Complement System - Innate Immunity | PDF

Complement, Pentraxins & Defensins https://www.news-medical.net/news/20210224/Complement-system-appears-to-be-specifically-implicated-in-severe-COVID-19.aspx The complement system  As soon as a pathogen penetrates the epithelial barrier and starts to live in...

Complement, Pentraxins & Defensins https://www.news-medical.net/news/20210224/Complement-system-appears-to-be-specifically-implicated-in-severe-COVID-19.aspx The complement system  As soon as a pathogen penetrates the epithelial barrier and starts to live in human tissue, the defense mechanisms of innate immunity are initiated https://www.theguardian.com/society/2020/jan/13/organ-donation-new-technique-can-preserve-human-livers-for-a-week  One of the first weapons utilized is a system of soluble proteins made by the liver and known as complement  Complement coats the surface of bacteria and extracellular virus particles and makes them more easily phagocytosed (“eaten by a cell”) Phagocyte Pathogen (immune cell) Complement  Although more than 30 proteins make up the complement system, complement component 3 (C3) is the most important  C3 serves 3 key functions: Opsonize MAC lysis Chemotaxis https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905230/ Complement Activation  In the absence of infection complement proteins exist in an inactive form called zymogen  Infection triggers complement activation  Complement activation leads to the cleavage of C3 into two pieces:  a small C3a fragment  a large C3b fragment  Complement proteins are cleaved by enzymes called convertases  The main convertases involved in complement activation are C3 convertase and C5 convertase C3 Activation & fixation of complement  Complement activation leads to the cleavage of C3 into two pieces:  a small C3a fragment  a large C3b fragment  During activation some C3b fragments become covalently bound to the pathogen’s surface  Attachment of C3b to pathogen surfaces is the essential function of the complement system; it is called complement fixation What do the cleaved components do?  C3b opsonizes (“prepares to eat”) particles for engulfment by macrophage  Innate immune cells have receptors for C3b to “eat” tagged bacteria Phagocyte Complement (immune cell) receptor Complement  C3b also initiates formation of the membrane attack complex (MAC)  C3a is a chemotactic for (attracts other immune cells to site of infection Complement Facilitated Phagocytosis Phagocytosis by macrophages  Macrophages phagocytose bacteria and other microorganisms in a nonspecific fashion  Bacteria coated with C3b are more efficiently phagocytosed than uncoated bacteria  The coating of a pathogen with a protein that facilitates phagocytosis is called opsonization Phagocytosis by macrophages  Macrophage have multiple receptors that recognize intact (C3b) or inactivated (iC3b) complement on pathogen surfaces  For example:  complement receptor 1 (CR1) on macrophages binds to C3b fragments that have been deposited on the surface of a pathogen Membrane attack complex (Complement-Mediated Lysis) Membrane attack complex  In addition to C3b binding to pathogen surfaces, complement proteins play other roles in pathogen neutralization  Five additional complement components C5, C6, C7, C8, and C9 participate in the formation of a membrane-attack complex (MAC), which perforates the membranes of bacterial pathogens and eukaryotic cells Membrane attack complex  Formation of a membrane attack complex (MAC) is initiated when complement protein C5 is cleaved by a convertase  The C5 convertase cleaves complement protein C5 into C5a and C5b Membrane attack complex (MAC)  The function of C5b is to initiate the formation of a membrane-attack complex  After C5b binds to the pathogen surface, C6, C7, C8 and C9 bind in succession to create the MAC  C9 is the component that forms the transmembrane pores Complement regulatory proteins - membrane proteins  When complement proteins attach to a human cell surface, they are:  rapidly removed by decay-accelerating factor (DAF)  inactivated by membrane cofactor protein (MCP)  In combination, these regulatory proteins ensure that much complement is fixed to pathogen surfaces and little is fixed to human cell surfaces  Most pathogens lack membrane proteins that can remove or inactivate complement proteins deposited on their surface Medical example for importance of complement regulation  Paroxysmal Nocturnal Hemoglobinuria (PNH) occurs when mutations of a gene called PIG-A occur in a bone marrow stem cell  PIG-A protein helps produce the GPI anchors which facilitate the attachment of DAF and other complement regulatory proteins to human cells  Cells harboring PIG-A mutations are deficient GPI-anchored proteins, causing lysis of red blood cells (RBC) by complement proteins  Urine in the morning is dark brown, due to complement lysis of RBC https://www.jci.org/articles/view/131647/figure/1 Complement regulatory proteins - plasma proteins  The plasma protein properdin (factor P) increases the speed and power of complement activation by binding to the C3 convertase on microbial surfaces and preventing its degradation by proteases increase C3 convertase formation  Countering the effect of properdin is plasma protein factor H, which binds to C3b and facilitates its further cleavage to a form called iC3b by the plasma serine protease factor I  Fragment iC3b cannot assemble a C3 convertase, so the combined action of factors H and I is to decrease the number of C3 convertase molecules on the pathogen surface decrease C3 convertase formation The cheaters  As a strategy to evade the actions of complement, some species of bacteria, such as Streptococcus pyogenes and Staphylococcus aureus, cover their cell surfaces with sialic acid and so mimic human cells  factor H has a binding site for sialic acid, a component of human cell-surface carbohydrates that is absent from most bacteria  When C3b becomes deposited on the surface of these bacteria it is readily inactivated by factor H bound to the bacterial sialic acid C3a & C5a induced inflammation  C3a and C5a are physiologically active fragments that sometimes induce anaphylactic shock  Both C3a and C5a are anaphylatoxins but C5a is more potent than C3a  Anaphylactic shock: an acute inflammatory reaction that occurs simultaneously in tissues throughout the body  Inflammation is a major consequence of the innate immune response to infection, which is also called the inflammatory response Cellulitis  C3a & C5a induced inflammation  Phagocytes, endothelial cells, and mast cells have specific receptors for C5a and C3a  Anaphylatoxins: induce the contraction of smooth muscle Induce the degranulation of mast cells and basophils, with the consequent release of histamine and other vasoactive substances that increase capillary permeability have direct vasoactive effects on local blood vessels, increasing blood flow and vascular permeability  These changes make it easier for plasma proteins and cells to pass out of the blood into the site of an infection  C5a acts directly on neutrophils and monocytes to increase their adherence to blood vessel walls, and serves as a chemoattractant to direct their migration toward sites of complement fixation  It also increases the phagocytic capacity of these cells, as well as raising the expression of CR1 and CR3 on their surfaces Acute phase proteins Acute phase proteins  In addition to complement, several other types of plasma proteins impede the invasion and colonization of human tissues by microorganisms complement  Acute phase proteins are produced in the liver in response to infection pentraxins liver  Acute phase protein levels increase in inflammatory states serum amyloid A coagulation factors  Examples of acute phase proteins are the pentraxins, and the coagulation factors and serum amyloid A, Pentraxins  The pentraxins are a family of proteins that circulate in the blood and lymph https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3791837/  Pentraxins have a similar role in the innate immune response to that of antibodies in the adaptive immune response, bind to the surfaces of various pathogens and target them for destruction Pentraxins  There are two subfamilies of pentraxins: short pentraxins (C-reactive protein (CRP), serum amyloid P component - SAP) long pentraxins (PTX3) Pentraxins  Among the acute-phase proteins, members of the pentraxin family of proteins (e.g., C-reactive protein), stand out, because their concentrations rise several hundredfold  C-reactive protein (CRP) concentration is used clinically as a diagnostic test for infection, inflammation, and tissue damage Pentraxins - C-reactive protein  C-reactive protein binds to pathogens and acts as an opsonin, triggering the complement activation  C-reactive protein also binds to the surface of phagocytes, delivers pathogens to these cells for elimination  The increased concentration of C-reactive protein in the acute-phase response is a strategy of overwhelming force to overcome the population of pathogens Coagulation proteins  Damage to blood vessels activates the coagulation system, a cascade of plasma enzymes that forms blood clots  Microorganisms are immobilized in the clots, which prevent them from entering the blood and lymph, as well as decreasing the loss of blood and fluid  During clot formation platelets release highly active substances (e.g. prostaglandins, hydrolytic enzymes, growth factors) from their storage granules that stimulate cells to contribute to:  antimicrobial defense  wound healing  inflammation Other Plasma Proteins of Innate Immunity Antimicrobial peptides (AMPs)  Antimicrobial peptides (AMPs) are soluble effector molecules of innate immunity that: kill/inactivate pathogens (bacterial, viral and fungal) neutralize toxins  The predominant family of human AMPs is the defensins  Defensins are expressed predominantly in neutrophils and epithelial cells