Misplaced Pages

#590409

112-463: In 1937, an antibody was observed in horses hyper-immunized with pneumococcus polysaccharide that was much larger in size than the typical rabbit γ-globulin, with a molecular weight of 990,000 daltons . In accordance with its larger size, the new antibody was originally referred to as γ-macroglobulin, and subsequently termed IgM—M for “macro”. The V domains of normal immunoglobulin are highly heterogeneous, reflecting their role in protecting against

224-472: A "sandwich" shape, the immunoglobulin fold , held together by a disulfide bond. Secreted antibodies can occur as a single Y-shaped unit, a monomer . However, some antibody classes also form dimers with two Ig units (as with IgA), tetramers with four Ig units (like teleost fish IgM), or pentamers with five Ig units (like shark IgW or mammalian IgM, which occasionally forms hexamers as well, with six units). IgG can also form hexamers, though no J chain

336-520: A B cell changes during cell development and activation. Immature B cells, which have never been exposed to an antigen, express only the IgM isotype in a cell surface bound form. The B lymphocyte, in this ready-to-respond form, is known as a " naive B lymphocyte ." The naive B lymphocyte expresses both surface IgM and IgD. The co-expression of both of these immunoglobulin isotypes renders the B cell ready to respond to antigen. B cell activation follows engagement of

448-600: A Y shape. In humans and most other mammals , an antibody unit consists of four polypeptide chains ; two identical heavy chains and two identical light chains connected by disulfide bonds . Each chain is a series of domains : somewhat similar sequences of about 110 amino acids each. These domains are usually represented in simplified schematics as rectangles. Light chains consist of one variable domain V L and one constant domain C L , while heavy chains contain one variable domain V H and three to four constant domains C H 1, C H 2, ... Structurally an antibody

560-441: A distinct epitope of an antigen. Although a huge repertoire of different antibodies is generated in a single individual, the number of genes available to make these proteins is limited by the size of the human genome. Several complex genetic mechanisms have evolved that allow vertebrate B cells to generate a diverse pool of antibodies from a relatively small number of antibody genes. The chromosomal region that encodes an antibody

672-451: A disulfide bond in the Cμ2 domains; this (μL)2 structure is often referred to as the IgM "monomer", as it is analogous in some ways to the structure of immunoglobulin G (IgG) . On the basis of its sedimentation velocity and appearance in electron micrographs, it was inferred that IgM usually occurs as a "pentamer", i.e., a polymer composed of five “monomers” [(μL)2]5, and was originally depicted by

784-488: A functional form (see V(D)J recombination ). In the case of the heavy chain, three germ-line segments denoted V, D and J are ligated together and adjoined to the DNA encoding the μ heavy chain constant region. Early in ontogeny, B cells express both the μ and the δ heavy chains; co-expression of these two heavy chains, each bearing the same V domain depends on alternative splicing and alternative poly-A addition sites. The expression of

896-542: A given microbe – that is, the ability of the microbe to enter the body and begin to replicate (not necessarily to cause disease) – depends on sustained production of large quantities of antibodies, meaning that effective vaccines ideally elicit persistent high levels of antibody, which relies on long-lived plasma cells. At the same time, many microbes of medical importance have the ability to mutate to escape antibodies elicited by prior infections, and long-lived plasma cells cannot undergo affinity maturation or class switching. This

1008-430: A half-life of 13.22 hours. The emitted 159  keV gamma ray is used in single-photon emission computed tomography (SPECT). A 127 keV gamma ray is also emitted. I is frequently used in radioimmunoassays because of its relatively long half-life (59 days) and ability to be detected with high sensitivity by gamma counters. I is present in the environment as a result of the testing of nuclear weapons in

1120-484: A half-life of 5730 years. It is continuously produced in the upper atmosphere of the earth, so it occurs at a trace level in the environment. However, it is not practical to use naturally-occurring C for tracer studies. Instead it is made by neutron irradiation of the isotope C which occurs naturally in carbon at about the 1.1% level. C has been used extensively to trace the progress of organic molecules through metabolic pathways. N decays by positron emission with

1232-403: A half-life of 9.97 min. It is produced by the nuclear reaction N is used in positron emission tomography (PET scan). O decays by positron emission with a half-life of 122 seconds. It is used in positron emission tomography. F decays predominantly by β emission, with a half-life of 109.8 min. It is made by proton bombardment of O in a cyclotron or linear particle accelerator . It

SECTION 10

#1732844946591

1344-473: A half-life of approximately 66 hours (2.75 days), so the generator has a useful life of about two weeks. Most commercial Tc generators use column chromatography , in which Mo in the form of molybdate, MoO 4 is adsorbed onto acid alumina (Al 2 O 3 ). When the Mo decays it forms pertechnetate TcO 4 , which because of its single charge is less tightly bound to the alumina. Pulling normal saline solution through

1456-510: A half-life: 6.01 hours. The short half-life ensures that the body-concentration of the radioisotope falls effectively to zero in a few days. I is produced by proton irradiation of Xe . The caesium isotope produced is unstable and decays to I. The isotope is usually supplied as the iodide and hypoiodate in dilute sodium hydroxide solution, at high isotopic purity. I has also been produced at Oak Ridge National Laboratories by proton bombardment of Te . I decays by electron capture with

1568-408: A huge number of antibodies, each with different paratopes , and thus different antigen specificities. The rearrangement of several subgenes (i.e. V2 family) for lambda light chain immunoglobulin is coupled with the activation of microRNA miR-650, which further influences biology of B-cells. RAG proteins play an important role with V(D)J recombination in cutting DNA at a particular region. Without

1680-440: A manifestation of immunological memory. In the course of an immune response, B cells can progressively differentiate into antibody-secreting cells or into memory B cells. Antibody-secreting cells comprise plasmablasts and plasma cells , which differ mainly in the degree to which they secrete antibody, their lifespan, metabolic adaptations, and surface markers. Plasmablasts are rapidly proliferating, short-lived cells produced in

1792-400: A mast cell, triggering its degranulation : the release of molecules stored in its granules. Binds to allergens and triggers histamine release from mast cells and basophils , and is involved in allergy . Humans and other animals evolved IgE to protect against parasitic worms , though in the present, IgE is primarily related to allergies and asthma. Although The antibody isotype of

1904-660: A model for a J chain-containing pentamer that reflects evidence that the J chain joins μ chains that are not joined to other μ chains by the cysteines in the Cμ3 domains. These and other models, both regular and irregular are discussed elsewhere. Pentameric IgM is typically represented as containing a single J chain per polymer, but in actuality the measurements of J chain stoichiometry have ranged from one J molecule per polymer to three J molecules per polymer. The wide range might be due to technical problems, such as incomplete radiolabeling or imprecisely quantitating an Ouchterlony line. However,

2016-481: A much stronger antibody response to the erythrocytes is induced than when erythrocytes are administered alone. Several lines of evidence indicate that the ability of IgM to activate complement is required for its enhancing effect. That is, IgM-mediated enhancement does not occur in animals that have been depleted for complement component C3, nor in mutant animals lacking complement receptors 1 and 2. Similarly, mutant IgM that cannot activate complement does not enhance

2128-455: A number of tests, such as Tc in autoradiography and nuclear medicine , including single-photon emission computed tomography (SPECT), positron emission tomography (PET) and scintigraphy . The urea breath test for helicobacter pylori commonly used a dose of C labeled urea to detect h. pylori infection. If the labeled urea was metabolized by h. pylori in the stomach, the patient's breath would contain labeled carbon dioxide. In recent years,

2240-444: A part of a virus that is essential for its invasion). More narrowly, an antibody ( Ab ) can refer to the free (secreted) form of these proteins, as opposed to the membrane-bound form found in a B cell receptor. The term immunoglobulin can then refer to both forms. Since they are, broadly speaking, the same protein, the terms are often treated as synonymous. To allow the immune system to recognize millions of different antigens,

2352-408: A protective effect. IgM in normal serum is often found to bind to specific antigens, even in the absence of prior immunization. For this reason, IgM has sometimes been called a "natural antibody". This phenomenon is probably due to the high avidity of IgM that allows it to bind detectably even to weakly cross-reacting antigens that are naturally occurring. For example, the IgM antibodies that bind to

SECTION 20

#1732844946591

2464-462: A secondary immune response, undergoing class switching, affinity maturation, and differentiating into antibody-secreting cells. Antibodies are central to the immune protection elicited by most vaccines and infections (although other components of the immune system certainly participate and for some diseases are considerably more important than antibodies in generating an immune response, e.g. herpes zoster ). Durable protection from infections caused by

2576-504: A short stem. IgM interacts with several other physiological molecules: Specific immunoglobulins that are injected into animals together with their antigen can influence the antibody response to this same antigen. Endogenous antibodies produced after a primary immunization can also affect the antibody response to a booster immunization, suggesting that similar effects occur during physiological conditions. The ”regulatory” effects can be either positive or negative. That is, depending on

2688-435: A source of homogeneous immunoglobulins of various isotypes, including IgM (reviewed in). More recently, the expression of engineered immunoglobulin genes in tissue culture can be used to produce IgM with specific alterations and thus to identify the molecular requirements for features of interest. Immunoglobulins are composed of light chains and heavy chains. The light chain (λ or κ) is a protein of ~220 amino acids, composed of

2800-432: A specific antigen is present in the body and triggers B cell activation. The BCR is composed of surface-bound IgD or IgM antibodies and associated Ig-α and Ig-β heterodimers , which are capable of signal transduction . A typical human B cell will have 50,000 to 100,000 antibodies bound to its surface. Upon antigen binding, they cluster in large patches, which can exceed 1 micrometer in diameter, on lipid rafts that isolate

2912-429: A strong survival signal during interactions with other cells, whereas those with low affinity antibodies will not, and will die by apoptosis . Thus, B cells expressing antibodies with a higher affinity for the antigen will outcompete those with weaker affinities for function and survival allowing the average affinity of antibodies to increase over time. The process of generating antibodies with increased binding affinities

3024-516: A variable domain, VL (a segment of approximately 110 amino acids), and a constant domain, CL (also approximately 110 amino acids long). The μ heavy chain of IgM is a protein of ~576 amino acids, includes a variable domain (VH ~110 amino acids), four distinct constant region domains (Cμ1, Cμ2, Cμ3, Cμ4, each ~110 amino acids) and a "tailpiece" of ~20 amino acids. The μ heavy chain bears oligosaccharides at five asparagine residues. The oligosaccharides on mouse and human IgM have been partially characterized by

3136-700: A variety of techniques, including NMR, lectin binding, various chromatographic systems, and enzymatic sensitivity (reviewed in). The structure of the oligosaccharides at each site varies in detail, and the predominant oligosaccharides—biantennary, triantennary, and high mannose—differ among the sites. The multimeric structure of IgM is shown schematically in Figure 1. Figure 1A shows the "heterodimer" composed of one light chain, denoted L, and one heavy chain, denoted μ. The heavy and light chains are held together both by disulfide bonds (depicted as red triangles) and by non-covalent interactions. Figure 1B shows two μL units linked by

3248-883: Is Ga for gallium scans . Ga is used because, like Tc, it is a gamma-ray emitter and various ligands can be attached to the Ga ion, forming a coordination complex which may have selective affinity for particular sites in the human body. An extensive list of radioactive tracers used in hydraulic fracturing can be found below. In metabolism research, tritium and C -labeled glucose are commonly used in glucose clamps to measure rates of glucose uptake , fatty acid synthesis , and other metabolic processes. While radioactive tracers are sometimes still used in human studies, stable isotope tracers such as C are more commonly used in current human clamp studies. Radioactive tracers are also used to study lipoprotein metabolism in humans and experimental animals. In medicine , tracers are applied in

3360-641: Is a synthetic derivative of a natural compound in which one or more atoms have been replaced by a radionuclide (a radioactive atom). By virtue of its radioactive decay , it can be used to explore the mechanism of chemical reactions by tracing the path that the radioisotope follows from reactants to products. Radiolabeling or radiotracing is thus the radioactive form of isotopic labeling . In biological contexts, experiments that use radioisotope tracers are sometimes called radioisotope feeding experiments. Radioisotopes of hydrogen , carbon , phosphorus , sulfur , and iodine have been used extensively to trace

3472-406: Is also a beta-emitter, with a half-life of 25.4 days. Though more expensive than P , the emitted electrons are less energetic, permitting better resolution in, for example, DNA sequencing. Both isotopes are useful for labeling nucleotides and other species that contain a phosphate group. S is made by neutron bombardment of Cl It decays by beta-decay with a half-life of 87.51 days. It

Immunoglobulin M - Misplaced Pages Continue

3584-522: Is also partitioned into two antigen-binding fragments (Fab), containing one V L , V H , C L , and C H 1 domain each, as well as the crystallisable fragment (Fc), forming the trunk of the Y shape. In between them is a hinge region of the heavy chains, whose flexibility allows antibodies to bind to pairs of epitopes at various distances, to form complexes ( dimers , trimers, etc.), and to bind effector molecules more easily. In an electrophoresis test of blood proteins , antibodies mostly migrate to

3696-467: Is an important isotope in the radiopharmaceutical industry. For example, it is used to make labeled fluorodeoxyglucose (FDG) for application in PET scans. P is made by neutron bombardment of S It decays by beta decay with a half-life of 14.29 days. It is commonly used to study protein phosphorylation by kinases in biochemistry. P is made in relatively low yield by neutron bombardment of P . It

3808-406: Is broken by the activity of a series of enzymes at two selected S-regions. The variable domain exon is rejoined through a process called non-homologous end joining (NHEJ) to the desired constant region (γ, α or ε). This process results in an immunoglobulin gene that encodes an antibody of a different isotype. Radiolabeling A radioactive tracer , radiotracer , or radioactive label

3920-415: Is called affinity maturation . Affinity maturation occurs in mature B cells after V(D)J recombination, and is dependent on help from helper T cells . Isotype or class switching is a biological process occurring after activation of the B cell, which allows the cell to produce different classes of antibody (IgA, IgE, or IgG). The different classes of antibody, and thus effector functions, are defined by

4032-448: Is closer to human IgG2 than human IgG1 in terms of its function. The term humoral immunity is often treated as synonymous with the antibody response, describing the function of the immune system that exists in the body's humors (fluids) in the form of soluble proteins, as distinct from cell-mediated immunity , which generally describes the responses of T cells (especially cytotoxic T cells). In general, antibodies are considered part of

4144-544: Is compensated for through memory B cells: novel variants of a microbe that still retain structural features of previously encountered antigens can elicit memory B cell responses that adapt to those changes. It has been suggested that long-lived plasma cells secrete B cell receptors with higher affinity than those on the surfaces of memory B cells, but findings are not entirely consistent on this point. Antibodies are heavy (~150 k Da ) proteins of about 10 nm in size, arranged in three globular regions that roughly form

4256-431: Is envisaged to bind two other μ chains. However, neither model alone can fully account for the structure of polymeric IgM. For example, the model in Figure 1C predicts that the disulfide bond between the Cμ2 domains is essential for making disulfide-bonded polymeric IgM. The model in Figure 1D predicts that the disulfide bond between the Cμ3 domains is essential. Disulfide bonded, polymeric, IgM can still be made if any one of

4368-507: Is large and contains several distinct gene loci for each domain of the antibody—the chromosome region containing heavy chain genes ( IGH@ ) is found on chromosome 14 , and the loci containing lambda and kappa light chain genes ( IGL@ and IGK@ ) are found on chromosomes 22 and 2 in humans. One of these domains is called the variable domain, which is present in each heavy and light chain of every antibody, but can differ in different antibodies generated from distinct B cells. Differences between

4480-442: Is necessary and sufficient for the formation of polymeric immunoglobulins. That is, deleting the tailpiece from the μ heavy chain prevents the formation of polymeric IgM. Conversely, cells expressing a γ heavy chain that has been modified to include the tailpiece produce polymeric IgG. The role of the cysteine in the Cμ3 domain is more subtle. Figures 1C and 1D represent possible models for pentameric IgM. In these models, each μ chain

4592-455: Is performed in a nuclear reactor . The other main method used to synthesize radioisotopes is proton bombardment. The proton are accelerated to high energy either in a cyclotron or a linear accelerator . Tritium (hydrogen-3) is produced by neutron irradiation of Li : Tritium has a half-life 4500 ± 8 days (approximately 12.32 years) and it decays by beta decay . The electrons produced have an average energy of 5.7 keV. Because

Immunoglobulin M - Misplaced Pages Continue

4704-419: Is predominantly hexameric, IgM from bony fish is predominantly tetrameric, and IgM from cartilaginous fish (mainly sharks) is predominantly pentameric. Although the pentameric form predominates in mice and humans, the hexameric form has also been observed. Subsequent studies using recombinant DNA expression systems indicated that a hexamer is a major form of mouse IgM when the IgM is produced under conditions where

4816-458: Is present, ensuring that antibody levels to the antigen in question do not fall to 0, provided the plasma cell stays alive. The rate of antibody secretion, however, can be regulated, for example, by the presence of adjuvant molecules that stimulate the immune response such as TLR ligands. Long-lived plasma cells can live for potentially the entire lifetime of the organism. Classically, the survival niches that house long-lived plasma cells reside in

4928-430: Is required. IgA tetramers and pentamers have also been reported. Antibodies also form complexes by binding to antigen: this is called an antigen-antibody complex or immune complex . Small antigens can cross-link two antibodies, also leading to the formation of antibody dimers, trimers, tetramers, etc. Multivalent antigens (e.g., cells with multiple epitopes) can form larger complexes with antibodies. An extreme example

5040-625: Is reversible, and the antibody's affinity towards an antigen is relative rather than absolute. Relatively weak binding also means it is possible for an antibody to cross-react with different antigens of different relative affinities. The main categories of antibody action include the following: More indirectly, an antibody can signal immune cells to present antibody fragments to T cells , or downregulate other immune cells to avoid autoimmunity . Activated B cells differentiate into either antibody-producing cells called plasma cells that secrete soluble antibody or memory cells that survive in

5152-410: Is the clumping, or agglutination , of red blood cells with antibodies in blood typing to determine blood groups : the large clumps become insoluble, leading to visually apparent precipitation . The membrane-bound form of an antibody may be called a surface immunoglobulin (sIg) or a membrane immunoglobulin (mIg). It is part of the B cell receptor (BCR), which allows a B cell to detect when

5264-463: Is the presence of an antigen that drives the formation of an antigen-specific antibody. Each tip of the "Y" of an antibody contains a paratope that specifically binds to one particular epitope on an antigen, allowing the two molecules to bind together with precision. Using this mechanism, antibodies can effectively "tag" a microbe or an infected cell for attack by other parts of the immune system, or can neutralize it directly (for example, by blocking

5376-529: Is thought to be, in part, the result of natural antibodies circulating in the serum of the recipient binding to α-Gal antigens expressed on the donor tissue. Virtually all microbes can trigger an antibody response. Successful recognition and eradication of many different types of microbes requires diversity among antibodies; their amino acid composition varies allowing them to interact with many different antigens. It has been estimated that humans generate about 10 billion different antibodies, each capable of binding

5488-451: Is triggered by cytokines; the isotype generated depends on which cytokines are present in the B cell environment. Class switching occurs in the heavy chain gene locus by a mechanism called class switch recombination (CSR). This mechanism relies on conserved nucleotide motifs, called switch (S) regions , found in DNA upstream of each constant region gene (except in the δ-chain). The DNA strand

5600-454: Is used clinically to prevent Rh-negative mothers from becoming immunized against fetal Rh-positive erythrocytes, and its use has dramatically decreased the incidence of hemolytic disease in newborns. In contrast to the effect of IgG, antigen-specific IgM can greatly enhance the antibody response, especially in the case of large antigens. Thus, when IgM specific for erythrocytes is injected into animals (including humans) together with erythrocytes,

5712-455: Is used to label the sulfur-containing amino-acids methionine and cysteine . When a sulfur atom replaces an oxygen atom in a phosphate group on a nucleotide a thiophosphate is produced, so S can also be used to trace a phosphate group. Tc is a very versatile radioisotope, and is the most commonly used radioisotope tracer in medicine. It is easy to produce in a technetium-99m generator , by decay of Mo . The molybdenum isotope has

SECTION 50

#1732844946591

5824-416: The adaptive immune system , though this classification can become complicated. For example, natural IgM, which are made by B-1 lineage cells that have properties more similar to innate immune cells than adaptive, refers to IgM antibodies made independently of an immune response that demonstrate polyreactivity- they recognize multiple distinct (unrelated) antigens. These can work with the complement system in

5936-736: The iota (ι) chain, are found in other vertebrates like sharks ( Chondrichthyes ) and bony fishes ( Teleostei ). In most placental mammals , the structure of antibodies is generally the same. Jawed fish appear to be the most primitive animals that are able to make antibodies similar to those of mammals, although many features of their adaptive immunity appeared somewhat earlier. Cartilaginous fish (such as sharks) produce heavy-chain-only antibodies (i.e., lacking light chains) which moreover feature longer chain pentamers (with five constant units per molecule). Camelids (such as camels, llamas, alpacas) are also notable for producing heavy-chain-only antibodies. The antibody's paratope interacts with

6048-702: The mu chain within IgM causes autosomal recessive agammaglobulinemia . The presence of IgM or, rarely, IgG is one of the obligate criteria for a diagnosis of Schnitzler's syndrome . Antibody An antibody ( Ab ) or immunoglobulin ( Ig ) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses , including those that cause disease. Antibodies can recognize virtually any size antigen with diverse chemical compositions from molecules. Each antibody recognizes one or more specific antigens . Antigen literally means "antibody generator", as it

6160-437: The "classical" complement system. This results in the killing of bacteria in two ways. First, the binding of the antibody and complement molecules marks the microbe for ingestion by phagocytes in a process called opsonization ; these phagocytes are attracted by certain complement molecules generated in the complement cascade. Second, some complement system components form a membrane attack complex to assist antibodies to kill

6272-428: The 1943 Nobel Prize for Chemistry "for his work on the use of isotopes as tracers in the study of chemical processes". There are two main ways in which radioactive tracers are used The commonly used radioisotopes have short half lives and so do not occur in nature in large amounts. They are produced by nuclear reactions . One of the most important processes is absorption of a neutron by an atomic nucleus, in which

6384-610: The BCRs from most other cell signaling receptors. These patches may improve the efficiency of the cellular immune response . In humans, the cell surface is bare around the B cell receptors for several hundred nanometers, which further isolates the BCRs from competing influences. Antibodies can come in different varieties known as isotypes or classes . In humans there are five antibody classes known as IgA, IgD, IgE, IgG, and IgM, which are further subdivided into subclasses such as IgA1, IgA2. The prefix "Ig" stands for immunoglobulin , while

6496-513: The F V region. It is the subregion of Fab that binds to an antigen. More specifically, each variable domain contains three hypervariable regions – the amino acids seen there vary the most from antibody to antibody. When the protein folds, these regions give rise to three loops of β-strands , localized near one another on the surface of the antibody. These loops are referred to as the complementarity-determining regions (CDRs), since their shape complements that of an antigen. Three CDRs from each of

6608-455: The Fc region and influence interactions with effector molecules. The N-terminus of each chain is situated at the tip. Each immunoglobulin domain has a similar structure, characteristic of all the members of the immunoglobulin superfamily : it is composed of between 7 (for constant domains) and 9 (for variable domains) β-strands , forming two beta sheets in a Greek key motif . The sheets create

6720-486: The Fc region of an antibody, while the complement system is activated by binding the C1q protein complex. IgG or IgM can bind to C1q, but IgA cannot, therefore IgA does not activate the classical complement pathway . Another role of the Fc region is to selectively distribute different antibody classes across the body. In particular, the neonatal Fc receptor (FcRn) binds to the Fc region of IgG antibodies to transport it across

6832-491: The V, D and J gene segments exist, and are tandemly arranged in the genomes of mammals . In the bone marrow, each developing B cell will assemble an immunoglobulin variable region by randomly selecting and combining one V, one D and one J gene segment (or one V and one J segment in the light chain). As there are multiple copies of each type of gene segment, and different combinations of gene segments can be used to generate each immunoglobulin variable region, this process generates

SECTION 60

#1732844946591

6944-450: The adaptive immune system is regulated by interactions between idiotypes. The Fc region (the trunk of the Y shape) is composed of constant domains from the heavy chains. Its role is in modulating immune cell activity: it is where effector molecules bind to, triggering various effects after the antibody Fab region binds to an antigen. Effector cells (such as macrophages or natural killer cells ) bind via their Fc receptors (FcR) to

7056-410: The antibody (also known as effector functions), in addition to some other structural features. Antibodies from different classes also differ in where they are released in the body and at what stage of an immune response. Between species, while classes and subclasses of antibodies may be shared (at least in name), their functions and distribution throughout the body may be different. For example, mouse IgG1

7168-683: The antibody generates a large cavalry of antibodies with a high degree of variability. This combination is called V(D)J recombination discussed below. Somatic recombination of immunoglobulins, also known as V(D)J recombination , involves the generation of a unique immunoglobulin variable region. The variable region of each immunoglobulin heavy or light chain is encoded in several pieces—known as gene segments (subgenes). These segments are called variable (V), diversity (D) and joining (J) segments. V, D and J segments are found in Ig heavy chains , but only V and J segments are found in Ig light chains . Multiple copies of

7280-556: The antigen's epitope. An antigen usually contains different epitopes along its surface arranged discontinuously, and dominant epitopes on a given antigen are called determinants. Antibody and antigen interact by spatial complementarity (lock and key). The molecular forces involved in the Fab-epitope interaction are weak and non-specific – for example electrostatic forces , hydrogen bonds , hydrophobic interactions , and van der Waals forces . This means binding between antibody and antigen

7392-421: The antigen-binding sites at both tips of the antibody come in an equally wide variety. The rest of the antibody structure is much less variable; in humans, antibodies occur in five classes , sometimes called isotypes : IgA , IgD , IgE , IgG , and IgM . Human IgG and IgA antibodies are also divided into discrete subclasses (IgG1, IgG2, IgG3, IgG4; IgA1 and IgA2). The class refers to the functions triggered by

7504-482: The atmosphere. It was also produced in the Chernobyl and Fukushima disasters. I decays with a half-life of 15.7 million years, with low-energy beta and gamma emissions. It is not used as a tracer, though its presence in living organisms, including human beings, can be characterized by measurement of the gamma rays. Many other isotopes have been used in specialized radiopharmacological studies. The most widely used

7616-401: The bacterium directly (bacteriolysis). To combat pathogens that replicate outside cells, antibodies bind to pathogens to link them together, causing them to agglutinate . Since an antibody has at least two paratopes, it can bind more than one antigen by binding identical epitopes carried on the surfaces of these antigens. By coating the pathogen, antibodies stimulate effector functions against

7728-434: The bloodstream, they are said to be part of the humoral immune system . Circulating antibodies are produced by clonal B cells that specifically respond to only one antigen (an example is a virus capsid protein fragment). Antibodies contribute to immunity in three ways: They prevent pathogens from entering or damaging cells by binding to them; they stimulate removal of pathogens by macrophages and other cells by coating

7840-424: The body for years afterward in order to allow the immune system to remember an antigen and respond faster upon future exposures. At the prenatal and neonatal stages of life, the presence of antibodies is provided by passive immunization from the mother. Early endogenous antibody production varies for different kinds of antibodies, and usually appear within the first years of life. Since antibodies exist freely in

7952-477: The bone marrow, though it cannot be assumed that any given plasma cell in the bone marrow will be long-lived. However, other work indicates that survival niches can readily be established within the mucosal tissues- though the classes of antibodies involved show a different hierarchy from those in the bone marrow. B cells can also differentiate into memory B cells which can persist for decades similarly to long-lived plasma cells. These cells can be rapidly recalled in

8064-408: The case of the γ heavy chain, the only inter-γ bonds are formed by cysteines in the hinge, and accordingly, each γ chain binds to only one other γ chain. By contrast, the Cμ2 and Cμ3 domains and the tailpiece each include a cysteine that form a disulfide bond with another μ chain. The cysteines in the Cμ2 domains mediate the formation of monomeric IgM (μL)2. The tailpiece along with the included cysteine

8176-430: The cell-bound antibody molecule with an antigen, causing the cell to divide and differentiate into an antibody-producing cell called a plasma cell . In this activated form, the B cell starts to produce antibody in a secreted form rather than a membrane -bound form. Some daughter cells of the activated B cells undergo isotype switching , a mechanism that causes the production of antibodies to change from IgM or IgD to

8288-423: The classical complement pathway leading to lysis of enveloped virus particles long before the adaptive immune response is activated. Antibodies are produced exclusively by B cells in response to antigens where initially, antibodies are formed as membrane-bound receptors, but upon activation by antigens and helper T cells, B cells differentiate to produce soluble antibodies. Many natural antibodies are directed against

8400-450: The column of immobilized Mo elutes the soluble Tc, resulting in a saline solution containing the Tc as the dissolved sodium salt of the pertechnetate. The pertechnetate is treated with a reducing agent such as Sn and a ligand . Different ligands form coordination complexes which give the technetium enhanced affinity for particular sites in the human body. Tc decays by gamma emission, with

8512-403: The constant (C) regions of the immunoglobulin heavy chain. Initially, naive B cells express only cell-surface IgM and IgD with identical antigen binding regions. Each isotype is adapted for a distinct function; therefore, after activation, an antibody with an IgG, IgA, or IgE effector function might be required to effectively eliminate an antigen. Class switching allows different daughter cells from

8624-501: The detailed three-dimensional structure of the chain. The domains of the heavy chain, like those of other immunoglobulins, have the distinctive overlaying -sheets of seven strands, which are stabilized by intra-domain disulfide linkages. Overall, the IgM constant region has a "mushroom-like" shape, with the C2-C3 domains forming a disk similar to the mushroom's head and the C4tp domains protruding like

8736-410: The disaccharide galactose α(1,3)-galactose (α-Gal), which is found as a terminal sugar on glycosylated cell surface proteins, and generated in response to production of this sugar by bacteria contained in the human gut. These antibodies undergo quality checks in the endoplasmic reticulum (ER), which contains proteins that assist in proper folding and assembly. Rejection of xenotransplantated organs

8848-414: The diversity of the antibody pool and impacts the antibody's antigen-binding affinity . Some point mutations will result in the production of antibodies that have a weaker interaction (low affinity) with their antigen than the original antibody, and some mutations will generate antibodies with a stronger interaction (high affinity). B cells that express high affinity antibodies on their surface will receive

8960-583: The earliest phases of an immune response to help facilitate clearance of the offending antigen and delivery of the resulting immune complexes to the lymph nodes or spleen for initiation of an immune response. Hence in this capacity, the function of antibodies is more akin to that of innate immunity than adaptive. Nonetheless, in general antibodies are regarded as part of the adaptive immune system because they demonstrate exceptional specificity (with some exception), are produced through genetic rearrangements (rather than being encoded directly in germline ), and are

9072-602: The early phases of the immune response (classically described as arising extrafollicularly rather than from the germinal center ) which have the potential to differentiate further into plasma cells. The literature is sloppy at times and often describes plasmablasts as just short-lived plasma cells- formally this is incorrect. Plasma cells, in contrast, do not divide (they are terminally differentiated ), and rely on survival niches comprising specific cell types and cytokines to persist. Plasma cells will secrete huge quantities of antibody regardless of whether or not their cognate antigen

9184-423: The emitted electrons have relatively low energy, the detection efficiency by scintillation counting is rather low. However, hydrogen atoms are present in all organic compounds, so tritium is frequently used as a tracer in biochemical studies. C decays by positron emission with a half-life of ca. 20 min. C is one of the isotopes often used in positron emission tomography . C decays by beta decay , with

9296-414: The genes encoding the variable domains of the heavy and light chains undergo a high rate of point mutation , by a process called somatic hypermutation (SHM). SHM results in approximately one nucleotide change per variable gene, per cell division. As a consequence, any daughter B cells will acquire slight amino acid differences in the variable domains of their antibody chains. This serves to increase

9408-505: The great variety of infectious microbes, and this heterogeneity impeded detailed structural analysis of IgM. Two sources of homogeneous IgM were subsequently discovered. First, the high molecular weight protein produced by some multiple myeloma patients was recognized to be a tumor-produced γ-macroglobulin, and because the tumor is a clone , the IgM it produces is homogeneous. In the 1960s, methods were developed for inducing immunoglobulin-producing tumors (plasmacytomas) in mice, thus providing

9520-846: The heavy and light chains together form an antibody-binding site whose shape can be anything from a pocket to which a smaller antigen binds, to a larger surface, to a protrusion that sticks out into a groove in an antigen. Typically though, only a few residues contribute to most of the binding energy. The existence of two identical antibody-binding sites allows antibody molecules to bind strongly to multivalent antigen (repeating sites such as polysaccharides in bacterial cell walls , or other sites at some distance apart), as well as to form antibody complexes and larger antigen-antibody complexes . The structures of CDRs have been clustered and classified by Chothia et al. and more recently by North et al. and Nikoloudis et al. However, describing an antibody's binding site using only one single static structure limits

9632-429: The human placenta (only isotype IgG ). These two biological properties of IgM make it useful in the diagnosis of infectious diseases. Demonstrating IgM antibodies in a patient's serum indicates recent infection, or in a neonate's serum indicates intrauterine infection (e.g. congenital rubella syndrome ). The development of anti-donor IgM after organ transplantation is not associated with graft rejection but it may have

9744-456: The immune response. A possible explanation for IgM-mediated enhancement is that B lymphocytes capture IgM-antigen-complement complexes and transport the complexes into areas in the spleen where efficient immune responses are generated. Because IgM is produced early in an immune response, this might be important in the initiation of antibody responses. In germ-line cells (sperm and ova) the genes that will eventually encode immunoglobulins are not in

9856-457: The incorporation of the J chain is prevented, either by producing IgM in cells that lack the J chain or by producing IgM with a μ heavy chain that lacks the cysteine in the tailpiece. In summary, hexameric IgM never contains the J chain; pentameric IgM can be formed so as to include or not include the J chain. An important difference between the μ and γ heavy chains is the availability of cysteines for forming disulfide bonds between heavy chains. In

9968-769: The invading microbe. The activation of natural killer cells by antibodies initiates a cytotoxic mechanism known as antibody-dependent cell-mediated cytotoxicity (ADCC) – this process may explain the efficacy of monoclonal antibodies used in biological therapies against cancer . The Fc receptors are isotype-specific, which gives greater flexibility to the immune system, invoking only the appropriate immune mechanisms for distinct pathogens. Humans and higher primates also produce "natural antibodies" that are present in serum before viral infection. Natural antibodies have been defined as antibodies that are produced without any previous infection, vaccination , other foreign antigen exposure or passive immunization . These antibodies can activate

10080-459: The last, gamma globulin fraction. Conversely, most gamma-globulins are antibodies, which is why the two terms were historically used as synonyms, as were the symbols Ig and γ . This variant terminology fell out of use due to the correspondence being inexact and due to confusion with γ (gamma) heavy chains which characterize the IgG class of antibodies. The variable domains can also be referred to as

10192-405: The mass number of the element concerned increases by 1 for each neutron absorbed. For example, In this case the atomic mass increases, but the element is unchanged. In other cases the product nucleus is unstable and decays, typically emitting protons, electrons ( beta particle ) or alpha particles . When a nucleus loses a proton the atomic number decreases by 1. For example, Neutron irradiation

10304-472: The models in Figures 1C and 1D, with disulfide bonds between the Cμ3 domains and between the tail pieces. Also shown is that pentameric IgM includes a third protein, the J chain. J chain (J for joining) was discovered as a covalently bonded component of polymeric IgA and IgM. The J chain is a small (~137 amino acids), acidic protein. As shown, the J chain joins two μ chains via disulfide bonds involving cysteines in

10416-442: The naturally occurring carbon-14 isotope as an isotopic label . Isotopes of a chemical element differ only in the mass number. For example, the isotopes of hydrogen can be written as H , H and H , with the mass number superscripted to the left. When the atomic nucleus of an isotope is unstable, compounds containing this isotope are radioactive . Tritium is an example of a radioactive isotope. The principle behind

10528-557: The other antibody isotypes, IgE, IgA, or IgG, that have defined roles in the immune system. In mammals there are two types of immunoglobulin light chain , which are called lambda (λ) and kappa (κ). However, there is no known functional difference between them, and both can occur with any of the five major types of heavy chains. Each antibody contains two identical light chains: both κ or both λ. Proportions of κ and λ types vary by species and can be used to detect abnormal proliferation of B cell clones. Other types of light chains, such as

10640-428: The other isotypes (γ, ε and α) is affected by another type of DNA rearrangement, a process called Immunoglobulin class switching . IgM is the first immunoglobulin expressed in the human fetus (around 20 weeks) and phylogenetically the earliest antibody to develop. IgM antibodies appear early in the course of an infection and usually reappear, to a lesser extent, after further exposure. IgM antibodies do not pass across

10752-504: The path of biochemical reactions . A radioactive tracer can also be used to track the distribution of a substance within a natural system such as a cell or tissue , or as a flow tracer to track fluid flow . Radioactive tracers are also used to determine the location of fractures created by hydraulic fracturing in natural gas production. Radioactive tracers form the basis of a variety of imaging systems, such as, PET scans , SPECT scans and technetium scans . Radiocarbon dating uses

10864-584: The pathogen in cells that recognize their Fc region. Those cells that recognize coated pathogens have Fc receptors, which, as the name suggests, interact with the Fc region of IgA, IgG, and IgE antibodies. The engagement of a particular antibody with the Fc receptor on a particular cell triggers an effector function of that cell; phagocytes will phagocytose , mast cells and neutrophils will degranulate , natural killer cells will release cytokines and cytotoxic molecules; that will ultimately result in destruction of

10976-455: The pathogen; and they trigger destruction of pathogens by stimulating other immune responses such as the complement pathway . Antibodies will also trigger vasoactive amine degranulation to contribute to immunity against certain types of antigens (helminths, allergens). Antibodies that bind to surface antigens (for example, on bacteria) will attract the first component of the complement cascade with their Fc region and initiate activation of

11088-599: The placenta, from the mother to the fetus. In addition to this, binding to FcRn endows IgG with an exceptionally long half-life relative to other plasma proteins of 3-4 weeks. IgG3 in most cases (depending on allotype) has mutations at the FcRn binding site which lower affinity for FcRn, which are thought to have evolved to limit the highly inflammatory effects of this subclass. Antibodies are glycoproteins , that is, they have carbohydrates (glycans) added to conserved amino acid residues. These conserved glycosylation sites occur in

11200-437: The presence of these proteins, V(D)J recombination would not occur. After a B cell produces a functional immunoglobulin gene during V(D)J recombination, it cannot express any other variable region (a process known as allelic exclusion ) thus each B cell can produce antibodies containing only one kind of variable chain. Following activation with antigen, B cells begin to proliferate rapidly. In these rapidly dividing cells,

11312-401: The red blood cell A and B antigens might be formed in early life as a result of exposure to A- and B-like substances that are present in bacteria or perhaps also in plant materials. IgM antibodies are mainly responsible for the clumping ( agglutination ) of red blood cells if the recipient of a blood transfusion receives blood that is not compatible with their blood type . A mutation of

11424-437: The same activated B cell to produce antibodies of different isotypes. Only the constant region of the antibody heavy chain changes during class switching; the variable regions, and therefore antigen specificity, remain unchanged. Thus the progeny of a single B cell can produce antibodies, all specific for the same antigen, but with the ability to produce the effector function appropriate for each antigenic challenge. Class switching

11536-444: The suffix denotes the type of heavy chain the antibody contains: the heavy chain types α (alpha), γ (gamma), δ (delta), ε (epsilon), μ (mu) give rise to IgA, IgG, IgD, IgE, IgM, respectively. The distinctive features of each class are determined by the part of the heavy chain within the hinge and Fc region. The classes differ in their biological properties, functional locations and ability to deal with different antigens, as depicted in

11648-440: The table. For example, IgE antibodies are responsible for an allergic response consisting of histamine release from mast cells , often a sole contributor to asthma (though other pathways exist as do exist symptoms very similar to yet not technically asthma). The antibody's variable region binds to allergic antigen, for example house dust mite particles, while its Fc region (in the ε heavy chains) binds to Fc receptor ε on

11760-412: The tailpieces. It was initially expected that the J chain would be important for forming the polymeric immunoglobulins, and indeed polymerization of IgA depends strongly (but not absolutely) on the J chain. In contrast, polymeric IgM forms efficiently in the absence of the J chain. The predominant form of human and mouse IgM is the pentamer. By way of comparison, the structure of IgM from frogs (Xenopus)

11872-406: The three cysteines is absent. In the context of models in which each μ chain interacts with only two other μ chains, these results suggest that some molecules are like Figure 1C and some like Figure 1D. However, the availability of three cysteines for inter-μ chain bonding suggests that the μ chains might each bind three other μ chains, as illustrated in Figure 2. In the same spirit, Figure 2C presents

11984-441: The type of antigen and the isotype of the antibody, the effect can be suppression or enhancement of the antibody response. Such effects are well illustrated by experiments involving immunization with xenogenic (foreign) erythrocytes (red blood cells). For example, when IgG is administered together with xenogenic erythrocytes, this combination causes almost complete suppression of the erythrocyte-specific antibody response. This effect

12096-430: The understanding and characterization of the antibody's function and properties. To improve antibody structure prediction and to take the strongly correlated CDR loop and interface movements into account, antibody paratopes should be described as interconverting states in solution with varying probabilities. In the framework of the immune network theory , CDRs are also called idiotypes. According to immune network theory,

12208-569: The use of radioactive tracers is that an atom in a chemical compound is replaced by another atom, of the same chemical element. The substituting atom, however, is a radioactive isotope. This process is often called radioactive labeling. The power of the technique is due to the fact that radioactive decay is much more energetic than chemical reactions. Therefore, the radioactive isotope can be present in low concentration and its presence detected by sensitive radiation detectors such as Geiger counters and scintillation counters . George de Hevesy won

12320-404: The use of substances enriched in the non-radioactive isotope C has become the preferred method, avoiding patient exposure to radioactivity. In hydraulic fracturing , radioactive tracer isotopes are injected with hydraulic fracturing fluid to determine the injection profile and location of created fractures. Tracers with different half-lives are used for each stage of hydraulic fracturing. In

12432-412: The variable domains are located on three loops known as hypervariable regions (HV-1, HV-2 and HV-3) or complementarity-determining regions (CDR1, CDR2 and CDR3). CDRs are supported within the variable domains by conserved framework regions. The heavy chain locus contains about 65 different variable domain genes that all differ in their CDRs. Combining these genes with an array of genes for other domains of

12544-427: The variation might also be due to heterogeneity in the IgM preparations, i.e., the various preparations might have differed substantially in their content of J-containing and J-deficient polymers. Individual C2, C3, and C4tp domains were generated independently in E. coli and then studied using a range of approaches, including sedimentation rate, X-ray crystallography , and NMR spectroscopy , to obtain insight into

#590409