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1. Discuss the processes by which phagocytes are attracted to a site of infection and the mechanism by which they destroy a foreign particle (PA).
The pathological state of the body that results from invasion of the host by harmful pathogenic micro-organisms such as disease causing bacteria, fungi, viruses, parasites and other invaders is termed as an infection. Immune system is a system that comprises of a network of various biological organelles and processes within an organism which work together to help protect the organism against various infectious diseases and other invaders by distinguishing these foreign invaders from the organism's own healthy tissues and cells and identifying the pathogenic organisms and killing them. This is done by a series of steps called immune response. The immune system of the body exists in two major forms:
Innate immune system (non-specific) and
Adaptive immune system (specific).
Even though, both these systems function to protect the body from various infections, they are different in a number of ways. The innate immune system forms the first line of defence and acts upon an infection immediately whereas, the adaptive immune system forms the second line of defence and takes time to react to an invading organism.
The cells involved in the immune response of the body are white blood cells, or Leukocytes. These leukocytes are stored in various locations in the body and circulate through the body between the organs and nodes via blood vessels and lymphatic vessels. In this way, the immune system works in a co-ordinated manner to help protect the body from harmful infections.
Phagocytes (type of leukocytes) are a group of immune cells that are specialized in finding and eating up bacteria, virus and other harmful infectious organisms with the help of extended portions of its plasma membrane which wrap around the pathogen until it is fully enveloped. This process by which the phagocytes engulf and destroy pathogenic organisms is termed as phagocytosis and the principle cells involved are neutrophils/polymorphonuclear cells, macrophages and dendritic cells. Neutrophils have a short life span and survive in the tissues of the organism for a few days and macrophages, unlike neutrophils have a long life span and survive in the tissues for many months. Phagocytes are motile and move throughout the bloodstream, the lymphatic system etc. in search of the invading organisms to attack. Whenever a foreign particle is encountered, it is taken up by the phagocyte and destroyed.
In order to enter the infected tissues, the neutrophils and monocytes circulating in the blood must first attach to and then move across the endothelial cell lining of the blood vessels. This process of migration of the phagocytes to the infected tissues is explained below:
Phagocytes identify the invading organisms with the help of N-formylated peptides, activated complement proteins and mediators of inflammation.
The presence of a pathogen in the body leads to a number of host responses like inflammation. The first step involved in the biological function of phagocytes is known as rolling or margination. The leukocytes are transported by the blood stream to the post capillary venules where a firm interaction between the cells and the endothelial cell lining takes place. At the sites of inflammation, the rate of blood flow is very less due to the dilation of blood vessels which increase the chances of collision between the leukocytes and the endothelial cell lining. Adherence of the phagocytic cells to the endothelium is a regulated process. Two sets of adherence molecules carry out this process namely selectins and integrins.
Interaction of the cells to the endothelium is initiated by L-selectin which interacts with the carbohydrates present on the endothelial cells. Rolling increases with inflammation as two new selectins come into picture. P-selectin and E- selectin are released on exposure to C5a or histamine released due to inflammation. These molecules together allow a loose attachment between the phagocytic cell surface and the endothelium.
Platelets release cytokines such as IL-8 and PAF which influence thae phagocytes to upregulate the expression of integrins. These integrins include LFA-1 (Leukocyte function associated Antigen -1) and MAC-1 that co-ordinate the important steps in the migration of leukocytes. These two integrins further attach to other integrin molecules such as ICAM-1 (Intracellular adhesion molecule-1) and ICAM-2 that are shown on the endothelial cell surfaces. The marginated leukocytes are arrested by these adhesion molecules that allow them to stick to the endothelium.
The integrin mediated adhesive interaction causes the phagocytes to move towards the endothelial cell junctions. Vasodilators that are produced at the site of infection cause these junctions to loosen making it easier for the phagocytic cells to cross the endothelial barrier. This process by which the phagocytic cells migrate across the vascular walls through mediators of inflammation is known as diapedesis. After the phagocytes reach the infected tissue, they need to locate the pathogenic microbe which is signalled in many ways.
Many microbial proteins possess N-formyl methionine at their amino terminal end which acts as chemoattractants for the phagocytes. The process by which the phagocytes are attracted towards the site of infection by a certain chemical stimulus is called as chemotaxis.
The phagocytic cells have a number of receptors on their surfaces that help them attach to the infectious agents invading the host organism such as Fc Receptors and toll like receptors.
Fc receptor is a protein that is found on the surface of macrophages and neutrophils. It functions by binding to the Fc fragment of the antibodies that are attached to the invading pathogens which further stimulates the phagocytic cells to destroy the pathogenic organisms
Toll like receptors:
Phagocytes possess toll like receptors or pattern recognition receptors (PRR's) on their surfaces that identify and bind to various Pathogen associated molecular patterns (PAMP's) on invading micro-organisms. This binding results into phagocytosis and also the release of various cytokines by the phagocytes.
Phagocytic cells of the body also possess a receptor for the third component of the complement system i.e. C3b. phagocytosis is initiated when pathogens coated with C3b bind to this receptor. The inflammatory response produced by the complement system further draws phagocytes to the area of infection in the host organism. This is called as opsonization. Opsonins are specific antibodies that bind to the microbe and render its surface sticky so that they are easily engulfed by the phagocytic cells. Opsonization of bacteria increases the rate of attachment and ingestion by phagocytes to a great extent. As a result, bacteria in the blood that are bound to opsonins are easily cleared by the action of phagocytes.
Phagocytes also attach to the microbes in the absence of opsonins by a mechanism which is non-specific. This type of attachment which takes place in the absence of phagocytes involves hydrophobic and electrostatic (net surface charge on the surface of the phagocyte) attraction between the phagocytes and the microbes.
In the absence of any kind of specific interaction, the phagocyte simply physically traps the microbe against a tissue surface and initiates ingestion.
This process is called as surface phagocytosis which can prove an important defense mechanism as it slows down the activity of the microbes until opsonins are available to enhance the process of phagocytosis.
Once the phagocytes attach to the microbe, a series of poor signals are generated that trigger ingestion of the pathogenic microbe. This involves the engulfment of the microbe by the phagocyte. The phagocyte begins to extend pseudopods around the bacterium that fuse together and form a pouch which contains the microbe. This microbe now becomes enclosed in a structure called phagosome. However, this process is incomplete without the presence of ATP. The phagocyte's metabolism also changes from aerobic respiratory to anaerobic fermentative due to contact between the microbe and the phagocyte releasing lactic acid as the final end product. As the amount of lactic acid increases, the pH of the cytoplasm is lowered, further enhancing the activity of various degradative enzymes.
This structure i.e. the phagosome soon moves into the cytoplasm and collides with a series of lysosomal granules which discharge their contents into the phagosome. This includes the release of large number of toxic macromolecules and other compounds. The membranes of phagosome and lysosome fuse together forming a digestive vacuole known as a phagolysosome
The killing and the digestion of the engulfed microbe takes place in this newly formed phagolysosome and is restricted to the phagolysosome itself so that no toxic substances and harmful activities of the phagocyte are turned against themselves thus protecting the cytoplasm of the phagocyte.
After the phagolysosome is formed, the very first effect that is seen on the microbe is the loss of viability (the ability to reproduce). The next effect seen on the microbe is the inhibition of synthesis of macromolecules and after 15-30 minutes of ingestion, many pathogenic and non-pathogenic microbes are killed. The mechanisms used by the phagocytes to carry out ingestion are diverse and various lysosomal and metabolic constituents are used in the process. Each type of phagocyte uses a slightly different combination of killing mechanisms which can be divided into two main groups:
Oxygen dependent and oxygen independent.
As mentioned earlier, the process of phagocytosis involves the binding of Fc receptors on neutrophils, macrophages and monocytes. This binding results in an increase in the glucose and oxygen consumption by the phagocyte which is known as a respiratory burst. This respiratory burst results in the production of a large number of oxygen containing compounds that eventually kill the microbe being phagocytised. This is known as oxygen dependent mechanism of intracellular killing.
Also, microbes can be killed by other pre formed substances that are released from the granules or lysosomes when they fuse with the phagosome. This is known as oxygen-independent mechanism of intracellular killing.
Oxygen dependent mechanism:
The receptors that bind to the phagocytic cells activate a membrane bound NADPH oxidase which uses oxygen to oxidize the NADPH. This results in the formation of a superoxide anion. Later on with the help of the enzyme superoxide dismutase, the superoxide anion decays to hydroxide radical (OH) or is converted into hydrogen peroxide (H2O2). Also, superoxide can react with hydrogen peroxide resulting in the production of hydroxyl radical and more singlet oxygen molecules. O2-, OH and H2O2 are the toxic oxygen species that attack many targets in the invading microbes such as membranes and nucleic acids i.e. they overcome the protective mechanisms of the invading microbes resulting in their killing. Furthermore, these reactive oxygen species can act in association with the lysosomal enzyme called myeloperoxidase which is released into the phagocytic vacuole during fusion to form the phagolysosome. This enzyme uses the hydrogen peroxide generated from the respiratory burst to catalyse halogenation of the phagocytosed microbes, which means mainly chlorination of the microbes. This mechanism of halogenation usually proves an effective measure for killing of the microbes.
The combination of the NADPH oxidase and myeloperoxidase systems results in destructive oxygenation and halogenation of the engulfed microbes.
Oxygen independent mechanism:
In this type of activity the phagocytes do not require oxygen for the destruction of microbes. Pre formed substances released from granules and lysosomes as well as the external conditions of the phagolysosome play an important role in this mechanism. The pH of phagolysosome is as low as 4.0 due to the accumulation of lactic acid which is acidic enough to kill and prevent the growth of most of the pathogens. This low pH also enhances the activity of degradative enzymes present in the phagolysosome such as lysozyme, glycosylases, phospholipases and nucleases that destroy the microbes. The pre formed proteins released from the lysosomes help inhibit various viruses, yeast and bacteria. The phagolysosome of neutrophils also contains lactoferrin that chelates iron, depriving the bacteria of this important nutrient.
The dead microbes accumulated in the phagolysosome are degraded to low-molecular weight components by various hydrolytic enzymes. Following extended phagocytosis, killing and digestion of the microbes, the neutrophils lyse and die which makes up most of the material in pus. Once the microbes are destroyed, the unwanted organic material is ejected from the cell by a process called as exocytosis. Macrophages then allow the insertion of microbial antigenic components into the plasma membrane for presentation to lymphocytes in the immune system.
As a result, the process of phagocytosis not only allows the host organisms to get rid of harmful invading pathogens but also helps in the maintenance of healthy tissues in the body. In the absence of this particular process, accumulation of non-functional substances may occur in the body that will hamper the smooth functioning of the body. Therefore, the removal of invading pathogenic organisms becomes very important for the body for which the mechanism of phagocytosis is bought into use.
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