TNF receptor-associated factor 2 is a protein that in humans is encoded by the TRAF2 gene. The protein encoded by this gene is a member of the TNF receptor associated factor protein family. TRAF proteins associate with, mediate the signal transduction from members of the TNF receptor superfamily; this protein directly interacts with TNF receptors, forms complexes with other TRAF proteins. TRAF2 is required for TNF-alpha-mediated activation of MAPK8/JNK and NF-κB; the protein complex formed by TRAF2 and TRAF1 interacts with the IAP family members cIAP1 and cIAP2, functions as a mediator of the anti-apoptotic signals from TNF receptors. The interaction of this protein with TRADD, a TNF receptor associated apoptotic signal transducer, ensures the recruitment of IAPs for the direct inhibition of caspase activation. CIAP1 can ubiquitinate and induce the degradation of this protein, thus potentiate TNF-induced apoptosis. Multiple alternatively spliced transcript variants have been found for this gene, but the biological validity of only one transcript has been determined.
TRAF2 has been shown to interact with: Model organisms have been used in the study of TRAF2 function. A conditional knockout mouse line called Traf2tm1aWtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping
Chromosome 20 is one of the 23 pairs of chromosomes in humans. Chromosome 20 spans around 63 million base pairs and represents between 2 and 2.5 percent of the total DNA in cells. Chromosome 20 was sequenced in 2001 and was reported to contain over 59 million base pairs representing 99.4% of the euchromatic DNA. Since due to sequencing improvements and fixes, the length of chromosome 20 has been updated to just over 63 million base pairs; the following are some of the gene count estimates of human chromosome 20. Because researchers use different approaches to genome annotation their predictions of the number of genes on each chromosome varies. Among various projects, the collaborative consensus coding sequence project takes an conservative strategy. So CCDS's gene number prediction represents a lower bound on the total number of human protein-coding genes; the following is a partial list of genes on human chromosome 20. For complete list, see the link in the infobox on the right; the following diseases are some of those related to genes on chromosome 20: Albright's hereditary osteodystrophy Arterial tortuosity syndrome Adenosine deaminase deficiency Alagille syndrome Fatal familial insomnia Galactosialidosis - CTSA Maturity onset diabetes of the young type 1 Neuronal ceroid lipofuscinosis Pantothenate kinase-associated neurodegeneration Transmissible spongiform encephalopathy Waardenburg syndrome National Institutes of Health.
"Chromosome 20". Genetics Home Reference. Retrieved 2017-05-06. "Chromosome 20". Human Genome Project Information Archive 1990–2003. Retrieved 2017-05-06
A T cell, or T lymphocyte, is a type of lymphocyte that plays a central role in cell-mediated immunity. T cells can be distinguished from other lymphocytes, such as B cells and natural killer cells, by the presence of a T-cell receptor on the cell surface, they are called T cells. The several subsets of T cells each have a distinct function; the majority of human T cells, termed alpha beta T cells, rearrange their alpha and beta chains on the cell receptor and are part of the adaptive immune system. Specialized gamma delta T cells, have invariant T-cell receptors with limited diversity, that can present antigens to other T cells and are considered to be part of the innate immune system. Effector cells are the superset of all the various T cell types that respond to a stimulus, such as co-stimulation; this includes helper, killer and other T cell types. Memory cells are their opposite counterpart that are longer lived to target future infections as necessary. T helper cells assist other white blood cells in immunologic processes, including maturation of B cells into plasma cells and memory B cells, activation of cytotoxic T cells and macrophages.
These cells are known as CD4+ T cells because they express the CD4 glycoprotein on their surfaces. Helper T cells become activated when they are presented with peptide antigens by MHC class II molecules, which are expressed on the surface of antigen-presenting cells. Once activated, they divide and secrete small proteins called cytokines that regulate or assist in the active immune response; these cells can differentiate into one of several subtypes, including TH1, TH2, TH3, TH17, TH9, or TFH, which secrete different cytokines to facilitate different types of immune responses. Signalling from the APC directs T cells into particular subtypes. Cytotoxic T cells destroy virus-infected cells and tumor cells, are implicated in transplant rejection; these cells are known as CD8+ T cells since they express the CD8 glycoprotein at their surfaces. These cells recognize their targets by binding to antigen associated with MHC class I molecules, which are present on the surface of all nucleated cells. Through IL-10, other molecules secreted by regulatory T cells, the CD8+ cells can be inactivated to an anergic state, which prevents autoimmune diseases.
Antigen-naïve T cells expand and differentiate into memory and effector T cells after they encounter their cognate antigen within the context of an MHC molecule on the surface of a professional antigen presenting cell. Appropriate co-stimulation must be present at the time of antigen encounter for this process to occur. Memory T cells were thought to belong to either the effector or central memory subtypes, each with their own distinguishing set of cell surface markers. Subsequently, numerous new populations of memory T cells were discovered including tissue-resident memory T cells, stem memory TSCM cells, virtual memory T cells; the single unifying theme for all memory T cell subtypes is that they are long-lived and can expand to large numbers of effector T cells upon re-exposure to their cognate antigen. By this mechanism they provide the immune system with "memory" against encountered pathogens. Memory T cells may be either CD4+ or CD8+ and express CD45RO. Memory T cell subtypes: Central memory T cells express CD45RO, C-C chemokine receptor type 7, L-selectin.
Central memory T cells have intermediate to high expression of CD44. This memory subpopulation is found in the lymph nodes and in the peripheral circulation.. Effector memory T cells lack expression of CCR7 and L-selectin, they have intermediate to high expression of CD44. These memory T cells lack lymph node-homing receptors and are thus found in the peripheral circulation and tissues. TEMRA stands for terminally differentiated effector memory cells re-expressing CD45RA, a marker found on naive T cells. Tissue resident memory T cells occupy tissues without recirculating. One cell surface marker, associated with TRM is the integrin αeβ7. Virtual memory T cells differ from the other memory subsets in that they do not originate following a strong clonal expansion event. Thus, although this population as a whole is abundant within the peripheral circulation, individual virtual memory T cell clones reside at low frequencies. One theory is. Although CD8 virtual memory T cells were the first to be described, it is now known that CD4 virtual memory cells exist.
Regulatory T cells are crucial for the maintenance of immunological tolerance. Their major role is to shut down T cell-mediated immunity toward the end of an immune reaction and to suppress autoreactive T cells that escaped the process of negative selection in the thymus. Suppressor T cells along with Helper T cells can collectively be called Regulatory T cells due to their regulatory functions. Two major classes of CD4 + Treg cells have been described -- FOXP3 − Treg cells. Regulatory T cells can develop either during normal development in the thymus, are known as thymic Treg cells, or can be induced peripherally and are called peripherally derived Treg cel
Nitric oxide is a colorless gas with the formula NO. It is one of the principal oxides of nitrogen. Nitric oxide is a free radical, i.e. it has an unpaired electron, sometimes denoted by a dot in its chemical formula, i.e. ·NO. Nitric oxide is a heteronuclear diatomic molecule, a historic class that drew researches which spawned early modern theories of chemical bonding. An important intermediate in chemical industry, nitric oxide forms in combustion systems and can be generated by lightning in thunderstorms. In mammals, including humans, nitric oxide is a signaling molecule in many physiological and pathological processes, it was proclaimed the "Molecule of the Year" in 1992. The 1998 Nobel Prize in Physiology or Medicine was awarded for discovering nitric oxide's role as a cardiovascular signalling molecule. Nitric oxide should not be confused with nitrous oxide, an anesthetic, or with nitrogen dioxide, a brown toxic gas and a major air pollutant. Upon condensing to a liquid, nitric oxide dimerizes to dinitrogen dioxide, but the association is weak and reversible.
The N–N distance in crystalline NO is 218 pm, nearly twice the N–O distance. Since the heat of formation of ·NO is endothermic, NO can be decomposed to the elements. Catalytic converters in cars exploit this reaction: 2 NO → O2 + N2; when exposed to oxygen, nitric oxide converts into nitrogen dioxide: 2 NO + O2 → 2 NO2. This conversion has been speculated as occurring via the ONOONO intermediate. In water, nitric oxide reacts with water to form nitrous acid; the reaction is thought to proceed via the following stoichiometry: 4 NO + O2 + 2 H2O → 4 HNO2. Nitric oxide reacts with fluorine and bromine to form the nitrosyl halides, such as nitrosyl chloride: 2 NO + Cl2 → 2 NOCl. With NO2 a radical, NO combines to form the intensely blue dinitrogen trioxide: NO + NO2 ⇌ ON−NO2; the addition of a nitric oxide moiety to another molecule is referred to as nitrosylation. Nitric oxide reacts with acetone and an alkoxide to a diazeniumdiolate or nitrosohydroxylamine and methyl acetate: This reaction, discovered around 1898, remains of interest in nitric oxide prodrug research.
Nitric oxide can react directly with sodium methoxide, forming sodium formate and nitrous oxide. Nitric oxide reacts with transition metals to give complexes called metal nitrosyls; the most common bonding mode of nitric oxide is the terminal linear type. Alternatively, nitric oxide can serve as a one-electron pseudohalide. In such complexes, the M−N−O group is characterized by an angle between 120° and 140°; the NO group can bridge between metal centers through the nitrogen atom in a variety of geometries. In commercial settings, nitric oxide is produced by the oxidation of ammonia at 750–900 °C with platinum as catalyst: 4 NH3 + 5 O2 → 4 NO + 6 H2OThe uncatalyzed endothermic reaction of oxygen and nitrogen, effected at high temperature by lightning has not been developed into a practical commercial synthesis: N2 + O2 → 2 NO In the laboratory, nitric oxide is conveniently generated by reduction of dilute nitric acid with copper: 8 HNO3 + 3 Cu → 3 Cu2 + 4 H2O + 2 NOAn alternative route involves the reduction of nitrous acid in the form of sodium nitrite or potassium nitrite: 2 NaNO2 + 2 NaI + 2 H2SO4 → I2 + 4 NaHSO4 + 2 NO 2 NaNO2 + 2 FeSO4 + 3 H2SO4 → Fe23 + 2 NaHSO4 + 2 H2O + 2 NO 3 KNO2 + KNO3 + Cr2O3 → 2 K2CrO4 + 4 NOThe iron sulfate route is simple and has been used in undergraduate laboratory experiments.
So-called NONOate compounds are used for nitric oxide generation. Nitric oxide concentration can be determined using a chemiluminescent reaction involving ozone. A sample containing nitric oxide is mixed with a large quantity of ozone; the nitric oxide reacts with the ozone to produce oxygen and nitrogen dioxide, accompanied with emission of light: NO + O3 → NO2 + O2 + hνwhich can be measured with a photodetector. The amount of light produced is proportional to the amount of nitric oxide in the sample. Other methods of testing include electroanalysis, where ·NO reacts with an electrode to induce a current or voltage change; the detection of NO radicals in biological tissues is difficult due to the short lifetime and concentration of these radicals in tissues. One of the few practical methods is spin trapping of nitric oxide with iron-dithiocarbamate complexes and subsequent detection of the mono-nitrosyl-iron complex with electron paramagnetic resonance. A group of fluorescent dye indicators that are available in acetylated form for intracellular measurements exist.
The most common compound is 4,5-diaminofluorescein. Nitric oxide reacts with the hydroperoxy radical to form nitrogen dioxide, which can react with a hydroxyl radical to produce nitric acid: ·NO + HO2•→ •NO2 + •OH ·NO2 + •OH → HNO3Nitric acid, along with sulfuric acid, contribute acid rain deposition. Furthermore, ·NO participates in ozone layer depletion. In this process, nitric oxide reacts with stratospheric ozone to form O2 and nitrogen dioxide: ·NO + O3 → NO2 + O2As seen in the Concentration Measurement section, this reaction is utilized to measure concentrations of ·NO in control volumes; as seen in the Acid deposition section, nitric oxide can transform into nitrogen dioxide. Symptoms of short-term nitrogen dioxide exposure include nausea and headache. Long-term effects could include impaired respiratory function. NO is a gaseous signaling molecule, it is a key vertebrate biological messenger. It is
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
Reactive oxygen species
Reactive oxygen species are chemically reactive chemical species containing oxygen. Examples include peroxides, hydroxyl radical, singlet oxygen, alpha-oxygen. In a biological context, ROS are formed as a natural byproduct of the normal metabolism of oxygen and have important roles in cell signaling and homeostasis. However, during times of environmental stress, ROS levels can increase dramatically; this may result in significant damage to cell structures. Cumulatively, this is known as oxidative stress; the production of ROS is influenced by stress factor responses in plants, these factors that increase ROS production include drought, chilling, nutrient deficiency, metal toxicity and UV-B radiation. ROS are generated by exogenous sources such as ionizing radiation; the reduction of molecular oxygen produces superoxide and is the precursor of most other reactive oxygen species: O2 + e− → •O−2Dismutation of superoxide produces hydrogen peroxide: 2 H+ + •O−2 + •O−2 → H2O2 + O2Hydrogen peroxide in turn may be reduced to hydroxyl radical or reduced to water: H2O2 + e− → HO− + •OH 2 H+ + 2 e− + H2O2 → 2 H2O Exogenous ROS can be produced from pollutants, smoke, xenobiotics, or radiation.
Ionizing radiation can generate damaging intermediates through the interaction with water, a process termed radiolysis. Since water comprises 55–60% of the human body, the probability of radiolysis is quite high under the presence of ionizing radiation. In the process, water loses an electron and becomes reactive. Through a three-step chain reaction, water is sequentially converted to hydroxyl radical, hydrogen peroxide, superoxide radical, oxygen; the hydroxyl radical is reactive and removes electrons from any molecule in its path, turning that molecule into a free radical and thus propagating a chain reaction. However, hydrogen peroxide is more damaging to DNA than the hydroxyl radical, since the lower reactivity of hydrogen peroxide provides enough time for the molecule to travel into the nucleus of the cell, subsequently reacting with macromolecules such as DNA. ROS are produced intracellularly through multiple mechanisms and depending on the cell and tissue types, the major sources being the "professional" producers of ROS: NADPH oxidase complexes in cell membranes, mitochondria and endoplasmic reticulum.
Mitochondria convert energy for the cell into adenosine triphosphate. The process in which ATP is produced, called oxidative phosphorylation, involves the transport of protons across the inner mitochondrial membrane by means of the electron transport chain. In the electron transport chain, electrons are passed through a series of proteins via oxidation-reduction reactions, with each acceptor protein along the chain having a greater reduction potential than the previous; the last destination for an electron along this chain is an oxygen molecule. In normal conditions, the oxygen is reduced to produce water. Superoxide is not reactive by itself, but can inactivate specific enzymes or initiate lipid peroxidation in its protonated form, hydroperoxyl HO•2; the pKa of hydroperoxyl is 4.8. Thus, at physiological pH, the majority will exist as superoxide anion. If too much damage is present in mitochondria, a cell undergoes programmed cell death. Bcl-2 proteins are layered on the surface of the mitochondria, detect damage, activate a class of proteins called Bax, which punch holes in the mitochondrial membrane, causing cytochrome C to leak out.
This cytochrome C binds to Apaf-1, or apoptotic protease activating factor-1, free-floating in the cell's cytoplasm. Using energy from the ATPs in the mitochondrion, the Apaf-1 and cytochrome C bind together to form apoptosomes; the apoptosomes activate caspase-9, another free-floating protein. The caspase-9 cleaves the proteins of the mitochondrial membrane, causing it to break down and start a chain reaction of protein denaturation and phagocytosis of the cell. Superoxide dismutases are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide; as such, they are an important antioxidant defense in nearly all cells exposed to oxygen. In mammals and most chordates, three forms of superoxide dismutase are present. SOD1 is located in the cytoplasm, SOD2 in the mitochondria and SOD3 is extracellular; the first is a dimer. SOD1 and SOD3 contain zinc ions, while SOD2 has a manganese ion in its reactive centre; the genes are located on chromosomes 21, 6, 4, respectively.
The SOD-catalysed dismutation of superoxide may be written with the following half-reactions: M+ − SOD + O−2 → Mn+ − SOD + O2 Mn+ − SOD + O−2 + 2H+ → M+ − SOD + H2O2.where M = Cu. In this reaction the oxidation state of the metal cation oscillates between n and n + 1. Catalase, concentrated in peroxisomes located next to mitochondria, reacts with the hydrogen peroxide to catalyze the formation of water and oxygen. Glutathione peroxidase reduces hydrogen peroxide by transferring the energy of the reactive peroxides to a small sulfur-containing protein called glutathione; the sulfur
Immunoglobulin class switching
Immunoglobulin class switching known as isotype switching, isotypic commutation or class-switch recombination, 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. Class switching occurs after activation of a mature B cell via its membrane-bound antibody molecule to generate the different classes of antibody, all with the same variable domains as the original antibody generated in the immature B cell during the process of VJ recombination, but possessing distinct constant domains in their heavy chains. Naïve mature B cells produce both IgM and IgD, which are the first two heavy chain segments in the immunoglobulin locus.
After activation by antigen, these B cells proliferate. If these activated B cells encounter specific signaling molecules via their CD40 and cytokine receptors, they undergo antibody class switching to produce IgG, IgA or IgE antibodies. During class switching, the constant region of the immunoglobulin heavy chain changes but the variable regions, therefore antigenic specificity, stay the same; this allows different daughter cells from the same activated B cell to produce antibodies of different isotypes or subtypes. The order of the heavy chain exons are as follows: μ - IgM δ - IgD γ3 - IgG3 γ1 - IgG1 α1 - IgA1 γ2 - IgG2 γ4 - IgG4 ε - IgE α2 - IgA2Class switching occurs by a mechanism called class switch recombination binding. Class switch recombination is a biological mechanism that allows the class of antibody produced by an activated B cell to change during a process known as isotype or class switching. During CSR, portions of the antibody heavy chain locus are removed from the chromosome, the gene segments surrounding the deleted portion are rejoined to retain a functional antibody gene that produces antibody of a different isotype.
Double-stranded breaks are generated in DNA at conserved nucleotide motifs, called switch regions, which are upstream from gene segments that encode the constant regions of antibody heavy chains. DNA is nicked and broken at two selected S-regions by the activity of a series of enzymes, including Activation-Induced Deaminase, uracil DNA glycosylase and apyrimidic/apurinic -endonucleases; the intervening DNA between the S-regions is subsequently deleted from the chromosome, removing unwanted μ or δ heavy chain constant region exons and allowing substitution of a γ, α or ε constant region gene segment. The free ends of the DNA are rejoined by a process called non-homologous end joining to link the variable domain exon to the desired downstream constant domain exon of the antibody heavy chain. In the absence of non-homologous end joining, free ends of DNA may be rejoined by an alternative pathway biased toward microhomology joins. With the exception of the μ and δ genes, only one antibody class is expressed by a B cell at any point in time.
While class switch recombination is a deletional process, rearranging a chromosome in "cis", it can occur as an inter-chromosomal translocation mixing immunoglobulin heavy chain genes from both alleles. T cell cytokines modulate class switching in human; these cytokines may have suppressive effect on production of IgM. In addition to the repetitive structure of the target S regions, the process of class switching needs S regions to be first transcribed and spliced out of the immunoglobulin heavy chain transcripts. Chromatin remodeling, accessibility to transcription and to AID and synapsis of broken S regions are under the control of a large super-enhancer, located downstream the more distal Calpha gene, the 3' regulatory region. In some occasions, the 3'RR super-enhancer can itself be targeted by AID and undergo DNA breaks and junction with Sµ, which deletes the Ig heavy chain locus and defines locus suicide recombination. Antibody Immune checkpoint Immunogenetics Immunoglobulin+class+switching at the US National Library of Medicine Medical Subject Headings