Peptides are short chains of amino acid monomers linked by peptide bonds. The covalent chemical bonds are formed when the carboxyl group of one amino acid reacts with the amino group of another; the shortest peptides are dipeptides, consisting of 2 amino acids joined by a single peptide bond, followed by tripeptides, etc. A polypeptide is a long and unbranched peptide chain. Hence, peptides fall under the broad chemical classes of biological oligomers and polymers, alongside nucleic acids and polysaccharides, etc. Peptides are distinguished from proteins on the basis of size, as an arbitrary benchmark can be understood to contain 50 or fewer amino acids. Proteins consist of one or more polypeptides arranged in a biologically functional way bound to ligands such as coenzymes and cofactors, or to another protein or other macromolecule, or to complex macromolecular assemblies. While aspects of the lab techniques applied to peptides versus polypeptides and proteins differ, the size boundaries that distinguish peptides from polypeptides and proteins are not absolute: long peptides such as amyloid beta have been referred to as proteins, smaller proteins like insulin have been considered peptides.
Amino acids that have been incorporated into peptides are termed "residues" due to the release of either a hydrogen ion from the amine end or a hydroxyl ion from the carboxyl end, or both, as a water molecule is released during formation of each amide bond. All peptides except cyclic peptides have an N-terminal and C-terminal residue at the end of the peptide. Many kinds of peptides are known, they have been categorized according to their sources and function. According to the Handbook of Biologically Active Peptides, some groups of peptides include plant peptides, bacterial/antibiotic peptides, fungal peptides, invertebrate peptides, amphibian/skin peptides, venom peptides, cancer/anticancer peptides, vaccine peptides, immune/inflammatory peptides, brain peptides, endocrine peptides, ingestive peptides, gastrointestinal peptides, cardiovascular peptides, renal peptides, respiratory peptides, opiate peptides, neurotrophic peptides, blood–brain peptides; some ribosomal peptides are subject to proteolysis.
These function in higher organisms, as hormones and signaling molecules. Some organisms produce peptides as antibiotics, such as microcins. Peptides have posttranslational modifications such as phosphorylation, sulfonation, palmitoylation and disulfide formation. In general, peptides are linear. More exotic manipulations do occur, such as racemization of L-amino acids to D-amino acids in platypus venom. Nonribosomal peptides are assembled by enzymes, not the ribosome. A common non-ribosomal peptide is glutathione, a component of the antioxidant defenses of most aerobic organisms. Other nonribosomal peptides are most common in unicellular organisms and fungi and are synthesized by modular enzyme complexes called nonribosomal peptide synthetases; these complexes are laid out in a similar fashion, they can contain many different modules to perform a diverse set of chemical manipulations on the developing product. These peptides are cyclic and can have complex cyclic structures, although linear nonribosomal peptides are common.
Since the system is related to the machinery for building fatty acids and polyketides, hybrid compounds are found. The presence of oxazoles or thiazoles indicates that the compound was synthesized in this fashion. Peptide fragments refer to fragments of proteins that are used to identify or quantify the source protein; these are the products of enzymatic degradation performed in the laboratory on a controlled sample, but can be forensic or paleontological samples that have been degraded by natural effects. Use of peptides received prominence in molecular biology for several reasons; the first is that peptides allow the creation of peptide antibodies in animals without the need of purifying the protein of interest. This involves synthesizing antigenic peptides of sections of the protein of interest; these will be used to make antibodies in a rabbit or mouse against the protein. Another reason is that techniques such as mass spectrometry enable the identification of proteins based on the peptide masses and sequence that result from their fragmentation.
Peptides have been used in the study of protein structure and function. For example, synthetic peptides can be used as probes to see where protein-peptide interactions occur- see the page on Protein tags. Inhibitory peptides are used in clinical research to examine the effects of peptides on the inhibition of cancer proteins and other diseases. For example, one of the most promising application is through peptides that target LHRH; these particular peptides act as an agonist, meaning that they bind to a cell in a way that regulates LHRH receptors. The process of inhibiting the cell receptors suggests that peptides could be beneficial in treating prostate cancer, but additional investigations and experiments are required before their cancer-fighting attributes can be considered definitive; the peptide families in this section are ribosomal peptides with hormonal activity. All of these peptides are synthesized by cells as longer "propeptides" or "proproteins" and truncated prior to exiting the cell.
They are released into the bloodstream. Magainin family Cecropin famil
Adaptive immune system
The adaptive immune system known as the acquired immune system or, more as the specific immune system, is a subsystem of the overall immune system, composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system is one of the two main immunity strategies found in vertebrates. Acquired immunity creates immunological memory after an initial response to a specific pathogen, leads to an enhanced response to subsequent encounters with that pathogen; this process of acquired immunity is the basis of vaccination. Like the innate system, the acquired system includes both humoral immunity components and cell-mediated immunity components; the term "adaptive" was first used by Robert Good in reference to antibody responses in frogs as a synonym for "acquired immune response" in 1964. Good acknowledged he used the terms as synonyms but explained only that he "preferred" to use the term "adaptive", he might have been thinking of the not implausible theory of antibody formation in which antibodies were plastic and could adapt themselves to the molecular shape of antigens, and/or to the concept of "adaptive enzymes" as described by Monod in bacteria, that is, enzymes whose expression could be induced by their substrates.
The phrase was used exclusively by Good and his students and a few other immunologists working with marginal organisms until the 1990's when it became used in tandem with the term "innate immunity" which became a popular subject after the discovery of the Toll receptor system in Drosophila, a marginal organism for the study of immunology. The term "adaptive" as used in immunology is problematic as acquired immune responses can be both adaptive and maladaptive in the physiological sense. Indeed, both acquired and innate immune responses can be both adaptive and maladaptive in the evolutionary sense. Most textbooks today, following the early use by Janeway, use "adaptive" exclusively and noting in glossaries that the term is synonymous with "acquired"; the classic sense of "acquired immunity" came to mean, since Tonegawas's discovery, "antigen-specific immunity mediated by somatic gene rearrangements that create clone-defining antigen receptors". In the last decade, the term "adaptive" has been applied to another class of immune response not so-far associated with somatic gene rearrangements.
These include expansion of natural killer cells with so-far unexplained specificity for antigens, expansion of NK cells expressing germ-line encoded receptors, activation of other innate immune cells to an activated state that confers a short-term "immune memory". In this sense, "adaptive immunity" more resembles the concept of "activated state" or "heterostasis", thus returning in sense to the physiological sense of "adaptation" to environmental changes. Unlike the innate immune system, the acquired immune system is specific to a particular pathogen. Acquired immunity can provide long-lasting protection. In other cases it does not provide lifetime protection; the acquired system response destroys invading pathogens and any toxic molecules they produce. Sometimes the acquired system is unable to distinguish harmful from harmless foreign molecules. Antigens are any substances; the cells that carry out the acquired immune response are white blood cells known as lymphocytes. Two main broad classes—antibody responses and cell mediated immune response—are carried by two different lymphocytes.
In antibody responses, B cells are activated to secrete antibodies, which are proteins known as immunoglobulins. Antibodies travel through the bloodstream and bind to the foreign antigen causing it to inactivate, which does not allow the antigen to bind to the host. In acquired immunity, pathogen-specific receptors are "acquired" during the lifetime of the organism; the acquired response is called "adaptive" because it prepares the body's immune system for future challenges. The system is adaptable because of somatic hypermutation, VJ recombination; this mechanism allows a small number of genes to generate a vast number of different antigen receptors, which are uniquely expressed on each individual lymphocyte. Since the gene rearrangement leads to an irreversible change in the DNA of each cell, all progeny of that cell inherit genes that encode the same receptor specificity, including the memory B cells and memory T cells that are the keys to long-lived specific immunity. A theoretical framework explaining the workings of the acquired immune system is provided by immune network theory.
This theory, which builds on established concepts of clonal selection, is being applied in the search for an HIV vaccine. Acquired immunity is triggered in vertebrates when a pathogen evades the innate immune system and generates a threshold level of antigen and generates "stranger" or "danger" signals activating dendritic cells; the major functions of the acquired immune system include: Recognition of specific "non-self" antigens in the presence of "self", during the process of antigen presentation. Generation of responses that are tailored to maximally eliminate specific pathoge
B cells known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system by secreting antibodies. Additionally, B cells present secrete cytokines. In mammals, B cells mature in the bone marrow, at the core of most bones. In birds, B cells mature in the bursa of Fabricius, a lymphoid organ.. B cells, unlike the other two classes of lymphocytes, T cells and natural killer cells, express B cell receptors on their cell membrane. BCRs allow the B cell to bind to a specific antigen, against which it will initiate an antibody response. B cells develop from hematopoietic stem cells. HSCs first differentiate into multipotent progenitor cells common lymphoid progenitor cells. From here, their development into B cells occurs in several stages, each marked by various gene expression patterns and immunoglobulin H chain and L chain gene loci arrangements, the latter due to B cells undergoing VJ recombination as they develop.
B cells undergo two types of selection while developing in the bone marrow to ensure proper development. Positive selection occurs through antigen-independent signaling involving both the pre-BCR and the BCR. If these receptors do not bind to their ligand, B cells do not receive the proper signals and cease to develop. Negative selection occurs through the binding of self-antigen with the BCR; this negative selection process leads to a state of central tolerance, in which the mature B cells don't bind with self antigens present in the bone marrow. To complete development, immature B cells migrate from the bone marrow into the spleen as transitional B cells, passing through two transitional stages: T1 and T2. Throughout their migration to the spleen and after spleen entry, they are considered T1 B cells. Within the spleen, T1 B cells transition to T2 B cells. T2 B cells differentiate into either follicular B cells or marginal zone B cells depending on signals received through the BCR and other receptors.
Once differentiated, they are now considered naive B cells. B cell activation occurs in the secondary lymphoid organs, such as the lymph nodes. After B cells mature in the bone marrow, they migrate through the blood to SLOs, which receive a constant supply of antigen through circulating lymph. At the SLO, B cell activation begins when the B cell binds to an antigen via its BCR. Although the events taking place after activation have yet to be determined, it is believed that B cells are activated in accordance with the kinetic segregation model determined in T lymphocytes; this model denotes that before antigen stimulation, receptors diffuse through the membrane coming into contact with Lck and CD45 in equal frequency, rendering a net equilibrium of phosphorylation and non-phosphorylation. It is only when the cell comes in contact with an antigen presenting cell that the larger CD45 is displaced due to the close distance between the two membranes; this allows for net phosphorylation of the BCR and the initiation of the signal transduction pathway.
Of the three B cell subsets, FO B cells preferentially undergo T cell-dependent activation while MZ B cells and B1 B cells preferentially undergo T cell-independent activation. B cell activation is enhanced through the activity of CD21, a surface receptor in complex with surface proteins CD19 and CD81; when a BCR binds an antigen tagged with a fragment of the C3 complement protein, CD21 binds the C3 fragment, co-ligates with the bound BCR, signals are transduced through CD19 and CD81 to lower the activation threshold of the cell. It has been shown that CD20 is directly required for BCR signalling in B cells, therapeutically used anti-CD20 antibodies such rituximab eliminate the B cells that have a high potential for activation of the BCR signalling pathway, it has been described that BCR signalling and B cell activation is inhibited by p53 stabilization during DNA damage response. Antigens that activate B cells with the help of T-cell are known as T cell-dependent antigens and include foreign proteins.
They are named as such because they are unable to induce a humoral response in organisms that lack T cells. B cell response to these antigens takes multiple days, though antibodies generated have a higher affinity and are more functionally versatile than those generated from T cell-independent activation. Once a BCR binds a TD antigen, the antigen is taken up into the B cell through receptor-mediated endocytosis and presented to T cells as peptide pieces in complex with MHC-II molecules on the cell membrane. T helper cells follicular T helper cells, that were activated with the same antigen recognize and bind these MHC-II-peptide complexes through their T cell receptor. Following TCR-MHC-II-peptide binding, T cells express the surface protein CD40L as well as cytokines such as IL-4 and IL-21. CD40L serves as a necessary co-stimulatory factor for B cell activation by binding the B cell surface receptor CD40, which promotes B cell proliferation, immunoglobulin class switching, somatic hypermutation as well as sustains T cell growth and differentiation.
T cell-derived cytokines bound
The T-cell receptor, or TCR, is a molecule found on the surface of T cells, or T lymphocytes, responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex molecules. The binding between TCR and antigen peptides is of low affinity and is degenerate: that is, many TCRs recognize the same antigen peptide and many antigen peptides are recognized by the same TCR; the TCR is composed of two different protein chains. In humans, in 95% of T cells the TCR consists of an alpha chain and a beta chain, whereas in 5% of T cells the TCR consists of gamma and delta chains; this ratio changes in diseased states. It differs between species. Orthologues of the 4 loci have been mapped in various species; each locus can produce a variety of polypeptides with variable regions. When the TCR engages with antigenic peptide and MHC, the T lymphocyte is activated through signal transduction, that is, a series of biochemical events mediated by associated enzymes, co-receptors, specialized adaptor molecules, activated or released transcription factors.
In 1984, Tak Wah Mak and Mark M. Davis discovered the mouse TCR respectively; these findings allowed the entity and structure of the elusive TCR, known before as the "Holy Grail of Immunology", to be revealed. This allowed scientists from around the world to carry out studies on the TCR, leading to important studies in the fields of CAR-T, Cancer immunotherapy and Checkpoint inhibition; the TCR is a disulfide-linked membrane-anchored heterodimeric protein consisting of the variable alpha and beta chains expressed as part of a complex with the invariant CD3 chain molecules. T cells expressing this receptor are referred to as α:β T cells, though a minority of T cells express an alternate receptor, formed by variable gamma and delta chains, referred as γδ T cells; each chain is composed of two extracellular domains: Variable region and a Constant region, both of Immunoglobulin superfamily domain forming antiparallel β-sheets. The Constant region is proximal to the cell membrane, followed by a transmembrane region and a short cytoplasmic tail, while the Variable region binds to the peptide/MHC complex.
The variable domain of both the TCR α-chain and β-chain each have three hypervariable or complementarity determining regions. There is an additional area of hypervariability on the β-chain that does not contact antigen and, therefore, is not considered a CDR; the residues in these variable domains are located in two regions of the TCR, at the interface of the α- and β-chains and in the β-chain framework region, thought to be in proximity to the CD3 signal-transduction complex. CDR3 is the main CDR responsible for recognizing processed antigen, although CDR1 of the alpha chain has been shown to interact with the N-terminal part of the antigenic peptide, whereas CDR1 of the β-chain interacts with the C-terminal part of the peptide. CDR2 is thought to recognize the MHC. CDR4 of the β-chain is not thought to participate in antigen recognition, but has been shown to interact with superantigens; the constant domain of the TCR consists of short connecting sequences in which a cysteine residue forms disulfide bonds, which form a link between the two chains.
The TCR is a member of the immunoglobulin superfamily, a large group of proteins involved in binding and adhesion. The TCR is similar to a half-antibody consisting of a single heavy and single light chain, except the heavy chain is without its crystallisable fraction; the two subunits of TCR are twisted together. Whereas the antibody uses its Fc region to bind to Fc Receptors on leukocytes, TCR is docked onto the cell membrane. However, it is not able to mediate signal transduction itself due to its short cytoplasmic tail, so TCR still requires CD3 and zeta to carry out the signal transduction in its place, just as antibodies require binding to FcRs to initiate signal transduction. In this way the MHC-TCR-CD3 interaction for T cells is functionally similar to the antigen-immunoglobulin-FcR interaction for myeloid leukocytes, Ag-Ig-CD79 interaction for B cells; the generation of TCR diversity is similar to that for B cell antigen receptors. It arises from genetic recombination of the DNA encoded segments in individual somatic T cells by somatic VJ recombination using RAG1 and RAG2 recombinases.
Unlike immunoglobulins, however, TCR genes do not undergo somatic hypermutation, T cells do not express activation-induced cytidine deaminase. The recombination pro cess that creates diversity in BCR and TCR is unique to lymphocytes during the early stages of their development in primary lymphoid organs; each recombined TCR possess unique antigen specificity, determined by the structure of the antigen-binding site formed by the α and β chains in case of αβ T cells or γ and δ chains on case of γδ T cells. The TCR alpha chain is generated by VJ recombination, whereas the beta chain is generated by VDJ recombination. Generation of the TCR gamma chain involves VJ recombination, whereas generation of the TCR delta chain occurs by VDJ recombination; the intersection of these specific regions corresponds to the CDR3 region, important for peptide/MHC recognition. It is the un
Protein A is a 42 kDa surface protein found in the cell wall of the bacteria Staphylococcus aureus. It is encoded by the spa gene and its regulation is controlled by DNA topology, cellular osmolarity, a two-component system called ArlS-ArlR, it has found use in biochemical research because of its ability to bind immunoglobulins. It is composed of five homologous Ig-binding domains; each domain is able to bind proteins from most notably IgGs. It binds the heavy chain within the Fc region of most immunoglobulins and within the Fab region in the case of the human VH3 family. Through these interactions in serum, where IgG molecules are bound in the wrong orientation, the bacteria disrupts opsonization and phagocytosis; as a by-product of his work on type-specific staphylococcus antigens, Verwey reported in 1940 that a protein fraction prepared from extracts of these bacteria non-specifically precipitated rabbit antisera raised against different staphylococcus types. In 1958, Jensen confirmed Verwey’s finding and showed that rabbit pre-immunization sera as well as normal human sera bound to the active component in the staphylococcus extract.
The misclassification of the protein was the result of faulty tests but it was not long thereafter that Löfkvist and Sjöquist corrected the error and confirmed that Antigen A was in fact a surface protein on the bacterial wall of certain strains of S. aureus. The Bergen group from Norway named the protein "Protein A" after the antigen fraction isolated by Jensen, it has been shown via crystallographic refinement that the primary binding site for protein A is on the Fc region, between the CH2 and CH3 domains. In addition, protein A has been shown to bind human IgG molecules containing IgG F2 fragments from the human VH3 gene family. Protein A can bind with strong affinity to the Fc portion of immunoglobulin of certain species as shown in the below table. In addition to protein A, other immunoglobulin-binding bacterial proteins such as Protein G, Protein A/G and Protein L are all used to purify, immobilize or detect immunoglobulins; as a pathogen, Staphylococcus aureus utilizes protein A, along with a host of other proteins and surface factors, to aid its survival and virulence.
To this end, protein A plays a multifaceted role: By binding the Fc portion of antibodies, protein A renders them inaccessible to the opsonins, thus impairing phagocytosis of the bacteria via immune cell attack. Protein A facilitates the adherence of S. aureus to human von Willebrand factor -coated surfaces, thus increasing the bacteria's infectiousness at the site of skin penetration. Protein A can inflame lung tissue by binding to tumor necrosis factor 1 receptors; this interaction has been shown to play a key role in the pathogenesis of staphylococcal pneumonia. Protein A has been shown to cripple humoral immunity which in turn means that individuals can be infected with S. aureus since they cannot mount a strong antibody response. Protein A has been shown to promote the formation of biofilms both when the protein is covalently linked to the bacterial cell wall as well as in solution. Protein A helps inhibit phagocytic engulfment and acts as an immunological disguise. Higher levels of protein A in different strains of S. aureus have been associated with nasal carriage of this bacteria.
Mutants of S. aureus lacking protein A are more efficiently phagocytosed in vitro, mutants in infection models have diminished virulence. Protein A is produced and purified in industrial fermentation for use in immunology, biological research and industrial applications. Natural protein A can be cultured in Staphylococcus aureus and contains the five homologous antibody binding regions described above and a C-terminal region for cell wall attachment. Today, protein A is more produced recombinantly in Escherichia coli. Recombinant versions of protein A contain the five homologous antibody binding domains but may vary in other parts of the structure in order to facilitate coupling to porous substrates Engineered versions of the protein are available, the first of, rProtein A, B4, C-CYS. Engineered versions are multimers of a single domain, modified to improve usability in industrial applications. Protein A is coupled to other molecules such as a fluorescent dye, biotin, colloidal gold or radioactive iodine without affecting the antibody binding site.
Examples including protein A–gold stain is used in immunogold labelling, fluorophore coupled protein A for immunofluorescence, DNA docking strand coupled protein A for DNA-PAINT imaging. It is widely utilized coupled to magnetic and agarose beads. Protein A is immobilized onto a solid support and used as reliable method for purifying total IgG from crude protein mixtures such as serum or ascites fluid, or coupled with one of the above markers to detect the presence of antibodies; the first example of protein A being coupled to a porous bead for purification of IgG was published in 1972. Immunoprecipitation studies with protein A conjugated to beads are commonly used to purify proteins or protein complexes indirectly through antibodies against the protein or protein complex of interest; the first reference in the literature to a commercially available protein A chromatography resin appeared in 1976. Today, chromatographic separation using protein A immobilized on porous substrates is the most established method for
Structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such as biological organisms and chemicals. Abstract structures include data structures in musical form. Types of structure include a hierarchy, a network featuring many-to-many links, or a lattice featuring connections between components that are neighbors in space. Buildings, skeletons, beaver dams and salt domes are all examples of load-bearing structures; the results of construction are divided into buildings and non-building structures, make up the infrastructure of a human society. Built structures are broadly divided by their varying design approaches and standards, into categories including building structures, architectural structures, civil engineering structures and mechanical structures; the effects of loads on physical structures are determined through structural analysis, one of the tasks of structural engineering.
The structural elements can be classified as two-dimensional, or three-dimensional. The latter was the main option available to early structures such as Chichen Itza. A one-dimensional element has one dimension much larger than the other two, so the other dimensions can be neglected in calculations. Two-dimensional elements with a thin third dimension have little of either but can resist biaxial traction; the structure elements are combined in structural systems. The majority of everyday load-bearing structures are section-active structures like frames, which are composed of one-dimensional structures. Other types are Vector-active structures such as trusses, surface-active structures such as shells and folded plates, form-active structures such as cable or membrane structures, hybrid structures. Load-bearing biological structures such as bones, teeth and tendons derive their strength from a multilevel hierarchy of structures employing biominerals and proteins, at the bottom of which are collagen fibrils.
In biology, structures exist at all levels of organization, ranging hierarchically from the atomic and molecular to the cellular, organ, organismic and ecosystem level. A higher-level structure is composed of multiple copies of a lower-level structure. Structural biology is concerned with the biomolecular structure of macromolecules proteins and nucleic acids; the function of these molecules is determined by their shape as well as their composition, their structure has multiple levels. Protein structure has a four-level hierarchy; the primary structure is the sequence of amino acids. It has a peptide backbone made up of a repeated sequence of two carbon atoms; the secondary structure consists of repeated patterns determined by hydrogen bonding. The two basic types are the β-pleated sheet; the tertiary structure is a back and forth bending of the polypeptide chain, the quaternary structure is the way that tertiary units come together and interact. Chemical structure refers to electronic structure.
The structure can be represented by a variety of diagrams called structural formulas. Lewis structures use a dot notation to represent the valence electrons for an atom. Bonds between atoms can be represented by lines with one line for each pair of electrons, shared. In a simplified version of such a diagram, called a skeletal formula, only carbon-carbon bonds and functional groups are shown. Atoms in a crystal have a structure; the atoms can be modeled as points on a lattice, one can explore the effect of symmetry operations that include rotations about a point, reflections about a symmetry planes, translations. Each crystal has a finite group, called the space group, of such operations. By Neumann's law, the symmetry of a crystal determines what physical properties, including piezoelectricity and ferromagnetism, the crystal can have. A large part of numerical analysis involves identifying and interpreting the structure of musical works. Structure can be found at the level of part of the entire work, or a group of works.
Elements of music such as pitch and timbre combine into small elements like motifs and phrases, these in turn combine in larger structures. Not all music has a hierarchical organization, but hierarchy makes it easier for a listener to understand and remember the music. In analogy to linguistic terminology and phrases can be combined to make complete musical ideas such as sentences and phrases. A larger form is known as the period. One such form, used between 1600 and 1900 has two phrases, an antecedent and a consequent, with a half cadence in the middle and a full cadence at the end providing punctuation. On a larger scale are single-movement forms such as the sonata form and the contrapuntal form, multi-movement forms such as the symphony. A social structure is a pattern of relationships, they are social organizations of individuals in various life situations. Structures are applicable to people in how a society is as a system organized by a characteristic pattern of relationships. This
VJ recombination is the unique mechanism of genetic recombination that occurs only in developing lymphocytes during the early stages of T and B cell maturation. It involves somatic recombination, results in the diverse repertoire of antibodies/immunoglobulins and T cell receptors found on B cells and T cells, respectively; the process is a defining feature of the adaptive immune system. VJ recombination occurs in the primary lymphoid organs and in a nearly random fashion rearranges variable, in some cases, diversity gene segments; the process results in novel amino acid sequences in the antigen-binding regions of Igs and TCRs that allow for the recognition of antigens from nearly all pathogens including bacteria, viruses and worms as well as "altered self cells" as seen in cancer. The recognition can be allergic in nature or may match host tissues and lead to autoimmunity. In 1987, Susumu Tonegawa was awarded the Nobel Prize in Physiology or Medicine "for his discovery of the genetic principle for generation of antibody diversity".
Human antibody molecules are composed of heavy and light chains, each of which contains both constant and variable regions, genetically encoded on three loci: The immunoglobulin heavy locus on chromosome 14, containing the gene segments for the immunoglobulin heavy chain. The immunoglobulin kappa locus on chromosome 2, containing the gene segments for part of the immunoglobulin light chain; the immunoglobulin lambda locus on chromosome 22, containing the gene segments for the remainder of the immunoglobulin light chain. Each heavy chain or light chain gene contains multiple copies of three different types of gene segments for the variable regions of the antibody proteins. For example, the human immunoglobulin heavy chain region contains 2 Constant gene segments and 44 Variable gene segments, plus 27 Diversity gene segments and 6 Joining gene segments; the light chains possess 2 Constant gene segments and numerous V and J gene segments, but do not have D gene segments. DNA rearrangement causes one copy of each type of gene segment to go in any given lymphocyte, generating an enormous antibody repertoire.
Most T cell receptors are composed of a beta chain. The T cell receptor genes are similar to immunoglobulin genes in that they too contain multiple V, D and J gene segments in their beta chains that are rearranged during the development of the lymphocyte to provide that cell with a unique antigen receptor; the T cell receptor in this sense is the topological equivalent to an antigen-binding fragment of the antibody, both being part of the immunoglobulin superfamily. Failure of the cell to create a successful product that does not self-react leads to apoptosis. Autoimmunity is prevented by eliminating lymphocytes that self-react in the thymus by testing them against an array of self antigens expressed through the function of Aire; the immunoglobulin lambda light chain locus contains protein-coding genes that can be lost with its rearrangement. This is not pathogenetic for leukemias or lymphomas. In the developing B cell, the first recombination event to occur is between one D and one J gene segment of the heavy chain locus.
Any DNA between these two gene segments is deleted. This D-J recombination is followed by the joining of one V gene segment, from a region upstream of the newly formed DJ complex, forming a rearranged VDJ gene segment. All other gene segments between V and D segments are now deleted from the cell’s genome. Primary transcript is generated containing the VDJ region of the heavy chain and both the constant mu and delta chains.. The primary RNA is processed to add a polyadenylated tail after the Cμ chain and to remove sequence between the VDJ segment and this constant gene segment. Translation of this mRNA leads to the production of the Ig M heavy chain protein; the kappa and lambda chains of the immunoglobulin light chain loci rearrange in a similar way, except that the light chains lack a D segment. In other words, the first step of recombination for the light chains involves the joining of the V and J chains to give a VJ complex before the addition of the constant chain gene during primary transcription.
Translation of the spliced mRNA for either the kappa or lambda chains results in formation of the Ig κ or Ig λ light chain protein. Assembly of the Ig μ heavy chain and one of the light chains results in the formation of membrane bound form of the immunoglobulin IgM, expressed on the surface of the immature B cell. During thymocyte development, the T cell receptor chains undergo the same sequence of ordered recombination events as that described for immunoglobulins. D-to-J recombination occurs first in the β chain of the TCR; this process can involve either the joining of the Dβ1 gene segment to one of six Jβ1 segments or the joining of the Dβ2 gene segment to one of six Jβ2 segments. DJ recombination is followed with Vβ-to-DβJβ rearrangements. All gene segments between the Vβ-Dβ-Jβ gene segments in the newly formed complex are deleted and the primary transcript is synthesized that incorporates the constant domain gene. MRNA transcription splices out any intervening sequence and allows translation of the full length protein for the TCR Cβ chain.
The rearrangement of the alpha chain of the TCR fo