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INNATE IMMUNITY: THE FIRST LINE AND SECOND LINE DEFENSE MECHANISM
Innate immunity is the immediate immune response to perform in protecting the body against infection of foreign entity such as microbes. Innate immunity or natural immunity is a nonspecific defence mechanism and is quick to act. This immunity is categorized into the first line defence mechanism and second line defence mechanism.

External mechanism
The first line defence involves external defence which are physical, chemical and biological. The physical defence involves organs. Examples of physical defence are:

In chemical defence, the chemicals are (not limited to):

Biological defence involves the normal flora that is present on the skin and in stomach. Normal flora provides competitive exclusion of microbes, produces compounds that are toxic to other microbes and stimulates immune system.

Internal mechanism
The second line defence involves internal defence which are cellular, circulating proteins and inflammation. Second line defence kicks in when microbes managed to pass through the first line defence. In response to invading microbes, complement proteins are fired first. Complements are circulating protein in the blood that is inactive. When microbes invade, complement will become activated and causes various effector mechanisms. Such effector mechanisms are phagocytosis and inflammation. The complements system facilitates the elimination of microbes in the innate immune system.

Overall, the components in the second line defence are the immune cells such as macrophages, dendritic cells, natural killer (NK) cells and neutrophils. These immune cells can recognize and act on microbes because immune cells and microbes have receptors that are attracted to each other. For example toll-like receptors (TLR) on immune cells. Receptors on microbes are (not limited to) PAMPs that are recognized by innate immune cells. Host cells that are abnormal have DAMPs receptors. The mechanism of complement, inflammation and phagocytosis will be explained later.

Skin
Skin is the largest organ of the body. In adults, the skin cover an area of about 2 square meters which is a very large coverage and weighs around 4.5–5 kg, which is about 16% of total body weight. If a person is 60 kg in weight, about 9.6 kg of the body is the skin. Skin consists of two main parts, epidermis and dermis. Hypodermis and in another name, subcutaneous layer is the most inner layer to the body and it is considered as not part of the skin.

There are various ways our skin can protect our body from microbes and pathogen. For example, keratin which is a type of protein that made up our hairs, skin and nails protects underlying tissue from microbes, scraping of the skin, heat and chemical that can endanger the skin.The oily sebum from sebaceous glands keeps skin and hairs from dehydrates and contain bactericidal chemical that kill bacteria. The acidic pH of perspiration retards growth of some microbes that cannot stand low pH environment. Epidermal Langerhans cells is a type of dendritic cell that lies in the epidermis layer of the skin. Epidermal Langerhans cells act as immunology component in the skin where it alert the immune system about potentially harmful microbial invaders that presence by recognizing and processing them. There is also macrophage in the dermis that will kill bacteria and virus that manage to pass Langerhans cell of the epidermis by phagocytizing it.

Mucous membrane
A mucous membrane or mucosa lines a body cavity that opens directly to the exterior, for example our skin. They consist of lining layer of epithelium and an underlying layer of connecting tissue.The epithelial layer of mucous membranes, which line body cavities, secrets a fluid called mucus that lubricates and moisten the cavity surface. The mucous membrane of upper respiratory tract contains cilia, microscopic hair-like projection on the surface of the epithelial cells. The waving action of cilia propels inhaled dust and microbes that become trapped in mucus towards the throat. Coughing and sneezing accelerate movement of mucus and and its entrapped pathogens out of the body.

Defensin
Defensins are small peptides which around 30-33 amino acids found in some macrophage of many species and specifically in human neutrophils. Defensin constitute up to 50% of the granule proteins. Defensins are able to kill a range of pathogens, including bacteria such as S. aureus, Psedomonas aeruginosa, E. Coli, fungi such as Cryptococcus neoformans and enveloped virus like herpes simplex. Defensin is a type of protein that constitutes one of the major killing mechanism of neutrophils and eosinophils. However, individual defensin are also produced by several cell types in tissues, particularly at epithelial surface in the lung, gut, and bladder. Some of these microbial peptide also cause mast cell degranulation with chemokine release and/or have direct chemotactic activity. They can therefore attract leukocytes to sites of infection.

Interferon (IFN)
Interferon is a group of molecule involved in signalling between cells of the immune system and in protection against viral infections. Interferons are cytokines that are particularly important in limiting the spread of certain viral infection, for example IFN and IFN, some type of interferon in the body is produced by cells that have become infected by a virus. Interferons induce a state of antiviral resistance in unaffected cells. They are produced very early in infection and are important in delaying the spread of a virus until such time as the adaptive immune response have developed.

Lysozyme
Lysozymes is a protective bactericidal enzyme produced by lacrimal glands. Lysozymes acts directly to the bacterial cell wall peptidoglycans, present especially in the exposed cell wall of Gram- positive bacteria. The cell wall of Gram-negative bacteria may also become exposed to lysozyme if they have been damaged by complement membrane attack complex. Lysozyme is constitutively produced by macrophages.

Low pH
Low pH can cause microbial invasion entering our body. Most bacteria grow best around neutral pH values (6.5 - 7.0), but some thrive in very acid conditions and some can even tolerate a pH as low as 1.0. Microbes that can stand is acidic environment are called acidophiles. Even though these microbes can live in very acid environments, their internal pH is much closer to neutral values.

Normal flora
Normal flora is a bacterial population that live in our skin and our mucous membrane in the body. This kind of bacterial population is ‘good’ bacteria that helps our body against microbes and pathogen that can endanger our health. Normal flora lives in our body starting from birth until human death. Normal flora is relatively stable which means that they are very compatible and does have various genes populates on various part of the body region. Mostly normal flora did not causing any harm to the organism, but sometimes when hosts were compromised, they can attack and cause disease.

Commensals which are the large population of bacteria inhabiting the host without causing any benefit or harms are considered as the normal flora. Virus and parasites are not normal flora as it is not a commensals and do not give any benefit to the host. Normal flora compete environment of the host more effectively than other pathogen such as Salmonella spp.

SECOND LINE DEFENSE MECHANISM
Internal defence of innate immunity or its other name, second line of defence is a non-specific type of resistance that results in destruction of pathogens that successfully invaded the external defence of human body, consisting mostly skin and mucus membranes. When a pathogen or any other foreign thing gets pass the external or first line of defence, the second line of defence will be automatically activated. Both second and first line of defence destroys potential invaders non- specifically, not targeting specific antigen specific receptor like adaptive immunity. Internal defence of human body comprises of phagocytic cells, circulating proteins and inflammatory responses. When a pathogen survives external defence, it usually leads to the migration and recruitment of phagocytic cells to the site of infection. Phagocytic cells such as macrophages and neutrophils together with dendritic cells and natural killer cells have huge roles in innate immune response, particularly in second line of defence. Dendritic cell, one of crucial immune cells which reside in most immature state of tissues will capture the microbe once it enters second line of defence. Every microbe possesses a type of molecules called pathogen-Associated molecular patterns (PAMPS) that are not possessed by human’s host cell. PAMPS will be recognized by pattern recognition receptors (PRR) that is expressed on the surface of antigen presenting cells (APC) such as dendritic cells and macrophage. One example of PRR is Toll-Like Receptor (TLR) also has the ability to recognize any cells are stressed or necrotic since these cells will exhibit damage-associated molecular patterns (DAMP). The recognition of PAMPS on microbe by PRR of dendritic cell will trigger signalling pathway that will result in activation of other immune cells. Neutrophil, a type of granular white blood cell usually the first immune cells to arrive at the site of infection though short-lived for few hours in circulation. Macrophage, a type of mononuclear phagocyte also migrates upon activation but it survives much longer at the site of infection. Both neutrophils and macrophages has phagocytic characteristic where both of them will engulf and kill the microbe. Natural killer cell, a large granular lymphocyte also has roles in destroying the targeted microbes by directly killing them.

COMPLEMENT SYSTEM
Circulating proteins such as complement system and cytokines are important proteins that involved in this non-specific type of resistance. Both of these types of proteins are central to the development of inflammatory reaction in human body. Cytokine, a cell signalling molecule acts as a mediator between the cells. During infection, tissue damage will cause the release of inflammatory cytokines from the circulating leukocytes in which the cytokines will manifest its regulatory role of inflammatory response. Inflammatory cytokines such as interferon (IFN), tumour necrosis factor (TNF), interleukin are often released by monocytes, macrophages, mast cells as well as endothelial cells during inflammation. Cytokines can act on its own cells (autocrine), neighbouring cells (paracrine) and distant cells (endocrine). Other type of circulatory protein that is dominating during innate immune response is complement system. Complement system is composed of wide array of heat-sensitive serum proteins that will trigger inflammatory reaction. Produced mainly by liver cells, plasma proteins of complement system circulate in blood as inactive precursors. Normally, tissue damage or injury will activate complementary system which will lead to the activation cascade of various complementary proteins by certain pathways that will result in subsequent inflammation. Other of its principal functions is such as opsonisation, lysis of cells by membrane attack complex and clearance of immune complexes.

INFLAMMATION
Another form of internal defence during innate immune response is inflammatory reaction. To avoid further damage to other living tissues, inflammatory response of body comes to action. Inflammatory cytokines specifically, chemokine which is a type of circulatory signalling protein are released upon the recognition of the microbe by PRR on innate immune cells. The release of chemokine will not only activate other white blood cells or leukocytes population to migrate to the site of infection, but it triggers the increase of blood flow to the affected site and increases the permeability and vasodilation of blood vessels, allowing more white blood cells to migrate to the site of infection. One example of the chemokine produced by a type of white blood cell which is basophil, histamine is released widely during inflammation. There are two types of inflammatory response where both of them are different in terms of duration of its response. Acute inflammation only lasts for few days and its site of inflammation normally has higher number of neutrophils. Meanwhile, chronic inflammation will last for a longer time as persistent agent causing the inflammation cannot be eliminated and the repair and regeneration of the infected tissue is interfered. The site of chronic inflammation will regularly dominated by macrophages. Among the signs that will be exhibited during inflammatory response are such as pain, swelling and redness of the affected area.

The complement system actively regulates various steps of an inflammatory response. Inflammation is currently viewed as a complex pathophysiologic process that engages literally hundreds of mediators and different cell types and tissues and can be initiated by any stimulus causing cell injury. Often, inflammation is a response to infection. However, chemical or physical injury alone can also induce this reaction. The ultimate goal of this process is to eliminate the causative agent with minimal destruction to host tissues and to repair the damage caused by the initiating factor.

The duration of an inflammatory response depends in part on whether a successful resolution and neutralization of the initiating agent has occurred. Acute inflammation is a relatively short process, lasting from minutes to a few days, and its main characteristics are an exudation of fluid and plasma proteins and an emigration of leukocytes into an extravascular compartment. These vascular and cellular responses are mediated by chemical factors derived from plasma or cells and are responsible for the classic clinical signs of inflammation, originally described by Aulus Cornelius Celsus and later modified by Rudolph Virchow: tumor (swelling), rubor (redness), dolor (pain), calor (warmth), and functio laesa (loss of function). If the acute response is unable to remove the causative factor or repair the damage at the site of inflammation, a chronic process, in which tissue destruction and repair occur while the inflammatory reaction continues, may develop.

Chronic inflammation can also result from stimuli that initiate a low-grade and asymptomatic response.Although an inflammatory reaction can occur in any tissue exposed to an injurious stimulus, the hallmark of this process is the response of vascularized connective tissue. The first changes observed during inflammation are alterations in the vascular flow and changes in the calibre of small blood vessels. Vasodilation of arterioles, resulting in the opening of new capillary beds in the area of injury, follows transient vasoconstriction, which lasts only seconds. Larger arterioles and newly opened capillary vessels increase the blood flow to this area. Gradually, progressive changes in the endothelium enhance the vascular permeability of the microvasculature, leading to the escape of the fluid into an extravascular compartment. The decrease in the amount of the fluid in the lumen of blood vessels enhances the viscosity of the blood and slows down the flow rate. As a result of these alterations in blood flow, the migration of leukocytes begins. Over time, leukocytes stick to the endothelium, at first transiently (rolling), then more avidly (adhesion), and soon afterward, they migrate through the vascular wall (transmigration) into the interstitial tissue. At this point, the essential goal of acute inflammation, to bring leukocytes and plasma mediators to site of injury, is achieved.

PHAGOCYTOSIS
Complement system also facilitates phagocytosis by phagocytes which are macrophage and neutrophil. The mechanism of phagocytosis is as below:

1.Chemotaxis

The migration of phagocytes to the infected site is stimulated by chemicals such as activated complement proteins, the PAMPs on microbes, leukocytes and DAMPs of

damaged tissue.

2. Adherence of microbe to phagocyte. Phagocytes bind to microbes and complement proteins enhances the adherence.

3.Ingestion of microbe to phagocyte. Phagocytes extend its arms or pseudopods and engulf the microbes forming a phagosome.

4.Digestion of ingested microbe by enzymes. Phagocytes have lysosome containing lysosymes. Lysosome will fuse with the phagosome forming a phagolysosome.

The lysosymes inside will digest the microbes. The digestion also is done by lethal oxidants in the phagocytes.

5.Discharge of waste materials. The undegraded materials will remain in residual bodies.