A complement protein attacking an invader. membrane attack complex ( MAC) is typically formed on the surface of intruding Pathogenic Bacterial cells as a result of the activation of the

The complement system is a biochemical cascade which helps clear pathogens from an organism. A biochemical cascade is a series of Chemical reactions in which the products of one reaction are consumed in the next reaction A pathogen (from Greek πάθος pathos "suffering passion" and γἰγνομαι (γεν- gignomai (gen- "I give birth to" infectious It is part of the larger immune system that is not adaptable and does not change over the course of an individual's lifetime; as such it belongs to the innate immune system. An immune system is a collection of mechanisms within an Organism that protects against Disease by identifying and killing Pathogens and Tumor Immune system|Adaptive immune systemThe innate immune system comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner However, it can be recruited and brought into action by the adaptive immune system. Immune system|Passive immunity|Innate immune system The adaptive immune system is composed of highly specialized systemic cells and processes that eliminate or prevent Pathogenic

The complement system consists of a number of small proteins found in the blood, normally circulating as inactive zymogens. A zymogen (or proenzyme) is an inactive Enzyme precursor. A zymogen requires a biochemical change (such as a Hydrolysis reaction revealing the When stimulated by one of several triggers, proteases in the system cleave specific proteins to release cytokines and initiate an amplifying cascade of further cleavages. A protease is any Enzyme that conducts Proteolysis, that is begins protein Catabolism by Hydrolysis of the Peptide bonds that link Cytokines are a category of signalling Proteins and Glycoproteins that like Hormones and Neurotransmitters, are used extensively in cellular The end result of this activation cascade is massive amplification of the response and activation of the cell-killing membrane attack complex. membrane attack complex ( MAC) is typically formed on the surface of intruding Pathogenic Bacterial cells as a result of the activation of the Over 20 proteins and protein fragments make up the complement system, including serum proteins, serosal proteins, and cell membrane receptors. Blood plasma is the Liquid component of Blood, in which the Blood cells are suspended These proteins are synthesized mainly in the liver, and they account for about 5% of the globulin fraction of blood serum. The liver is a vital organ in the human body and is present in Vertebrates and some other animals Globulin is one of the two types of serum Proteins the other being albumin.

Three biochemical pathways activate the complement system: the classical complement pathway, the alternative complement pathway, and the mannose-binding lectin pathway. In Biochemistry, a metabolic pathway is a series of chemical reactions occurring within a cell. The classical pathway of activation of the Complement system is a group of blood proteins that mediate the specific Antibody response The alternative pathway of the Complement system is a humoral component of the Immune system 's natural defense against infections which can operate without antibody The Mannan-binding lectin pathway (also known as the Ali/Krueger Pathway is homologous to the Classical complement pathway. ^[1]

History

In the late 19th century, blood serum was found to contain a "factor" or "principle" which was capable of killing bacteria. In 1896, Jules Bordet, a young Belgian scientist in Paris at the Pasteur Institute, demonstrated that this principle could be analyzed into two components: a heat-stable and a heat-labile component. Jules Jean Baptiste Vincent Bordet ( Soignies ( Belgium) 13 June, 1870 &ndash 6 April, 1961) was a Belgian (Heat-labile meaning that it lost its effectiveness if the serum was heated. ) The heat-stable component was found to confer immunity against specific microorganisms, while the heat-labile component was found to be responsible for the non-specific antimicrobial activity conferred by all normal serum. This heat-labile component is what we now call "complement".

The term "complement" was introduced by Paul Ehrlich in the late 1890s, as part of his larger theory of the immune system. Paul Ehrlich ( March 14, 1854 &ndash August 20, 1915) was a German Scientist who won the 1908 Nobel According to this theory, the immune system consists of cells which have specific receptors on their surface to recognize antigens. Upon immunization with an antigen, more of these receptors are formed, and they are then shed from the cells to circulate in the blood. These receptors, which we now call "antibodies", were called by Ehrlich "amboceptors" to emphasize their bifunctional binding capacity: they recognize and bind to a specific antigen, but they also recognize and bind to the heat-labile antimicrobial component of fresh serum. Ehrlich therefore named this heat-labile component "complement", because it is something in the blood which "complements" the cells of the immune system.

Ehrlich believed that each antigen-specific amboceptor had its own specific complement, while Bordet believed that there is only one type of complement. In the early 20th century, this controversy was resolved when it was understood that complement can act in combination with specific antibodies, or on its own in a non-specific way.

Overview

The C1 protein, showing subunits C1r, C1s, and the C1q tails.

The three pathways all generate homologous variants of the protease C3-convertase. A protease is any Enzyme that conducts Proteolysis, that is begins protein Catabolism by Hydrolysis of the Peptide bonds that link There are two forms of C3-convertase ( The first is an Enzyme composed of the C4b - C2b complex which forms during the Classical The classical complement pathway typically requires antibodies for activation (specific immune response), while the alternative and mannose-binding lectin pathways can be activated by C3 hydrolysis or antigens without the presence of antibodies (non-specific immune response). In all three pathways, a C3-convertase cleaves and activates component C3, creating C3a and C3b and causing a cascade of further cleavage and activation events. Complement component 3, often simply called C3, is a Protein of the Immune system. C3b binds to the surface of pathogens leading to greater internalization by phagocytic cells by opsonization. Phagocytes are cells that are found in the blood bone marrow and other tissues of Vertebrates. An opsonin is any molecule that acts as a binding Enhancer for the process of Phagocytosis, for example by coating the negatively-charged molecules on the membrane C5a is an important chemotactic protein, helping recruit inflammatory cells. C5a is a protein fragment released from complement component C5. Chemokines are a family of small Cytokines, or Proteins secreted by cells Proteins are classified as chemokines according to shared structural characteristics Both C3a and C5a have anaphylatoxin activity, directly triggering degranulation of mast cells as well as increasing vascular permeability and smooth muscle contraction. Anaphylatoxins, or anaphylotoxins, are fragments ( C3a, C4a and C5a) that are produced during the pathways of the Complement system Degranulation is a cellular process that releases Antimicrobial Cytotoxic molecules from secretory vesicles called granules found inside A mast cell (or mastocyte) is a resident cell of several types of tissues and contains many granules rich in Histamine and Heparin Smooth muscle is a type of non- Striated muscle, found within the Tunica media layer of large and small Arteries and Veins, the bladder C5b initiates the membrane attack pathway, which results in the membrane attack complex (MAC), consisting of C5b, C6, C7, C8, and polymeric C9. membrane attack complex ( MAC) is typically formed on the surface of intruding Pathogenic Bacterial cells as a result of the activation of the membrane attack complex ( MAC) is typically formed on the surface of intruding Pathogenic Bacterial cells as a result of the activation of the Complement component 6 is a protein involved in the Complement system. Complement component 7 is a protein involved in the Complement system. Complement component 8 is a protein involved in the Complement system. Complement component 9 is a protein involved in the Complement system. ^[2] MAC is the cytolytic endproduct of the complement cascade; it forms a transmembrane channel, which causes osmotic lysis of the target cell. Osmosis is the Diffusion of a solvent (frequently water through a semi-permeable membrane, from a solution of low solute concentration (high water potential Kupffer cells and other macrophage cell types help clear complement-coated pathogens. Kupffer cells, also known as Browicz-Kupffer cells, are specialized Macrophages located in the Liver that form part of the Reticuloendothelial system As part of the innate immune system, elements of the complement cascade can be found in species earlier than vertebrates; most recently in the protostome horseshoe crab species, putting the origins of the system back further than was previously thought.

Classical pathway

Main article: Classical complement pathway

The classical and alternative complement pathways. The classical pathway of activation of the Complement system is a group of blood proteins that mediate the specific Antibody response

The classical pathway is triggered by activation of the C1-complex (C1q, C1r, and C1s), which occurs when C1q binds to IgM or IgG complexed with antigens (a single IgM can initiate the pathway, while multiple IgG's are needed), or when C1q binds directly to the surface of the pathogen. The classical pathway of activation of the Complement system is a group of blood proteins that mediate the specific Antibody response Immunoglobulin M, or IgM for short is a basic Antibody that is present on B cells It is the primary antibody against A and B Immunoglobulin G ( IgG) is a Monomeric Immunoglobulin, built of two heavy chains γ and two light chains. An antigen (from antibody-generating) or immunogen is a substance that prompts the generation of Antibodies and can cause an immune response The C1q complex is potentially Multivalent for attachment to the complement fixation sites of Immunoglobulin. Such binding leads to conformational changes in the C1q molecule, which leads to the activation of two C1r (a serine protease) molecules. They then cleave C1s (another serine protease). Complement component 1S is a protein involved in the Complement system. The C1-complex now binds to and splits C4 and then C2, producing C2a and C4b. Complement component 4 is a protein involved in the Complement system. Complement component 2, also known as C2, is a human Gene. The protein encoded by this gene is part of the classical pathway of Complement system. The inhibition of C1r and C1s is controlled by C1-inhibitor. C1-inhibitor ( C1-inh, C1 esterase inhibitor) is a Serine protease inhibitor (serpin protein the main function of which is the inhibition of the C4b and C2a bind to form the classical pathway C3-convertase (C4b2a complex), which promotes cleavage of C3 into C3a and C3b; the latter joins with C2a and C4b (the C3 convertase) to make C5 convertase.

C3-convertase can be inhibited by Decay Accelerating Factor (DAF), which is bound to erythrocyte plasma membranes via a GPI anchor.

Alternative pathway

Main article: Alternative complement pathway

The alternative pathway is triggered by C3 hydrolysis directly on the surface of a pathogen. The alternative pathway of the Complement system is a humoral component of the Immune system 's natural defense against infections which can operate without antibody The alternative pathway of the Complement system is a humoral component of the Immune system 's natural defense against infections which can operate without antibody It does not rely on a pathogen-binding protein like the other pathways. ^[1] In the alternative pathway, the protein C3 is produced in the liver, and is then cleaved into C3a and C3b by enzymes in the blood. If there is no pathogen in the blood, the C3a and C3b protein fragments will be deactivated. However, if there is a nearby pathogen, some of the C3b is bound to the plasma membrane of the pathogen. Then, it will bind to factor B. Complement factor B, also known as CFB, is a human Gene. This complex will then be cleaved by factor D into Ba and the alternative pathway C3-convertase, Bb. Adipsin or Factor D is a protein involved in the Alternative complement pathway of the Complement system.

The C3bBb complex, which is "hooked" onto the surface of the pathogen, will then act like a "chain saw", catalyzing the hydrolysis of C3 in the blood into C3a and C3b, which positively affects the number of C3bBb hooked onto a pathogen.

After hydrolysis of C3, C3b complexes to become C3bBbC3b, which cleaves C5 into C5a and C5b. C5a and C3a are known to trigger mast cell degranulation. A mast cell (or mastocyte) is a resident cell of several types of tissues and contains many granules rich in Histamine and Heparin C5b with C6, C7, C8, and C9 (C5b6789) complex to form the membrane attack complex, also known as MAC, which is inserted into the cell membrane, "punches a hole", and initiates cells lysis. membrane attack complex ( MAC) is typically formed on the surface of intruding Pathogenic Bacterial cells as a result of the activation of the

Lectin pathway (MBL - MASP)

Main article: Mannose-binding lectin pathway

The lectin pathway is homologous to the classical pathway, but with the opsonin, mannose-binding lectin (MBL) and ficolins, instead of C1q. The Mannan-binding lectin pathway (also known as the Ali/Krueger Pathway is homologous to the Classical complement pathway. Lectins are sugar-binding Proteins which are highly specific for their sugar Moieties. This pathway is activated by binding mannose-binding lectin to mannose residues on the pathogen surface, which activates the MBL-associated serine proteases, MASP-1 and MASP-2 (very similar to C1r and C1s, respectively),which can then split C4 into C4a and C4b and C2 into C2a and C2b. C4b and C2a then bind together to form the C3-convertase, as in the classical pathway. Ficolins are homologous to MBL and function via MASP in a similar way. In invertebrates without an adaptive immune system, ficolins are expanded and their binding specificities diversified to compensate for the lack of pathogen-specific recognition molecules.

Regulation of the complement system

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. The Complement system distinguishes "self" from "non-self" via a range of specialized cell-surface and soluble proteins Some complement control proteins are present on the membranes of self-cells preventing them from being targeted by complement. One example is CD59, which inhibits C9 polymerisation during the formation of the membrane attack complex. Protectin a complement regulatory protein, also known as membrane attack complex ( MAC) is typically formed on the surface of intruding Pathogenic Bacterial cells as a result of the activation of the

Role in disease

Main article: Complement deficiency

It is thought that the complement system might play a role in many diseases with an immune component, such as Barraquer-Simons Syndrome, asthma, lupus erythematosus, glomerulonephritis, various forms of arthritis, autoimmune heart disease, multiple sclerosis, inflammatory bowel disease, and ischemia-reperfusion injuries. Complement deficiency is a condition of absent or suboptimal functioning of one of the Complement system proteins Barraquer-Simons syndrome (or acquired partial lipodystrophy) is a rare form of Lipodystrophy, which usually first affects the head and then spreads to the thorax Asthma is a chronic Condition involving the Respiratory system in which the airways occasionally constrict become inflamed, and are Systemic lupus erythematosus ( SLE or lupus,) is a chronic autoimmune disease that can be fatal though with recent medical advances fatalities are becoming Glomerulonephritis, also known as glomerular nephritis, abbreviated GN, is a renal disease characterized by Inflammation of the glomeruli Arthritis (from Greek arthro-, joint + -itis, inflammation plural arthritides is a group of conditions involving damage to the Joints of the body Autoimmune Heart Diseases are the effects of the body's own immune defense system mistaking cardiac Antigens as foreign and attacking them leading Multiple sclerosis (abbreviated MS also known as disseminated sclerosis or encephalomyelitis disseminata) is an autoimmune condition in which the The complement system is also becoming increasingly implicated in diseases of the central nervous system such as Alzheimer's disease, and other neurodegenerative conditions. Alzheimer's disease ( AD) also called Alzheimer disease or simply Alzheimer's, is the most common form of Dementia.

Deficiencies of the terminal pathway predispose to both autoimmune disease and infections (particularly Neisseria meningitis, due to the role that the C56789 complex plays in attacking Gram negative bacteria). Autoimmune diseases arise from an overactive Immune response of the body against substances and tissues normally present in the body An infection is the detrimental Colonization of a host Organism by a foreign Species. Neisseria meningitidis, also simply known as meningococcus, is a heterotrophic Gram-negative diplococcal Bacterium best known for Meningitis is Inflammation of the protective membranes covering the Brain and Spinal cord, known collectively as the Meninges. Gram-negative bacteria are those Bacteria that do not retain Crystal violet dye in the Gram staining protocol

Mutations in the complement regulators factor H and membrane cofactor protein have been associated with atypical haemolytic uraemic syndrome. Factor H is a member of the regulators of complement activation family and is a Complement control protein. CD46 is an inhibitory Complement receptor. ^[3][4] Moreover a common single nucleotide polymorphism in factor H (Y402H) has been associated with the common eye disease 'age related macular degeneration'. A single nucleotide polymorphism ( SNP, pronounced snip) is a DNA sequence variation occurring when a single Nucleotide - A, T Macular degeneration is a medical condition usually of older adults which results in a loss of vision in the center of the visual field (the Macula) because ^[5] Both of these disorders are currently thought to be due to aberrant complement activation on host surfaces.

Modulation by infections

Recent research has suggested that the complement system is manipulated during HIV/AIDS to further damage the body. Human immunodeficiency virus ( HIV) is a Lentivirus (a member of the Retrovirus family that can lead to acquired immunodeficiency syndrome ^[6][7]

Additional images

Classical

Alternative

Classical

References