life of secreted IgD is 185 kDa and 2.8 days, respectively. Secreted IgD is produced as a monomeric antibody with two heavy chains of the delta (δ) class, and two Ig light chains.

<span class="mw-page-title-main">Immunoglobulin E</span> Immunoglobulin E (IgE) Antibody

Immunoglobulin E (IgE) is a type of antibody that has been found only in mammals. IgE is synthesised by plasma cells. Monomers of IgE consist of two heavy chains and two light chains, with the ε chain containing four Ig-like constant domains (Cε1–Cε4). IgE is thought to be an important part of the immune response against infection by certain parasitic worms, including Schistosoma mansoni, Trichinella spiralis, and Fasciola hepatica. IgE is also utilized during immune defense against certain protozoan parasites such as Plasmodium falciparum. IgE may have evolved as a defense to protect against venoms.

<span class="mw-page-title-main">Immunoglobulin M</span> One of several isotypes of antibody

Immunoglobulin M (IgM) is one of several isotypes of antibody that are produced by vertebrates. IgM is the largest antibody, and it is the first antibody to appear in the response to initial exposure to an antigen. In humans and other mammals that have been studied, plasmablasts residing in the spleen are the main source for specific IgM production.

<span class="mw-page-title-main">Plasma cell</span> White blood cell that secretes large volumes of antibodies

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 substances called antigens. These antibodies are transported from the plasma cells by the blood plasma and the lymphatic system to the site of the target antigen, where they initiate its neutralization or destruction. B cells differentiate into plasma cells that produce antibody molecules closely modeled after the receptors of the precursor B cell.

<span class="mw-page-title-main">Superantigen</span> Antigen which strongly activates the immune system

Superantigens (SAgs) are a class of antigens that result in excessive activation of the immune system. Specifically they cause non-specific activation of T-cells resulting in polyclonal T cell activation and massive cytokine release. SAgs are produced by some pathogenic viruses and bacteria most likely as a defense mechanism against the immune system. Compared to a normal antigen-induced T-cell response where 0.0001-0.001% of the body's T-cells are activated, these SAgs are capable of activating up to 20% of the body's T-cells. Furthermore, Anti-CD3 and Anti-CD28 antibodies (CD28-SuperMAB) have also shown to be highly potent superantigens.

<span class="mw-page-title-main">Memory B cell</span>

In immunology, a memory B cell (MBC) is a type of B lymphocyte that forms part of the adaptive immune system. These cells develop within germinal centers of the secondary lymphoid organs. Memory B cells circulate in the blood stream in a quiescent state, sometimes for decades. Their function is to memorize the characteristics of the antigen that activated their parent B cell during initial infection such that if the memory B cell later encounters the same antigen, it triggers an accelerated and robust secondary immune response. Memory B cells have B cell receptors (BCRs) on their cell membrane, identical to the one on their parent cell, that allow them to recognize antigen and mount a specific antibody response.

<span class="mw-page-title-main">Immunoglobulin heavy chain</span> Large polypeptide subunit of an antibody

The immunoglobulin heavy chain (IgH) is the large polypeptide subunit of an antibody (immunoglobulin). In human genome, the IgH gene loci are on chromosome 14.

<span class="mw-page-title-main">Immunoglobulin class switching</span> Biological mechanism

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 isotype IgM to the isotype IgG. During this process, the constant-region portion of the antibody heavy chain is changed, but the variable region of the heavy chain stays the same. Since the variable region does not change, class switching does not affect antigen specificity. Instead, the antibody retains affinity for the same antigens, but can interact with different effector molecules.

<span class="mw-page-title-main">Immunoglobulin light chain</span> Small antibody polypeptide subunit (immunoglobin)

The immunoglobulin light chain is the small polypeptide subunit of an antibody (immunoglobulin).

<span class="mw-page-title-main">Allotype (immunology)</span>

The word allotype comes from two Greek roots, allo meaning 'other or differing from the norm' and typos meaning 'mark'. In immunology, allotype is an immunoglobulin variation that can be found among antibody classes and is manifested by heterogeneity of immunoglobulins present in a single vertebrate species. The structure of immunoglobulin polypeptide chain is dictated and controlled by number of genes encoded in the germ line. However, these genes, as it was discovered by serologic and chemical methods, could be highly polymorphic. This polymorphism is subsequently projected to the overall amino acid structure of antibody chains. Polymorphic epitopes can be present on immunoglobulin constant regions on both heavy and light chains, differing between individuals or ethnic groups and in some cases may pose as immunogenic determinants. Exposure of individuals to a non-self allotype might elicit an anti- allotype response and became cause of problems for example in a patient after transfusion of blood or in a pregnant woman. However, it is important to mention that not all variations in immunoglobulin amino acid sequence pose as a determinant responsible for immune response. Some of these allotypic determinants may be present at places that are not well exposed and therefore can be hardly serologically discriminated. In other cases, variation in one isotype can be compensated by the presence of this determinant on another antibody isotype in one individual. This means that divergent allotype of heavy chain of IgG antibody may be balanced by presence of this allotype on heavy chain of for example IgA antibody and therefore is called isoallotypic variant. Especially large number of polymorphisms were discovered in IgG antibody subclasses. Which were practically used in forensic medicine and in paternity testing, before replaced by modern day DNA fingerprinting.

B1 cells are a sub-class of B cell lymphocytes that are involved in the humoral immune response. They are not part of the adaptive immune system, as they have no memory, but otherwise, B1 cells perform many of the same roles as other B cells: making antibodies against antigens and acting as antigen-presenting cells. These B1 cells are commonly found in peripheral sites, but less commonly found in the blood. These cells are involved in antibody response during an infection or vaccination.

<span class="mw-page-title-main">Polymeric immunoglobulin receptor</span> Protein-coding gene in the species Homo sapiens

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 (pIg) and immune complexes. pIgRs are mainly located on the epithelial lining of mucosal surfaces of the gastrointestinal tract. The composition of the receptor is complex, including 6 immunoglobulin-like domains, a transmembrane region, and an intracellular domain. pIgR expression is under the strong regulation of cytokines, hormones, and pathogenic stimuli.

<span class="mw-page-title-main">Humoral immune deficiency</span> Medical condition

Humoral immune deficiencies are conditions which cause impairment of humoral immunity, which can lead to immunodeficiency. It can be mediated by insufficient number or function of B cells, the plasma cells they differentiate into, or the antibody secreted by the plasma cells. The most common such immunodeficiency is inherited selective IgA deficiency, occurring between 1 in 100 and 1 in 1000 persons, depending on population. They are associated with increased vulnerability to infection, but can be difficult to detect in the absence of infection.

<span class="mw-page-title-main">Lactobacillus vaccine</span> Vaccine using an inactivated strain of Lactobacillus

Lactobacillus vaccines are used in the therapy and prophylaxis of non-specific bacterial vaginitis and trichomoniasis. The vaccines consist of specific inactivated strains of Lactobacilli, called "aberrant" strains in the relevant literature dating from the 1980s. These strains were isolated from the vaginal secretions of patients with acute colpitis. The lactobacilli in question are polymorphic, often shortened or coccoid in shape and do not produce an acidic, anti-pathogenic vaginal environment. A colonization with aberrant lactobacilli has been associated with an increased susceptibility to vaginal infections and a high rate of relapse following antimicrobial treatment. Intramuscular administration of inactivated aberrant lactobacilli provokes a humoral immune response. The production of specific antibodies both in serum and in the vaginal secretion has been demonstrated. As a result of the immune stimulation, the abnormal lactobacilli are inhibited, the population of normal, rod-shaped lactobacilli can grow and exert its defense functions against pathogenic microorganisms.

Anti-immunoglobulin antibodies are defined as a protein that detects other antibodies from an organism. Specifically, anti-immunoglobulin antibodies are created by B-cells as antibodies to bind to other immunoglobulins. Immunoglobulins have two regions: the constant region and the variable region. The constant region is involved in effector function, while the variable region is involved in recognizing and binding to antigens. Anti-immunoglobulin antibodies may bind to either the variable or constant region of the immunoglobulin. Anti-immunoglobulin antibodies are a type of secondary antibody. They are able to detect primary antibodies through multiple methods such as a Western blot, immunohistochemistry, immunofluorescence staining, flow cytometry, and ELISA.

References

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  2. ↑ Stavnezer, Janet (1996). "Immunoglobulin Class Switching". Current Opinion in Immunology. 8 (2): 199–205. doi:10.1016/s0952-7915(96)80058-6. PMID   8725943.
  3. ↑ Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter (2002-01-01). "Helper T Cells and Lymphocyte Activation".{{cite journal}}: Cite journal requires |journal= (help)
  4. ↑ Chandra, Vivek; Bortnick, Alexandra; Murre, Cornelis (2015-09-01). "AID targeting: old mysteries and new challenges". Trends in Immunology. 36 (9): 527–535. doi:10.1016/j.it.2015.07.003. PMC   4567449 . PMID   26254147.
  5. ↑ Chen, J, Boes, M (1998). "A critical role of natural immunoglobulin M in immediate defense against systemic bacterial infection". J Exp Med. 188 (12): 2381–6. doi:10.1084/jem.188.12.2381. PMC   2212438 . PMID   9858525.
  6. ↑ Achatz, G., Geisberger, R. (2006). "The riddle of the dual expression of IgM and IgD". Immunology. 118 (4): 429–37. doi:10.1111/j.1365-2567.2006.02386.x. PMC   1782314 . PMID   16895553.
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  12. ↑ Wahren, B., Linde, G. A. (1983). "Virus-specific antibody activity of different subclasses of immunoglobulins G and A in cytomegalovirus infections". Infect Immun. 42 (1): 237–44. doi:10.1128/iai.42.1.237-244.1983. PMC   264549 . PMID   6311746.
  13. ↑ Honjo, T.; Făgărășan, Sidonia (2001). "In situ class switching and differentiation to IgA-producing cells in the gut lamina propria". Nature. 413 (6856): 639–43. Bibcode:2001Natur.413..639F. doi:10.1038/35098100. PMID   11675788. S2CID   4393498.
  14. ↑ Hilschmann, N., Bastian, A. (1992). "Intra- and interchain disulfide bridges of the human J chain in secretory immunoglobulin A". Biol Chem Hoppe-Seyler. 373 (2): 1255–63. doi:10.1515/bchm3.1992.373.2.1255. PMID   1292512.
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  19. ↑ Walport M, Janeway CA Jr (2001). Immunobiology: The Immune System in Health and Disease.
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