Anexo 7 inmunología (2012)Apunte Inglés
The lectin pathway of complement
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The Lectin pathway of complement
The complement system refers to a series of
circulating proteins in the blood and bathing
fluids surrounding tissues. These proteins are
called “complement factors” or “complement
components”. Many complement factors are
polymorphic and, with some exception, they
are represented by C followed by a number
(C1, C2, C3…).
The complement system can be activated through three pathways: the Alternative Pathway, the Classical Pathway and the Lectin Pathway. The alternative pathway is the first to appear in development and is explained in the “innate immunity” chapter. The classical pathway is explained in the “humoral immune response” chapter.
The lecting pathway is the last to be discovered. For simplicity it is not included in the regular explanation of Immunology in medicine nor in biology, but this short summary, written in May 2009 by the biology student Giulietta Barbero is a good account of the relevance of this pathway.
The Lectin Pathway: The mannan binding Lectin Pathway (also know as the Ali/Krueger Pathway) is initiated by the binding of mannose binding lectin (MBL) to a bacterial surface with mannose containing polysaccharides.
MBL is a proteins belonging to the collectin family in the C-type lectins super family that is produced by the liver. Is a 2-6 headed molecule that forms a complex with MASP-I (mannan-binding lectin associated serine protease) and MASP-II. Both are protease zymogens.
MBL has an oligomeric structure (400-700 KDa) built of subunits that contains three identical peptide chain of 32 KDa each. The subsequent complex cascade catalyzed by C3 convertase results in creating a membrane attack complex (MAC).
Binding of MBL to a pathogen results in the association of MASP-I and MASP-II.
Formation of MBL/MASP-I/MASP-II trimolecular complex results in the activation of the MASPs and subsequent cleavage of C4 into C4a and C4b. The C4b fragment binds to the membrane and the C4a fragment is released into the microenvironment. Activated MASP also cleaves C2 into C2a and C2b. C2a binds to the membrane in association with C4b, and C2b is released into the microenvironment.
C4a and C2b act as chemoattractant.
The resulting C4bC2a complex is a C3 convertase, which cleaves C3 into C3a and C3b. The C4bC2a active centre is located in the C2a component. C3b binds to the membrane in association with C4b and C2a and C3a is released to the microenvironment. The resulting C4bC2aC3b complex is a C5 convertase.
The generation of C5 convertase is the end of the Lectin Pathway.
The C5 convertase of the classical pathway cleaves C5 into C5a which is an anaphylotoxin and C5b is which is essential for the activation of the membrane attack pathway. And it is the first step on the lythic pathway.
C5b fragment binds noncovalently to C3b. The C5b capture C6 and C7 and it all form the C5bC6C7 complex which has chemoattractant activity and it can fixate to membranes.
If C8 binds to this complex now it can insert in membrane. If this complex binds to C9 the resulting complex is a MAC (Membrane Attack Complex) and it set up hydrophilic channels which induces cellular lysis.
The C3b factor bound to the membrane can be phagocyted because phagocytes have receptors to the C3b factor. The C3a anaphylotoxin strengthens inflammation.
It is important to realise the parallelism between the classical and the lectin pathways: Lecting pathway Calsical pathway MBL attaches to carbohydrates C1q attaches to antibodies MASP I and MASP II attach to MBL C1r and C1s attach to C1q C4 and C2 are cleaved C4 and C2 are cleaved Rest is identical in both pathways and lead to MAC formation The figure shows the similarities and differences between the three complement cascades.
In the alternative pathway C1q, C1r, C1s, C2 and C4 do not play any role.
All three cascades enD up in the formation of the Membrane Attack Complex (not shown) Complement System Functions: The biological activities and the regulatory proteins of the lectin pathway are the same as those of the classical pathway.
The biological activities of the complement system affect both the innate and the acquired immunity and reach far beyond the original observations of antibody-mediated lysis of bacteria and red blood cells. Structural comparisons of the proteins involved in complement pathways place the origin of this system in primitive organisms possessing the most rudimentary innate immune systems.
The functions are carried out by different actives complement fractions. The active factors usually do its function by binding to different membrane receptors.
After initial activation, the various complement components interact, in a highly regulated cascade, to carry out a number of basic functions including: Lysis of cells: once the complement cascade is set off, if C5bC6C7 final complex s formed, and C8 and C9 bind to it, cellular lysis take place on the membranes where these complexes were bound. A lot of pores are produced by the C5bC6C7C8C9 complex. This is known as complement dependent cytotoxicity.
Anaphylatoxic effect: C3a and C5a fragments, bound to membrane receptors (C3aR and C5aR) exert an anaphylotoxic effect, it has an activator effect on mast cells and basophiles which release inflammation mediators. These vasoactive substances released increase capillary permeability which helps leucocyte and other molecules affluence.
Chemoattractant activity: C5a fragment has and powerful chemoattractant activity, which determines leucocyte attraction to the inflammatory focus.
Opsonisation: macrophages and neutrophills have on its membranes receptors that are able to binds to C3b molecules and its activated complement derivatives. If C3b is bound to the microorganism membrane, phagocytes can found it.
Immune complex clearance: in normal conditions, we can find circulating soluble immune complex in blood. Those immune complexes are potentially dangerous because it can trigger inflammation. There is a clearance mechanism. Erythrocytes that are most common cells in the body have C1R on its membrane that are able to bind to C3b. when erythrocytes pass through liver and spleen macrophages can phagocyte them.
Bibliography: The Cancer Genome Anatomy project. Lectin Induce Complement Pathway: http://cgap.nci.nih.gov/Pathways/BioCarta/h_lectinPathway CCBC Student Linux Server. The innate immune system: http://student.ccbcmd.edu/courses/bio141/lecguide/unit4/innate/lectin.html Wikipedia. Mannan-binding Lectin Pathway: http://en.wikipedia.org/wiki/Lectin_pathway University of South Carolina. School of Medicine. Microbiology and immunology on-line.
Chapter II: Complement: http://pathmicro.med.sc.edu/ghaffar/complement.htm Inmunologiaonline. José Peña Martínez. Universidad de Córdoba y Sweden Diagnostics (Spain): http://www.uco.es/investiga/grupos/inmunologia-molecular/ ...