query: alternative pathway of complement activation is initiated by

pos: Alternative complement pathway related macular degeneration (AMD) is now believed to be caused, at least in part, by complement mediated attack on ocular tissues. Alternative pathway activation might also play a significant role in kidney pathology associated with lupus. Alternative complement pathway The alternative pathway of the complement system is an innate component of the immune system's natural defense against infections. The alternative pathway is one of three complement pathways that opsonize and kill pathogens. The pathway is triggered when the C3b protein directly binds a microbe. It can also be triggered by foreign materials and damaged tissues. This change in shape allows

pos: Alternative complement pathway Alternative complement pathway The alternative pathway of the complement system is an innate component of the immune system's natural defense against infections. The alternative pathway is one of three complement pathways that opsonize and kill pathogens. The pathway is triggered when the C3b protein directly binds a microbe. It can also be triggered by foreign materials and damaged tissues. This change in shape allows the binding of plasma protein Factor B, which allows Factor D to cleave Factor B into Ba and Bb. Bb remains bound to C3(HO) to form C3(HO)Bb. This complex is also known as a fluid-phase C3-convertase.

neg: C3a (complement) reaction catalyzed by C3-convertase. There are three pathways of activation, each of which leads to the formation of C3a and C3b, which is involved in antigen opsonization. Other than the alternative pathway, which is constantly active, C3a formation is triggered by pathogenic infection. The classical pathway of complement activation is initiated when the C1 complex, made up of C1r and C1s serine proteases, recognizes the Fc region of IgM or IgG antibodies bound to a pathogen. C1q mediates the classical pathway by activating the C1 complex, which cleaves C4 and C2 into smaller fragments (C4a, C4b, C2a, and C2b). C4a

neg: Complement factor B Complement factor B Complement factor B is a protein that in humans is encoded by the "CFB" gene. This gene encodes complement factor B, a component of the alternative pathway of complement activation. Factor B circulates in the blood as a single chain polypeptide. Upon activation of the alternative pathway, it is cleaved by complement factor D yielding the noncatalytic chain Ba and the catalytic subunit Bb. The active subunit Bb is a serine protease that associates with C3b to form the alternative pathway C3 convertase. Bb is involved in the proliferation of preactivated B lymphocytes, while Ba inhibits their

neg: Classical complement pathway the C5 convertase initiates the terminal phase of the complement system, leading to the assembly of the membrane attack complex (MAC). The membrane attack complex creates a pore on the target cell's membrane, inducing cell lysis and death. The classical complement pathway can also be activated by apoptotic cells, necrotic cells, and acute phase proteins. The classical pathway is distinct from the other complement pathways in its unique activation triggers and cascade sequence. Activation of the complement pathway through the classical, lectin or alternative complement pathway is followed by a cascade of reactions eventually leading to the membrane attack complex.

neg: Complement factor B proliferation. This gene localizes to the major histocompatibility complex (MHC) class III region on chromosome 6. This cluster includes several genes involved in regulation of the immune reaction. The polyadenylation site of this gene is 421 bp from the 5' end of the gene for complement component 2. Complement factor B Complement factor B is a protein that in humans is encoded by the "CFB" gene. This gene encodes complement factor B, a component of the alternative pathway of complement activation. Factor B circulates in the blood as a single chain polypeptide. Upon activation of the alternative pathway, it is

neg: Alicaforsen were well tolerated in healthy volunteers. Drug-related adverse events observed were dose related, modest ~1.5-fold at the 2-mg/kg dose, and transient (2–4 hours after dosing) increases in the activated partial thromboplastin time (aPTT) and threshold effects on complement C3, but not C5, conversion at the highest doses. (4) Both of these dose-related effects (prolongation of the intrinsic coagulation pathway and alternative pathway complement activation) have been observed in monkeys given alicaforsen and a spectrum of other phosphorothioate oligodeoxynucleotides.(5) Alternative pathway complement activation seemed to be mediated by an interaction with the inhibitory protein factor H.(6) The prolongation of aPTT appears

neg: Classical complement pathway Classical complement pathway The classical complement pathway is one of three pathways which activate the complement system, which is part of the immune system. The classical complement pathway is initiated by antigen-antibody complexes with the antibody isotypes IgG and IgM. Following activation, a series of proteins are recruited to generate C3 convertase (C4bC2a), which cleaves the C3 protein. The C3b component of the cleaved C3 binds to C3 convertase (C4bC2a) to generate C5 convertase (C4bC2aC3b), which cleaves the C5 protein. The cleaved products attract phagocytes to the site of infection and tags target cells for elimination by phagocytosis. In addition,

neg: Complement system cells of the genitourinary system and gastrointestinal tract. The three pathways of activation all generate homologous variants of the protease C3-convertase. The classical complement pathway typically requires antigen-antibody complexes for activation (specific immune response), whereas the alternative pathway can be activated by spontaneous complement component 3 (C3) hydrolysis, foreign material, pathogens, or damaged cells. The mannose-binding lectin pathway can be activated by C3 hydrolysis or antigens without the presence of antibodies (non-specific immune response). In all three pathways, C3-convertase cleaves and activates component C3, creating C3a and C3b, and causes a cascade of further cleavage and activation events. C3b binds

neg: Urticarial vasculitis certain diseases. C1q is an integral component within the complement pathway – a complicated cascade of protein interactions, culminating in an immune response against a broad variety of pathogens. The anti-C1q antibodies found in patients with hypocomplementemic urticarial vasculitis activate C1q, which instigates activation of the entire complement pathway. Consequently, levels of all complement proteins become low. The complement pathway is composed of several subset pathways: the lectin/mannose pathway, alternative pathway and the classical pathway. All pathways culminate in the production of a C3 convertase, which catalyses C3 into its constitutive parts (better detailed here – classical complement pathway). In

neg: Alternative complement pathway This convertase, the alternative pathway C3-convertase, although only produced in small amounts, can cleave multiple C3 proteins into C3a and C3b. The complex is believed to be unstable until it binds properdin, a serum protein. The addition of properdin forms the complex C3bBbP, a stable compound which can bind an additional C3b to form alternative pathway C5-convertase. The C5-convertase of the alternative pathway consists of (C3b)BbP (sometimes referred to as C3bBb). After the creation of C5 convertase (either as (C3b)BbP or C4b2a3b from the classical pathway), the complement system follows the same path regardless of the means of activation (alternative,

neg: Classical complement pathway The classical complement pathway can be initiated by the binding of antigen-antibody complexes to the C1q protein. The globular regions of C1q recognize and bind to the Fc region of antibody isotypes IgG or IgM. These globular regions of C1q can also bind to bacterial and viral surface proteins, apoptotic cells, and acute phase proteins. In the absence of these activation factors, C1q is part of the inactive C1 complex which consists of six molecules of C1q, two molecules of C1r, and two molecules of C1s . The binding of C1q leads to conformational changes and the activation of the

neg: Complement system C3b recruits more B, D and P activity and greatly amplifies the complement activation. When complement is activated on a cell surface, the activation is limited by endogenous complement regulatory proteins, which include CD35, CD46, CD55 and CD59, depending on the cell. Pathogens, in general, don't have complement regulatory proteins (there are many exceptions, which reflect adaptation of microbial pathogens to vertebrate immune defenses). Thus, the alternative complement pathway is able to distinguish self from non-self on the basis of the surface expression of complement regulatory proteins. Host cells don't accumulate cell surface C3b (and the proteolytic fragment of C3b

neg: Decay-accelerating factor Decay-accelerating factor Complement decay-accelerating factor, also known as CD55 or DAF, is a protein that, in humans, is encoded by the "CD55" gene. DAF regulates the complement system on the cell surface. It recognizes C4b and C3b fragments that are created during activation of C4 (classical or lectin pathway) or C3 (alternative pathway). Interaction of DAF with cell-associated C4b of the classical and lectin pathways interferes with the conversion of C2 to C2b, thereby preventing formation of the C4b2b C3-convertase, and interaction of DAF with C3b of the alternative pathway interferes with the conversion of factor B to Bb by

neg: Factor H Factor H Factor H is a member of the regulators of complement activation family and is a complement control protein. It is a large (155 kilodaltons), soluble glycoprotein that circulates in human plasma (at typical concentrations of 200–300 micrograms per milliliter). Its principal function is to regulate the alternative pathway of the complement system, ensuring that the complement system is directed towards pathogens or other dangerous material and does not damage host tissue. Factor H regulates complement activation on self cells and surfaces by possessing both cofactor activity for the Factor I mediated C3b cleavage, and decay accelerating activity against

neg: Opsonin that serve as opsonins. As a part of the alternative complement pathway, the spontaneous activation of a complement cascade converts C3 to C3b, a component that can serve as an opsonin when bound to an antigen's surface. Antibodies can also activate complement via the classical pathway, resulting in deposition of C3b and C4b onto the antigen surface. After C3b has bound to the surface of an antigen, it can be recognized by phagocyte receptors that signal for phagocytosis. Complement receptor 1 is expressed on all phagocytes and recognizes a number of complement opsonins, including C3b and C4b which are both

neg: Hemolytic-uremic syndrome diagnose HUS. Typically, this hemolysis results in a hemoglobin level of less than 80 g/L. Shiga-toxin directly activates the alternative complement pathway and also interferes with complement regulation by binding to complement factor H, an inhibitor of the complement cascade. Shiga-toxin causes complement-mediated platelet, leukocyte, and endothelial cell activation, resulting in systemic hemolysis, inflammation and thrombosis. Severe clinical complications of TMA have been reported in patients from 2 weeks to more than 44 days after presentation with STEC-HUS, with improvements in clinical condition extending beyond this time frame, suggesting that complement activation persists beyond the acute clinical presentation and for

neg: C3a (complement) and C2b form C4bC2b, also known as C3 convertase. The lectin pathway is activated when pattern-recognition receptors, like mannan-binding lectin or ficolins, recognize and bind to pathogen-associated molecular patterns on the antigen, including sugars. These bound receptors then complex with Mannose-Binding Lectin-Associated Serine Proteases (MASPs), which have proteolytic activity similar to the C1 complex. The MASPs cleave C4 and C2, resulting in C3 convertase formation. The alternative pathway of complement activation is typically always active at low levels in blood plasma through a process called tick-over, in which C3 spontaneously hydrolyzes into its active form, C3(H2O). This activation induces a

neg: Complement component 3 cleavage of C3 into C3a and C3b, generated during activation through the classical pathway as well as the lectin pathway. C3a is an anaphylotoxin and the precursor of some cytokines such as ASP, and C3b serves as an opsonizing agent. Factor I can cleave C3b into C3c and C3d, the latter of which plays a role in enhancing B cell responses. In the alternative complement pathway, C3 is cleaved by C3bBb, another form of C3-convertase composed of activated forms of C3 (C3b) and factor B (Bb). Once C3 is activated to C3b, it exposes a reactive thioester that allows the

neg: Neutrophil extracellular traps This NETosis pathway can be initiated through activation of Toll-like Receptors (TLRs), Fc receptors, and complement receptors with various ligands such as antibodies, PMA, and so on. The current understanding is that upon activation of these receptors, downstream signaling results in the release of calcium from the endoplasmic reticulum. This intracellular influx of calcium in turn activates NADPH oxidase, resulting in activation of the NETosis pathway as described above. Of note, suicidal NETosis can take hours, even with high levels of PMA stimulation, while vital NETosis that can be completed in a matter of minutes. Vital NETosis can be stimulated

neg: Alternative complement pathway classical, or lectin). C5-convertase cleaves C5 into C5a and C5b. C5b binds sequentially to C6, C7, C8 and then to multiple molecules of C9 to form membrane attack complex. Since C3b is free and abundant in the plasma, it can bind to either a host cell or a pathogen surface. To prevent complement activation from proceeding on the host cell, there are several different kinds of regulatory proteins that disrupt the complement activation process: Dysregulation of the complement system has been implicated in several diseases and pathologies, including Atypical hemolytic uremic syndrome in which the kidney fucntion is compromised. Age

neg: MASP1 (protein) lectin pathway, the mannose-binding lectin and the ficolins. This protein is not directly involved in complement activation but may play a role as an amplifier of complement activation by cleaving complement C2 or by activating another complement serine protease, MASP-2. MASP-1 is also able to cleave fibrinogen and factor XIII and may be involved in coagulation. A splice variant of this gene which lacks the serine protease domain functions as an inhibitor of the complement pathway. MASP1 (protein) Mannan-binding lectin serine protease 1 also known as mannose-associated serine protease 1 (MASP-1) is an enzyme that in humans is encoded by

neg: CFHR5 nephropathy thought to result from stimulation of the immune system leading to damage in the kidneys. A kidney biopsy in patients with CFHR5 nephropathy classically shows deposition of complement C3 in the kidney, without any detectable immunoglobulins there. This is evidence that the disease is caused by a problem with alternative complement pathway regulation, rather than activation of the complement system by other diseases. In addition, light microscopy often demonstrates histological features of mesangiocapillary glomerulonephritis. CFHR5 Nephropathy is histologically distinguished from dense deposit disease by the absence of dense transformation of the glomerular basement membrane – electron microscopy rather reveals mesangial,

neg: C3-convertase form an additional C3 convertase through the alternative pathway, this is a potential mechanism of signal amplification in the complement cascade resulting in the deposition of large numbers of C3b molecules on the surface of activating particles, enabling opsonisation and acute local inflammation. The C3 convertase formed in the classical or lectin pathways is formed of C4b and C2b instead (NB: C2b, the larger fragment of C2 cleavage, was formerly known as C2a). The cleavage of C4 and C2 is mediated by serine proteases. In the classical pathway, this is by sequential proteolytic activation of proteins within the C1 complex

neg: Membranoproliferative glomerulonephritis that DDD was due to abnormal activation of the complement alternative pathway (AP). There is now strong evidence that DDD is caused by uncontrolled AP activation. Spontaneous remissions of MPGN II are rare, approximately half of those affected with MPGN II will progress to end stage renal disease within 10 years. In many cases, people with MPGN II can develop drusen which is caused by same deposits within the Bruch's membrane beneath the retinal pigment epithelium (RPE) layer of the eye. Over time vision can deteriorate and subretinal neovascular membranes, macular detachment, and central serous retinopathy develop. Type III is

neg: Lectin pathway Lectin pathway The lectin pathway is a type of cascade reaction in the complement system, similar in structure to the classical complement pathway, in that, after activation, it proceeds through the action of C4 and C2 to produce activated complement proteins further down the cascade. In contrast to the classical complement pathway, the lectin pathway does not recognize an antibody bound to its target. The lectin pathway starts with mannose-binding lectin (MBL) or ficolin binding to certain sugars. In this pathway, mannose-binding lectin binds to mannose, glucose, or other sugars with 3- and 4-OH groups placed in the equatorial plane,

neg: Classical complement pathway complement activation has also been shown to combat Methicillin-resistant Staphylococcus aureus. Certain variants of the IgM antibody were found to bind the Methicillin-resistant "Staphylococcus aureus" these IgM were found to be critical in complement activation through the classical pathway and subsequent destruction of the bacteria. Therapies that utilize classical complement activation have been shown to be effective in targeting and killing cancer cells and destroying tumors. Tachyplesin, a small peptide, has been shown to exhibit these effects. When injected into target tissue encourages recruitment of C1q and activates downstream events, eventually leading to the formation of the C5b-9 complex which

neg: Thioester-containing protein 1 domain. These features determine how the complex interacts with TEP1. The complement system was previously thought to be an exclusive feature of the immune defense of vertebrates until complement-like molecules were cloned in non-vertebrate species such as the horseshoe crab and mosquitoes. The discovery of C3 like molecules in a diverse range of species suggests that the complement pathway in particular the alternative complement pathway is evolutionary ancient. The TEP1 cascade most closely resembles the alternative pathway as insects do not possess adaptive immunity. Therefore, unlike the classical complement pathway the TEP1 pathway is antibody independent and instead relies on

neg: Complement control protein the surfaces of foreign particles, means that these regulators perform the important task of targeting complement to where it is needed - on the invading bacterium for example - while preventing activation on host tissues. For example, C3b.Bb is an important convertase that is part of the alternative pathway, and it is formed when factor B binds C3b and is subsequently cleaved. To prevent this from happening, factor H competes with factor B to bind C3b; if it manages to bind, then the convertase is not formed. Factor H can bind C3b much more easily in the presence of sialic

neg: Collectin Collectin MBL is involved in activation of the lectin complement pathway. There are three serine proteases, MASP-1, 2 and 3 (MBL-associated serine proteases), which participate in activation of the lectin pathway. MASP-2 has a cleavage activity and it is essential for forming lectin C3 and C5 convertases and for activation of the complement. For more information and details see reviews: Collectin Collectins (collagen-containing C-type lectins) are a part of the innate immune system. They form a family of collagenous Ca-dependent defense lectins, which are found in animals. Collectins are soluble pattern recognition receptors (PRRs). Their function is to bind to

neg: Complement system to the activation of two C1r molecules. C1r is a serine protease. They then cleave C1s (another serine protease). The C1rs component now splits C4 and then C2, producing C4a, C4b, C2a, and C2b (historically, the larger fragment of C2 was called C2a but is now referred to as C2b). C4b and C2b bind to form the classical pathway C3-convertase (C4b2b complex), which promotes cleavage of C3 into C3a and C3b. C3b later joins with C4b2b to make C5 convertase (C4b2b3b complex). The alternative pathway is continuously activated at a low level, analogous to a car engine at idle, as

neg: Synaptic plasticity synapse. Recently, a number of attempts have been made to offer a comprehensive model that could account for most forms of synaptic plasticity Brief activation of an excitatory pathway can produce what is known as long-term depression (LTD) of synaptic transmission in many areas of the brain. LTD is induced by a minimum level of postsynaptic depolarization and simultaneous increase in the intracellular calcium concentration at the postsynaptic neuron. LTD can be initiated at inactive synapses if the calcium concentration is raised to the minimum required level by heterosynaptic activation, or if the extracellular concentration is raised. These alternative conditions

neg: Factor D Factor D Factor D (, "C3 proactivator convertase", "properdin factor D esterase", "factor D (complement)", "complement factor D", "CFD", "adipsin") a protein which in humans is encoded by the "CFD" gene. Factor D is involved in the alternative complement pathway of the complement system where it cleaves factor B. The protein encoded by this gene is a member of the trypsin family of peptidases. The encoded protein is a component of the alternative complement pathway best known for its role in humoral suppression of infectious agents. This protein is also a serine protease that is secreted by adipocytes into the

neg: Classical complement pathway of the classical pathway, which can lead to tissue inflammation and eventually insulin resistance, however the exact mechanisms that causes this is yet unknown. Immunotherapies have been developed to detect and destroy cells infected by the HIV virus via classical complement activation. This process involves creating synthetic peptides that target conserved regions in HIV specific proteins and induce an antibody specific immune response through IgG antibodies. This is important for targeting the virus in its intracellular phase because the antibodies specific to the synthetic peptides can trigger the classical complement pathway and induce the death of HIV infected cells. Classical

neg: MASP1 (protein) MASP1 (protein) Mannan-binding lectin serine protease 1 also known as mannose-associated serine protease 1 (MASP-1) is an enzyme that in humans is encoded by the "MASP1" gene. MASP-1 is involved in the lectin pathway of the complement system and is responsible for cleaving C4 and C2 to form C4b2a, a C3-convertase. MASP-1 is a serine protease that functions as a component of the lectin pathway of complement activation. The complement pathway plays an essential role in the innate and adaptive immune response. MASP-1 is synthesized as a zymogen and is activated when it complexes with the pathogen recognition molecules of

neg: CD19 cell activation. CD21, complement receptor 2, can bind fragments of C3 that have covalently attached to glycoconjugates by complement activation. Recognition of an antigen by the complement system enables the CD19/CD21 complex and associated intracellular signaling molecules to crosslink to the BCR. This results in phosphorylation of the cytoplasmic tail of CD19 by BCR-associated tyrosine kinases, ensuing is the binding of additional Src-family kinases, augmentation of signaling through the BCR, and recruitment of PI3K. The localization of PI3K initiates another signaling pathway leading to Akt activation. Varying expression of CD19 on the cell surface modulates tyrosine phosphorylation and Akt kinase

neg: Total complement activity Total complement activity Total complement activity is a test performed to assess the level of functioning of the complement system. The terms "CH50" or "CH100" may refer to this test. The test is based on the capacity of a serum to lyse sheep erythrocytes coated with anti-sheep antibodies (preferably rabbit IgG). In combination with the Alternative pathway hemolytic assay ("AH50") it can indicate terminal pathway deficiencies (C3, C5-C9; absence of hemolysis in both CH50 and AH50), classic pathway deficiencies (C1, C2, C4; absence of lysis in CH50) and alternative pathway deficiencies (Factor I, B, H, D, properdin; absence of lysis

neg: Complement factor I to low levels of complement component 3 (C3), factor B, factor H and properdin. In blood, due to unregulated activation of C3 convertase, and to low levels of IgG, due to loss of iC3b and C3dg production. In addition to the following diseases, low factor I is associated with recurrent bacterial infections in children. Age-Related Macular Degeneration Research suggests that mutations in the CFI gene contribute to development of age-related macular degeneration. This contribution is thought to be due to the dysregulation of the alternative pathway, leading to increased inflammation in the eye. Atypical Hemolytic Uremic Syndrome Atypical hemolytic uremic

neg: Lectin pathway frequency and severity. Although the clinical significance of MBL-Deficiency is debated Infants and young children with mannose-binding lectin deficiency seem to be more susceptible to infections, but adults can also develop recurrent infections. In addition, affected individuals undergoing chemotherapy or taking drugs that suppress the immune system are especially prone to infections. Lectin pathway The lectin pathway is a type of cascade reaction in the complement system, similar in structure to the classical complement pathway, in that, after activation, it proceeds through the action of C4 and C2 to produce activated complement proteins further down the cascade. In contrast to

neg: C1 complex C1 complex The C1 complex ("complement component 1", C1) is a protein complex involved in the complement system. It is the first component of the classical complement pathway and is composed of the subcomponents C1q, C1r and C1s. The C1 complex is composed of 1 molecule of C1q, 2 molecules of C1r and 2 molecules of C1s, or "C1qrs". Activation of the C1 complex initiates the classical complement pathway. This occurs when C1q binds to antigen-antibody complexes. The antibodies IgM or certain subclasses of IgG complexed with antigens are able to initiate the complement system: a single pentameric IgM can

neg: Complement component 3 Complement component 3 Complement component 3, often simply called C3, is a protein of the immune system. It plays a central role in the complement system and contributes to innate immunity. In humans it is encoded on chromosome 19 by a gene called "C3". C3 plays a central role in the activation of complement system. Its activation is required for both classical and alternative complement activation pathways. People with C3 deficiency are susceptible to bacterial infection. One form of C3-convertase, also known as C4b2b, is formed by a heterodimer of activated forms of C4 and C2. It catalyzes the proteolytic

neg: Phospholipid scramblase pathway. The extrinsic pathway is initiated by membrane bound death receptors, leading to activation of caspase 8, whereas the intrinsic pathway is triggered by DNA damaging drugs and UV radiation, leading to mitochondrial depolarization and subsequent activation of caspase 9. PLSCRs are supposed to play an important role in both intrinsic and extrinsic apoptotic responses that are linked to each other via the activation of caspase 8. Activated caspase 8 causes the cleavage of the amino terminal portion of the cytosolic protein Bid to generate t-Bid that is translocated into mitochondria during apoptosis. hPLSCR1 and its mitochondrial counterpart hPLSCR3 are

neg: Humoral immunity The complement system consists of more than 35 soluble and cell-bound proteins, 12 of which are directly involved in the complement pathways. The complement system is involved in the activities of both innate immunity and acquired immunity. Activation of this system leads to cytolysis, chemotaxis, opsonization, immune clearance, and inflammation, as well as the marking of pathogens for phagocytosis. The proteins account for 5% of the serum globulin fraction. Most of these proteins circulate as zymogens, which are inactive until proteolytic cleavage. Three biochemical pathways activate the complement system: the classical complement pathway, the alternate complement pathway, and the mannose-binding

neg: Complement component 3 been shown to interact with Factor H. Deficiencies in C3 lead to genetic infections, usually fatal to the newborn. Complement component 3 Complement component 3, often simply called C3, is a protein of the immune system. It plays a central role in the complement system and contributes to innate immunity. In humans it is encoded on chromosome 19 by a gene called "C3". C3 plays a central role in the activation of complement system. Its activation is required for both classical and alternative complement activation pathways. People with C3 deficiency are susceptible to bacterial infection. One form of C3-convertase, also

neg: Xenotransplantation integrin family. The binding of XNAs initiate complement activation through the classical complement pathway. Complement activation causes a cascade of events leading to: destruction of endothelial cells, platelet degranulation, inflammation, coagulation, fibrin deposition, and hemorrhage. The end result is thrombosis and necrosis of the xenograft. Since hyperacute rejection presents such a barrier to the success of xenografts, several strategies to overcome it are under investigation: "Interruption of the complement cascade" "Transgenic organs (Genetically engineered pigs)" Also known as delayed xenoactive rejection, this type of rejection occurs in discordant xenografts within 2 to 3 days, if hyperacute rejection is prevented. The

neg: C1-inhibitor leakage syndrome. C1-inhibitor C1-inhibitor (C1-inh, C1 esterase inhibitor) is a protease inhibitor belonging to the serpin superfamily. Its main function is the inhibition of the complement system to prevent spontaneous activation. C1-inhibitor is an acute-phase protein that circulates in blood at levels of around 0.25 g/L. The levels rise ~2-fold during inflammation. C1-inhibitor irreversibly binds to and inactivates C1r and C1s proteases in the C1 complex of classical pathway of complement. MASP-1 and MASP-2 proteases in MBL complexes of the lectin pathway are also inactivated. This way, C1-inhibitor prevents the proteolytic cleavage of later complement components C4 and C2 by

neg: C1-inhibitor C1-inhibitor C1-inhibitor (C1-inh, C1 esterase inhibitor) is a protease inhibitor belonging to the serpin superfamily. Its main function is the inhibition of the complement system to prevent spontaneous activation. C1-inhibitor is an acute-phase protein that circulates in blood at levels of around 0.25 g/L. The levels rise ~2-fold during inflammation. C1-inhibitor irreversibly binds to and inactivates C1r and C1s proteases in the C1 complex of classical pathway of complement. MASP-1 and MASP-2 proteases in MBL complexes of the lectin pathway are also inactivated. This way, C1-inhibitor prevents the proteolytic cleavage of later complement components C4 and C2 by C1 and

neg: Properdin Properdin Properdin is the only known positive regulator of complement activation that stabilizes the alternative pathway convertases. It is found in the blood serum of more complex animals. Properdin is a gamma globulin protein composed of multiple identical protein subunits with a separate ligand-binding site. Native properdin occurs in head-to-tail dimers, trimers and tetramers in the fixed ratio 22:52:28. It is known that it participates in some specific immune responses. It plays a part in tissue inflammation as well as the engulfing of pathogens by phagocytes. In addition it is known to help to neutralize some viruses. The properdin promotes

neg: Complement system make them soluble. The complement system has the potential to be extremely damaging to host tissues, meaning its activation must be tightly regulated. The complement system is regulated by complement control proteins, which are present at a higher concentration in the blood plasma than the complement proteins themselves. Some complement control proteins are present on the membranes of self-cells preventing them from being targeted by complement. One example is CD59, also known as protectin, which inhibits C9 polymerisation during the formation of the membrane attack complex. The classical pathway is inhibited by C1-inhibitor, which binds to C1 to prevent its

neg: Amita Aggarwal and at the University of Oklahoma Health Science Center on a research associateship from the Department of Biotechnology. Aggarwal, who is known for her research in the field of autoimmune rheumatic diseases, has identified the "presence of IgM rheumatoid factor demonstrated by ELISA" is an indicator of a severe clinical expression of juvenile rheumatoid arthritis. She also postulated that the "activation of complement by an alternate pathway is more important than activation by the classical pathway in the pathogenesis of rheumatoid arthritis" and these findings have assisted in a wider understanding of autoimmune rheumatic diseases such as Juvenile idiopathic arthritis

neg: Complement component 2 Complement component 2 Complement C2 is a protein that in humans is encoded by the "C2" gene. The protein encoded by this gene is part of the classical pathway of the complement system, acting as a multi-domain serine protease. Deficiency of C2 has been associated with certain autoimmune diseases. In the classical and lectin pathways of complement activation, formation of the C3-convertase and C5-convertases requires binding of C2 to an activated surface-bound C4b in the presence of Mg; the resultant C4bC2 complex is then cleaved by C1s or MASP2 into C2a and C2b. It is thought that cleavage of C2

neg: Humoral immunity lectin pathway. The classical complement pathway typically requires antibodies for activation and is a specific immune response, while the alternate pathway can be activated without the presence of antibodies and is considered a non-specific immune response. Antibodies, in particular the IgG1 class, can also "fix" complement. Immunoglobulins are glycoproteins in the immunoglobulin superfamily that function as antibodies. The terms "antibody" and "immunoglobulin" are often used interchangeably. They are found in the blood and tissue fluids, as well as many secretions. In structure, they are large Y-shaped globular proteins. In mammals there are five types of antibody: IgA, IgD, IgE, IgG,

neg: Properdin Pathology (now the Department of Pathology at Case Western Reserve University). Properdin deficiency is a rare X-linked disease in which properdin is deficient. Affected individuals are susceptible to fulminant meningococcal disease. Properdin Properdin is the only known positive regulator of complement activation that stabilizes the alternative pathway convertases. It is found in the blood serum of more complex animals. Properdin is a gamma globulin protein composed of multiple identical protein subunits with a separate ligand-binding site. Native properdin occurs in head-to-tail dimers, trimers and tetramers in the fixed ratio 22:52:28. It is known that it participates in some specific immune

neg: Complement component 4B Complement component 4B Complement component 4B (Chido blood group) is a protein that in humans is encoded by the C4B gene. This gene encodes the basic form of complement factor 4, part of the classical activation pathway. The protein is expressed as a single chain precursor which is proteolytically cleaved into a trimer of alpha, beta, and gamma chains prior to secretion. The trimer provides a surface for interaction between the antigen-antibody complex and other complement components. The alpha chain may be cleaved to release C4 anaphylatoxin, a mediator of local inflammation. Deficiency of this protein is associated with systemic

neg: Survivin have two main pathways that lead to apoptosis. 1. Extrinsic Pathway: Initiated by extrinsic ligands binding to death receptors on the surface of the cell. An example of this is the binding of tumour necrosis factor-alpha (TNF-alpha) to TNF-alpha receptor. An example of a TNF receptor is Fas (CD95), which recruits activator caspases like caspase-8 upon binding TNF at the cell surface. The activation of the initiator caspases then initiates a downstream cascade of events that results in the induction of effector caspases that function in apoptosis. 2. Intrinsic Pathway: This pathway is initiated by intracellular or environmental stimuli. It

neg: Complement component 4 and RD probe as positive control, showed that the liver contains the majority of transcripts throughout the body. Even so, moderate quantities were expressed in adrenal cortices/medulla, thyroid, and kidney. As noted, C4 (mixture of C4A and C4B) participates in all three of the complement pathways (classical, alternative, and lectin); the alternative pathway is "triggered spontaneously," while the classical and lectin pathways are elicited in response to the recognition of particular microbes. All three pathways converge at a step in which complement protein C3 is cleaved into proteins C3a and C3b, which results in a "lytic pathway" and formation of

neg: Complement component 1q Complement component 1q The complement component 1q (or simply C1q) is a protein complex involved in the complement system, which is part of the innate immune system. C1q together with C1r and C1s form the C1 complex. Antibodies of the adaptive immune system can bind antigen, forming an antigen-antibody complex. When C1q binds antigen-antibody complexes, the C1 complex becomes activated. Activation of the C1 complex intitiates the classical complement pathway of the complement system. The antibodies IgM and all IgG subclasses except IgG4 are able to initiate the complement system. C1q is a 400 kDa protein formed from 18 peptide

neg: Alicaforsen intercellular adhesion molecule–1 antisense oligonucleotide (ISIS 2302). J Pharmacol Exp Ther. 1997; 282: 1173–1180 5. Henry, SP, Bolte, H, Auletta, C, and Kornbrust, DJ. Evaluation of the toxicity of ISIS 2302, a phosphorothioate oligonucleotide, in a 4-week study in cynomolgus monkeys. Toxicology. 1997; 120: 145–155 6. Henry, SP, Giclas, PC, Leeds, J, Pangburn, M, Auletta, C, Levin, AA, and Kornbrust, DJ. Activation of the alternative pathway of complement by a phosphorothioate oligonucleotide: potential mechanism of action. J Pharmacol Exp Ther. 1997; 281: 810–816 7. Yacyshyn BR, Bowen-Yacyshyn MB, Jewell L, Tami JA, Bennett CF, Kisner DL, Shanahan WR Jr. A

neg: CD93 activated macrophages, B cell precursors until the T2 stage in the spleen, a subset of dendritic cells and of natural killer cells. Molecular characterization of CD93 revealed that this protein is identical with C1qRp, a human protein identified as a putative C1q receptor. C1q belongs to the complement activation proteins and plays a major role in the activation of the classical pathway of the complement, which leads to the formation of the membrane attack complex. C1q is also involved in other immunological processes such as enhancement of bacterial phagocytosis, clearance of apoptotic cells or neutralisation of virus. Strikingly, it has

neg: C3-convertase inactivator in the alternative pathway. C3b has different binding site for C3bINA, β1H, factor B and properdin. Binding β1H to C3b increases C3bINA binding, while factor B binding prevents C3bINA binding and is competitive with β1H binding. Regulation of the amplification phase of the alternative pathway is exerted by multiple mechanisms: The genes encoding C2, C4 and factor B are located on chromosome 6 between the B locus of class I products and the D locus of class II products in the MHC. C3-convertase C3 convertase (, "C""2 ", "C4bC2b", (formerly "C4bC2a")"C3bBb", "complement C.hivin.4.hivin2", "complement C3 convertase") belongs to family

neg: Lectin pathway (Map44). MASP-1, MASP-3 and MAp44 are alternative splice products of the MASP1 gene, while MASP-2 and MAp19 are alternative splice products of the MASP-2 gene. MAp44 has been suggested to act as a competitive inhibitor of lectin pathway activation, by displacing MASP-2 from MBL, hence preventing cleavage of C4 and C2 C4b tends to bind to bacterial cell membranes. If it is not then inactivated, it will combine with C2a to form the classical C3 convertase (C4bC2a) on the surface of the pathogen, as opposed to the alternative C3 convertase (C3bBb) involved in the alternative pathway. C4a and C2b act

neg: Alternative oxidase Alternative oxidase The alternative oxidase (AOX) is an enzyme that forms part of the electron transport chain in mitochondria of different organisms. Proteins homologous to the mitochondrial oxidase and the related plastid terminal oxidase have also been identified in bacterial genomes. The oxidase provides an alternative route for electrons passing through the electron transport chain to reduce oxygen. However, as several proton-pumping steps are bypassed in this alternative pathway, activation of the oxidase reduces ATP generation. This enzyme was first identified as a distinct oxidase pathway from cytochrome c oxidase as the alternative oxidase is resistant to inhibition by the

neg: Complement system the classical complement pathway, the alternative complement pathway, and the lectin pathway. In 1888, George Nuttall found that sheep blood serum had mild killing activity against the bacterium that causes anthrax. The killing activity disappeared when he heated the blood. In 1891, Hans Ernst August Buchner, noting the same property of blood in his experiments, named the killing property "alexin", which means "to ward off" in Greek. By 1884, several laboratories had demonstrated that serum from guinea pigs that had recovered from cholera killed the cholera bacterium "in vitro". Heating the serum destroyed its killing activity. Nevertheless, the heat-inactivated serum,

neg: C4A C4A Complement C4-A is a protein that in humans is encoded by the "C4A" gene. This gene encodes the acidic form of complement factor 4, part of the classical activation pathway. The protein is expressed as a single chain precursor which is proteolytically cleaved into a trimer of alpha, beta, and gamma chains prior to secretion. The trimer provides a surface for interaction between the antigen-antibody complex and other complement components. The alpha chain may be cleaved to release C4 anaphylatoxin, a mediator of local inflammation. Deficiency of this protein is associated with systemic lupus erythematosus and type I diabetes

neg: Clusterin death, and complement-mediated cell lysis. Overexpression of the secretory CLU isoform protects the cell from apoptosis induced by cellular stress, such as chemotherapy, radiotherapy, or androgen/estrogen depletion. CLU promotes cell survival by a number of means, including inhibition of BAX on the mitochondrial membrane, activation of the phosphatidylinositol 3-kinase/protein kinase B pathway, modulation of extracellularular signal-regulated kinase (ERK) 1/2 signaling and matrix metallopeptidase-9 expression, promotion of angiogenesis, and mediation of the nuclear factor kappa B (NF-κB) pathway. Meanwhile, its downregulation allows for p53 activation, which then skews the proapoptotic:antiapoptotic ratio of present Bcl-2 family members, resulting in mitochondrial dysfunction and

neg: Pattern recognition receptor proteins. One very important collectin is mannan-binding lectin (MBL), a major PRR of the innate immune system that binds to a wide range of bacteria, viruses, fungi and protozoa. MBL predominantly recognizes certain sugar groups on the surface of microorganisms but also binds phospholipids, nucleic acids and non-glycosylated proteins. Once bound to the ligands MBL and Ficolin oligomers recruit MASP1 and MASP2 and initiate the lectin pathway of complement activation which is somewhat similar to the classical complement pathway. Research groups have recently conducted extensive research into the involvement and potential use of patient's immune system in the therapy of

neg: Nerve growth factor receptor phosphorylation sites operate as Shc adaptor protein docking sites, which undergo phosphorylation by the TrkA receptor Once the cytoplasmic adaptor protein (Shc) is phosphorylated by the receptor cytoplasmic tail, cell survival is initiated through several intracellular pathways. One major pathway leads to the activation of the serine/threonine kinase, Akt. This pathway begins with the Trk receptor complex-recruitment of a second adaptor protein called growth factor-receptor bound protein-2 (Grb2) along with a docking protein called Grb2-associated Binder-1 (GAB1). Subsequently, phosphatidylinositol-3 kinase (PI3K) is activated, resulting in Akt kinase activation. Study results have shown that blocking PI3K or Akt activity results

neg: Interleukin-1 receptor associated kinase features of IRAK-M is that it is a negative regulator of TLR signaling to prevent excessive inflammation. It is thought that IRAK-M enhances the binding of MyD88 to IRAK-1 and IRAK-4, preventing IRAK-1 from dissociating from the receptor complex and inducing downstream NF-κB and MAPK signaling. It has also been shown that IRAK-M negatively regulates the alternative NF-κB pathway in TLR2 signaling. The alternative NF-κB pathway is predominantly triggered by CD40, lymphotoxin β receptor (LT), and the B-cell activating receptor belonging to the TNF family (BAFF receptor). The alternative NF-κB pathway involves the activation of NF-κN-inducing kinase (NIK) and subsequent

neg: Telomerase chromosome instability or loss, absence of apoptosis-induction pathways, and continued mitosis activation. This model of cancer in cell culture accurately describes the role of telomerase in actual human tumors. Telomerase activation has been observed in ~90% of all human tumors, suggesting that the immortality conferred by telomerase plays a key role in cancer development. Of the tumors without TERT activation, most employ a separate pathway to maintain telomere length termed Alternative Lengthening of Telomeres (ALT ). The exact mechanism behind telomere maintenance in the ALT pathway is unclear, but likely involves multiple recombination events at the telomere. Elizabeth Blackburn "et

neg: C5-convertase C5-convertase C5 convertase is an enzyme belonging to a family of serine proteases that play key role in the innate immunity. It participates in the complement system ending with cell death. There are four different C5 convertases able to specifically convert the protein C5 to C5a and C5b fragments. Two of the convertases are physiological complement enzymes, associate to the cell-surface and mediate the classical pathway (C4b2a3b, or "C4b2a3b" depending on source) or the alternative pathway (C3bBbC3b) of complement system. Two fluid phase C5 convertases have been described: the classical pathway enzyme, C4b2boxy3b and the cobra venom factor-dependent C5 convertase,

neg: CFHR5 complement C3, suggesting that CFHR5 is important in protecting the kidneys from attack by the complement system. CFHR5 Complement factor H-related protein 5 is a protein that in humans is encoded by the "CFHR5" gene. CFHR5 is structurally related to complement factor H which plays an important role in the regulation of a branch of the innate immune system called the alternative complement pathway. Like complement factor H, CFHR5 is able to bind to complement C3. A mutation in CHFR5 was found in patients with the disease CFHR5 nephropathy, which is a common cause of renal disease in Cyprus. The

neg: Staphopain A (Staphylococcus aureus) very broad specificity proteolysis. Staphopain A is inhibited by phosphorylated cystatin α and α-macroglobulin. Staphopain A can cleave and lower the activity α-antitrypsin, and inactivate several complement system components. Staphopain A was shown to inhibit activation of the complement system activation by cleaving components that are part of all three pathways (the classical, alternative, and lectin pathways) of activation. It shows a duplex role in affecting chemotaxis; while inactivating neutrophil CXCR2 receptor, generates an active C5a fragment of C5 (although inactivating C5b). However, it has yet to prove any significant impact on the outcome of infection. Inhibition of staphopain A

neg: Total complement activity in AH50). Increased CH50 values may be seen in cancer or ulcerative colitis. Decreased CH50 values may be seen in cirrhosis or hepatitis or Systemic lupus erythematosus. Total complement activity Total complement activity is a test performed to assess the level of functioning of the complement system. The terms "CH50" or "CH100" may refer to this test. The test is based on the capacity of a serum to lyse sheep erythrocytes coated with anti-sheep antibodies (preferably rabbit IgG). In combination with the Alternative pathway hemolytic assay ("AH50") it can indicate terminal pathway deficiencies (C3, C5-C9; absence of hemolysis in both

neg: Sprouty protein Sprouty protein In molecular biology, the protein Sprouty is a developmental protein involved in cell signalling. It works by inhibiting the MAPK/ERK pathway. The function of this protein has been found, in Drosophila to inhibit branching of the trachea by antagonizing the BNL-FGF pathway. Also in "Drosophila" it is an antagonist of EGFR-mediated signaling in the eye. Most notably, in humans, it suppresses the insulin receptor and EGFR-transduced MAPK signaling pathway, but does not inhibit MAPK activation by a constitutively active mutant Ras. Sprouty inhibits of the Ras/mitogen-activated protein kinase (MAPK) cascade, a pathway crucial for developmental processes initiated by

neg: Membranoproliferative glomerulonephritis is believed to be associated with the classical complement pathway. The preferred name is "dense deposit disease". Most cases of dense deposit disease do not show a membranoproliferative pattern, A 2012 review considers DDD to be in a continuum with C3 glomerulonephritis, one reason the use of type I to type III classification system is falling out of favour. Most cases are associated with the dysregulation of the alternative complement pathway. DDD is associated with deposition of complement C3 within the glomeruli with little or no staining for immunoglobulin. The presence of C3 without significant immunoglobulin suggested to early investigators

neg: Complement system called iC3b) because this is prevented by the complement regulatory proteins, while foreign cells, pathogens and abnormal surfaces may be heavily decorated with C3b and iC3b. Accordingly, the alternative complement pathway is one element of innate immunity. Once the alternative C3 convertase enzyme is formed on a pathogen or cell surface, it may bind covalently another C3b, to form C3bBbC3bP, the C5 convertase. This enzyme then cleaves C5 to C5a, a potent anaphylatoxin, and C5b. The C5b then recruits and assembles C6, C7, C8 and multiple C9 molecules to assemble the membrane attack complex. This creates a hole or pore

neg: Classical complement pathway interacts with its cognate C5a receptor (C5aR) to attract leukocytes. Subsequent interactions between C5b and other terminal components C6, C7, C8, and C9 form the membrane attack complex or the C5b-9 complex which forms pores on the target cell membranes to lysing. Because of its role in the innate immune system classical complement has been implicated in a number of pathogen related disorders. Complement is responsible for immune inflammatory response in adipose tissues which has been implicated in the development of obesity. Obesity in turn results in an abnormally high level of complement activation via production of the c1 component

neg: Aureolysin inactivating certain targets within the complement system. Of all the proteases, aureolysin is the most effective against the complement cascade. In all three pathways of complement activation, there is a target for the protease to manipulate. In the classical pathway, aureolysin not only decreases deposition of C1q on the "S. aureus" bacterial surface, it induces C1q to bind surfaces and deposit on commensal bacteria surfaces that typically do not activate the innate immune system. Aureolysin has also been noted to produce high levels of C5a in human plasma, which leads to overstimulation of neutrophils that ultimately results in neutrophil death

neg: CFHR5 CFHR5 Complement factor H-related protein 5 is a protein that in humans is encoded by the "CFHR5" gene. CFHR5 is structurally related to complement factor H which plays an important role in the regulation of a branch of the innate immune system called the alternative complement pathway. Like complement factor H, CFHR5 is able to bind to complement C3. A mutation in CHFR5 was found in patients with the disease CFHR5 nephropathy, which is a common cause of renal disease in Cyprus. The mutated form of the protein found in patients with this disease has impaired ability to bind to

neg: Alpha defensin prostaglandin D2) and suppressed levels of IL-10 at the site of microbial infection are likely to amplify local inflammatory responses. This might be further reinforced by the capacity of some human and rabbit alpha-defensins to inhibit the production of immunosuppressive glucocorticoids by competing for the binding of adrenocorticotropic hormone to its receptor. Moreover, human alpha-defensins can enhance or suppress the activation of the classical pathway of complement in vitro by binding to solid-phase or fluid-phase complement C1q, respectively. The capacity of defensins to enhance phagocytosis, promote neutrophil recruitment, enhance the production of proinflammatory cytokines, suppress anti-inflammatory mediators and regulate complement

neg: MASP2 (protein) MASP2 (protein) Mannan-binding lectin serine protease 2 also known as mannose-binding protein-associated serine protease 2 (MASP-2) is an enzyme that in humans is encoded by the "MASP2" gene. The Ra-reactive factor (RARF) is a complement-dependent bactericidal factor that binds to the Ra and R2 polysaccharides expressed by certain enterobacteria. Alternate splicing of this gene results in two transcript variants encoding two RARF components that are involved in the mannan-binding lectin pathway of complement activation. The longer isoform is cleaved into two chains which form a heterodimer linked by a disulfide bond. The encoded proteins are members of the trypsin family

neg: C4A mellitus. This gene localizes to the major histocompatibility complex (MHC) class III region on chromosome 6. Varying haplotypes of this gene cluster exist, such that individuals may have 1, 2, or 3 copies of this gene. C4A Complement C4-A is a protein that in humans is encoded by the "C4A" gene. This gene encodes the acidic form of complement factor 4, part of the classical activation pathway. The protein is expressed as a single chain precursor which is proteolytically cleaved into a trimer of alpha, beta, and gamma chains prior to secretion. The trimer provides a surface for interaction between

neg: Opsonin the classical complement pathway and marking the antigen with C3b. C3b can spontaneously bind to pathogen surfaces through the alternative complement pathway. Furthermore, pentraxins can directly bind to C1q from the C1 complex. SP-A opsonizes a number of bacterial and viral pathogens for clearance by lung alveolar macrophages. Opsonin An opsonin (from the Greek "opsōneîn", to prepare for eating) is any molecule that enhances phagocytosis by marking an antigen for an immune response or marking dead cells for recycling (i.e., causes the phagocyte to "relish" the marked cell). "Opson" in ancient Greece referred to the delicious side-dish of any meal,

neg: C5-convertase phase C5 convertase CVFBb is stable (half-life at 37 °C = 7 h). The oxidation of C2 protein stabilizes the C4b2aoxy complex. The "Factor H–related protein 1" (CFHR1) has been identified as a novel inhibitor of the complement pathway. CFHR1 blocks C5 convertase activity and interferes with C5b surface deposition and membrane attack complex (MAC) formation. Apparently Factor H and CFHR1 control complement activation in a sequential manner. In hemolytic uremic syndrome (HUS), the absence of CFHR1 may result in reduced inhibition of terminal complex formation and in reduced protection of endothelial cells upon complement attack. C5-convertase C5 convertase is

neg: Linker for Activation of T cells Linker for Activation of T cells The Linker for Activation of T cells, also known as Linker of Activated T cells or LAT, is a protein which in humans is encoded by the "LAT" gene. Alternative splicing results in multiple transcript variants encoding different isoforms. The protein encoded by this gene is phosphorylated by ZAP70/Syk protein tyrosine kinases following activation of the T-cell antigen receptor (TCR) signal transduction pathway. This transmembrane protein localizes to lipid rafts (also known as glycosphingolipid-enriched microdomains or GEMs) and acts as a docking site for SH2 domain-containing proteins. Upon phosphorylation, this protein recruits multiple adaptor

neg: NF-κB transduced through LTβR, potentiate NF-κB dimer activation in a NIK dependent non-canonical pathway. Activation of the NF-κB is initiated by the signal-induced degradation of IκB proteins. This occurs primarily via activation of a kinase called the IκB kinase (IKK). IKK is composed of a heterodimer of the catalytic IKKα and IKKβ subunits and a "master" regulatory protein termed NEMO (NF-κB essential modulator) or IKK gamma. When activated by signals, usually coming from the outside of the cell, the IκB kinase phosphorylates two serine residues located in an IκB regulatory domain. When phosphorylated on these serines (e.g., serines 32 and 36

neg: Properdin the association of C3b with Factor B and provides a focal point for the assembly of C3bBb on a surface. It binds to preformed alternative pathway C3-convertases. Properdin also inhibits the Factor H – mediated cleavage of C3b by Factor I. The alternative pathway is not dependent on antibodies. This branch of the complement system is activated by IgA immune complexes and bacterial endotoxins, polysaccharides, and cell walls, and results in producing anaphylatoxins, opsonins, chemotactic factors, and the membrane attack complex, all of which help fight pathogens. Properdin was discovered in 1954 by Dr. Louis Pillemer of the Institute of

neg: B cell 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 (all three are collectively known as the B cell coreceptor complex). 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, and signals are transduced through CD19 and CD81

neg: Complement system in the protostome horseshoe crab species, putting the origins of the system back further than was previously thought. The classical pathway is triggered by activation of the C1-complex. The C1-complex is composed of 1 molecule of C1q, 2 molecules of C1r and 2 molecules of C1s, or "C1qrs". This occurs when C1q binds to IgM or IgG complexed with antigens. A single pentameric IgM can initiate the pathway, while several, ideally six, IgGs are needed. This also occurs when C1q binds directly to the surface of the pathogen. Such binding leads to conformational changes in the C1q molecule, which leads

neg: Decay-accelerating factor human enterovirus that was tested binds much more strongly to human DAF than to mouse or rat DAF. Echoviruses and coxsackie B viruses that use human decay-accelerating factor (DAF) as a receptor do not bind the rodent analogues of DAF. and DAF-Fc has yet to be tested in humans. Decay-accelerating factor Complement decay-accelerating factor, also known as CD55 or DAF, is a protein that, in humans, is encoded by the "CD55" gene. DAF regulates the complement system on the cell surface. It recognizes C4b and C3b fragments that are created during activation of C4 (classical or lectin pathway) or C3

neg: 5-HT2A receptor Gα and β-γ subunits dissociate to initiate downstream effector pathways. Gα stimulates phospholipase C (PLC) activity, which subsequently promotes the release of diacylglycerol (DAG) and inositol triphosphate (IP3), which in turn stimulate protein kinase C (PKC) activity and Ca release. There are many additional signal cascade components that include the formation of arachidonic acid through PLA2 activity, activation of phospholipase D, Rho/Rho kinase, and ERK pathway activation initiated by agonist stimulation of the receptor. Physiological processes mediated by the receptor include: Activation of the 5-HT receptor is necessary for the effects of the "classic" psychedelics like LSD, psilocin and mescaline,

neg: C5-convertase binds to C3b and is cleaved by a plasma serine protease "Factor D". The C3bBb complex (= alternative pathway C3 convertase) remains attached to the cell-surface. This complex might interact with another C3b and thus form the alternative pathway C5 convertase. CVFBb is a noncovalent association product of CVF3 and the complement fragment Bb. The catalytic subunits of these multimolecular proteases are "C2b" and "Bb". These subunits belong to atypical serine proteases. CVFBb does not require C3 for cleavage of C5, whereas C4b2boxy need native C3 for cleavage of C5 protein. The modified C5 convertase, C4b2boxy3b, contains C2b that is

neg: Mannan-binding lectin of MBL is that this molecule binds senescent and apoptotic cells and enhances engulfment of whole, intact apoptotic cells, as well as cell debris by phagocytes. The complement system can be activated through three pathways: the classical pathway, the alternative pathway, and the lectin pathway. One way that the most-recently discovered lectin pathway is activated is through mannose-binding lectin protein. MBL binds to carbohydrates (to be specific, D-mannose and L-fucose residues) found on the surfaces of many pathogens. For example, MBL has been shown to bind to: MBL in the blood is complexed with (bound to) another protein, a serine

neg: Collectin inhibition of ligand-induced inflammatory by macrophage chemokine production. SP-A and SP-D can suppress activated T-lymphocytes and IL-2 (interleukin-2) production. SP-D increases bacterial antigen presentation by dendritic cells whereas SP-A blocs differentation of the immature dendritic cells. Collectins SP-A and SP-D have anti-allergic effects: they inhibit IgE binding to allergens, decrease histamine release from basophils, and inhibit T-lymphocyte production in the late phase of the inflammation. Collectins SP-A and SP-D enhance clearance of apoptotic cells by macrophages. Collectins are linked with activation of lectin pathway of complement activation. At the beginning, there is a binding of collectin to PAMPs or DAMPs.

neg: Classical complement pathway attacks. Deficiency in the C1q protein of the classical complement pathway can lead to development of systemic lupus erythematosus. Among the many functions of C1q, C1q triggers clearance of immune complexes and apoptotic cells by activating the classical pathway and binding directly onto phagocytes. Consequently, systemic lupus erythematosus from insufficient amounts of C1q is characterized by the accumulation of autoantibodies and apoptotic cells. Studies are being done to look into antibodies against C1q as a diagnostic marker for systemic lupus erythematosus. Classical complement pathway The classical complement pathway is one of three pathways which activate the complement system, which is

neg: MAP4K4 p53. Upon binding, p53 up-regulates MAP4K4 expression leading to the activation of the JNK signaling pathway. siRNA knockdown experiments have also shown a reduction of p53 induced apoptosis. Current evidence therefore suggests that MAP4K4 has a modulating effect on p53 induced apoptosis in the JNK signaling pathway. MAP4K4 has been identified to be involved in the negative regulation of insulin-dependent glucose transport. There is increasing evidence suggesting cytokines such as TNF-α mediate biological effects antagonistic to insulin action and induce inflammation observed in obesity. TNF-α specifically attenuates the signaling pathway initiated by insulin receptors, reducing the amount of glucose transport

neg: Cancer immunotherapy NK cells encounter antibody-coated cells, the latter's Fc regions interact with their Fc receptors, releasing perforin and granzyme B to kill the tumor cell. Examples include Rituximab, Ofatumumab and Alemtuzumab. Antibodies under development have altered Fc regions that have higher affinity for a specific type of Fc receptor, FcγRIIIA, which can dramatically increase effectiveness. The complement system includes blood proteins that can cause cell death after an antibody binds to the cell surface (the classical complement pathway, among the ways of complement activation). Generally the system deals with foreign pathogens, but can be activated with therapeutic antibodies in cancer. The

neg: Cross-presentation exogenous antigen are catalysts for dendritic cell licensing, and thus the cross presentation and activation of naive CD8+ cytotoxic T cells. In addition to solid structure uptake, dendritic cell phagocytosis simultaneously modifies the kinetics of endosomal trafficking and maturation. As a consequence, external soluble antigens are targeted into the MHC class I cross-presentation pathway instead of the MHC Class II pathway.However, there is still uncertainty in regard to a mechanistic pathway for cross presentation within an antigen presenting cell. Currently, there are two main pathways proposed, cytosolic and vacuolar. The vacuolar pathway is initiated through the endocytosis of an extracellular

neg: Erythrogenic toxin well as through cleavage of C3b, inhibiting recruitment of phagocytic cells and the complement activation pathway. This results in decreased inflammation and neutrophil levels around the site of infection, preventing clearance and through phagocytosis and promoting the survival of "S. pyogenes." The toxin also induces apoptosis in host cells after GAS internalization. Evidence suggests that this may take place through extrinsic and intrinsic caspase pathways. The receptor-binding pathway and Fas-mediated apoptotic signaling pathway have been implicated in this process. The induction of apoptosis results in necrotizing fasciitis. Erythrogenic toxin Erythrogenic toxins, also referred to as streptococcal pyrogenic exotoxins, are secreted

neg: Superantigen the TCR for a lengthy enough time period, and the SAg mimics this temporal bonding. Low levels of Zap-70 have been found in T-cells activated by SAgs, indicating that the normal signaling pathway of T-cell activation is impaired. It is hypothesized that Fyn rather than Lck is activated by a tyrosine kinase, leading to the adaptive induction of anergy. Both the protein kinase C pathway and the protein tyrosine kinase pathways are activated, resulting in upregulating production of proinflammatory cytokines. This alternative signaling pathway impairs the calcium/calcineurin and Ras/MAPkinase pathways slightly, but allows for a focused inflammatory response.υι SAg stimulation