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INNATE MOLECULAR DEFENCE AGAINST MOCROBES. Innate molecular immune defense. There are many molecules of the innate immune system which are important in mediating protection against microbes during the period before the development of adaptive immunity.
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Innate molecular immune defense • There are many molecules of the innate immune system which are important in mediating protection against microbes during the period before the development of adaptive immunity. • Although these molecules react with particular structures associated with microbes, they are nonspecific in that they can react with many different microbes that express these structures. • The major molecules are those of the complement system, acute phase proteins and cytokines, especially the interferons. • The complement system can be activated by antibodies, and cytokines are involved in activation of antigen presenting cells critical to triggering T lymphocyte response. • Cytokines released by macrophages also play a role n acute inflammation
The complement system • The complement system is a protective system common to all vertebrates. • In man it consists of set of over 20 soluble glycoproteins, many of which are produced by hepatocytes and monocytes. • They are constitutively present in blood and other body fluids and may be present in quite large amounts. • For example C3, the pivotal molecule of the complement system, is present at about 1g in serum. On appropriate triggering, these components interact sequentially with each other like. • This “cascade” of molecular events involves cleavage of some complement components into active fragments which contribute to activation of the next component, ultimately leading to lysis of, and / or protection against, a variety of microbes.
Activation • Complement can be “activated” directly by certain molecules associated with microbes (alternative pathway), or by antibodies bound to a microbe or any other antigen (classical pathway), C3 present at high concentration in the serum, is critical to both of these pathways and its cleavage into C3a and C3b is the single most important event in the activation of the complement system. Alternative pathway Classical pathway (microbe alone) (antibodies-mediated) Activation leads to Inflammation Lysis Enhanced Phagocytes C3
This may be achieved by two different cleavage enzymes, C3 convertases – one as a component of the alternative pathway, the other a part of the classical pathway. • In the absence of antibody mediate immunity, the alternative pathway is activated by interaction of C3 with certain types of molecules on microbes or by self molecules which react with the microbes. • More specifically the alternative pathway depends on the normal continuous low level breakdown of C3. One of the fragments, C3b , is very reactive and can covalently bind to virtually any molecules or cell. If C3b binds to a self cell, regulatory molecules associated with this cell inactive it, protecting the cell form complement mediated damage. However, if C3b binds to a microbe, factor B is usually activated and its cleavage product Bb binds to C3b on the microbe. This C3Bb complex is enzymatically active and amplifies the breakdown of additional C3 to C3b.
Functions The major functions of the complement system are: a. Initiation of inflammation by direct activation of mast cells. b. Attraction of neutrophils to the site of microbial attack. c. Enhancement of the attachment of the microbe to the phagocyte. • Killing of the microbe activating the membrane attack complex.
Regulation • The complement system is a powerful mediator of inflammation and destructions and could cause extensive damage to host cells if uncontrolled. However, complement components rapidly lose binding capacity after activation, limiting their membrane-damaging ability to the immediate vicinity of the activation site. This system is also tightly regulated by inhibitory / regulatory proteins. • It is important to note that, since the activated complement components are unstable, activation of complement components are depressed complement levels in an individual may indicate that complement is being used up faster than it is being produced, suggesting chronic activation of complement perhaps resulting from continuous in vivo formation of antigen-antibody complexes.
The Proteins • Acute phase proteins are important in innate defense against microbes and in limiting tissue damage caused by microbial infection, trauma, malignancy and other diseases e.g. rheumatoid arthritis. • They are also important in tissue repair. • These molecules include C-reactive proteins, complement components, opsonic proteins such as a mannose binding protein, metal binding protein and protease inhibitors. • The major acute phase proteins and serum amyloid protein A have similar structures and are termed pentraxins, based on the pentagonal association of their subunits. 2. CRP, which was named based on its ability to react with the C-protein of pneumococcus, is composed of five identical polypeptides associated by glycolipids expressed by microbes in a form different from that on mammalian cells. Its binding properties permit it to interact with a variety of pathogens.
Production • These proteins, mainly produced by the liver, or are present at low levels and rapidly increase following infection. • They are produced by hepatocytes in the liver in response to the cytokines • IL-1, • IL-6, • TNFaand • IFNyreleased by activated macrophages and NK cells. • IL-6 appears to be the major cytokine of importance in enhancing production of acute phase proteins.
Protection against virus infection • Interferons are important molecules which can mediate protection against virus infection, and are thus particularly important in limiting infection during the period when specific humoral and cellular immunity is developing. • However, they do not simply function by interfering with virus replication but also act as communication molecules between cells. • Type I interferons, a and b, are cytokines produced by many different cells in response to a virus and protect adjacent cells form viral infection. • Type II IFN, IFNy, is produced by specialist cell of the immune system and is important not only for antiviral cytokines.
Type I interferons (IFNα and β) • Their synthesis is induced by viral or bacterial infections and in particular by intracellular microbes. • At least 12 different, highly homologous species of IFNα are produced, primarily by infected leukocytes as well as by epithelial cells and fibroblasts. • In contrast, a single species of IFN β is produced, normally by fibroblasts and epithelial cells. • The proinflammatory cytokines IL-1 and TNF α are potent inducers of IFN-α/ β secretion, as are endotoxins derived form the cell wall of gram negative bacteria. • These IFNs play an important role in innate defense against viral infections. • Both IFNα and IFNβ inhibit protein synthesis in virally infected cells preventing mRNA translation and DNA replication.
Type II interferons (IFNgamma) • IFNr is a multi-functional cytokines produced by Th 1 cells and NK cells. • It enhances the phagocyticfunction of these cells.
Collectins & Peptide Antibiotics • Collectins are a group of carbohydrate binding proteins. • These molecules act as opsonins and are probably important in the innate immune response to infections. • They include mannose binding protein, an acute phase protein, and conglutinin. • A family of small peptides, peptide antibiotics, have potent antibacterial activities. These molecules include cecropins, magainins and defensins and are part of the body’s innate defense mechanisms against microbial infection. In general, they are basic peptides with molecular weights of 3-5 kDa and are effective against both gram positive and gram negative bacteria.
