The human body is provided with a number of natural barriers which protect it from all types of foreign invaders. These include: 1. Skin 2. Mucous Membrane 3. Chemical Factors 4. Commensal Organisms 5. Cellular Components 6. Some Proteins Involved in Non-Specific Defense 7. Inflammation.
Contents
1. Skin:
The human body is externally covered by skin which gives the first line of defense against the microbial invaders. The skin has two distinct layers — an outer layer called epidermis and an inner one called dermis. The epidermis is a comparatively thin layer consisting of tightly packed cells covered externally by dead cells which are continuously sloughed off as the skin grows.
These cells are rich in keratin, a type of protein which is very resistant to microbial decomposition. The dry dead epidermal cells are inhospitable to microbes. Also, if any microbe settles on the epidermal cells, the chance of its elimination through natural sloughing is high. All these features make the skin an effective barrier to all types of microbes.
However, the intact skin may be breached accidentally through a cut or bruise or burn injuries or by an insect sting. Such a breach in the skin makes open a passage through which microbes may enter into the tissues underlying the skin.
In case of stinging insects like mosquitoes, tsetse-fly, sand-fly, ticks etc., the sting not only pierces the skin, but also specific pathogens carried in the mouthparts of those insects are injected in the interior of the body. As a result, diseases like malaria, sleeping sickness, yellow-fever or plague may develop.
A diagrammatic sketch of an intact skin layers is shown in Fig. 10.1:
In case a breach of the skin occurs either accidentally or by stinging insects and microbes gain entry into the deeper layers of the skin, they face the next line of defense. This is provided by certain cells of the dermis, known as Langerhans cells.
These cells can recognize microbes as foreign elements with the help of their innate receptors. They phagocytize the microbial cells and destroy them. Langerhans cells form a part of the skin associated lymphoid tissue (SALT).
They are able to process antigens (microbes) and present them to T-lymphocytes. T-lymphocytes play an important role in the specific defense. Thus, SALT forms an important link between non-specific and specific defense systems. Langerhans cells are a type of dendritic cells. These cells have an elaborately branched folded membrane giving the appearance of a branched tree from which its name is derived (Fig. 10.2).
2. Mucous Membranes:
While the skin covers the external surface of the body, the mucous membranes line the passages like GI tract, respiratory tract etc. The mucous membranes consist of an epithelial layer and underlying tissues. The epithelium is mostly a single cell layer, except in mouth, urinary bladder and vagina.
As most of these passages come in contact with materials from outside, like food, air etc., they are exposed to microbes and viruses and therefore need protection against microbial attack. This is provided by the mucous membranes, although they are not as effective as the skin.
The protective power of the mucous membranes is primarily due to the secretion of a thick sticky substance called mucus which consists of some proteins and polysaccharides. Mucus forms a viscous covering over the epithelial layer lining the tracts. Its main function is to trap microbes.
As mucus is continuously formed and diffuses into the passages, the trapped microbes are also removed. In case of the GI tract, the washed out microbes are transferred to the stomach where the acidic environment and proteolytic enzyme kill them.
The elimination of microbes and other particulate bodies from the lower respiratory tract is facilitated by the presence of ciliary cells on the epithelial layer. Synchronous movement of these cells propels mucus with embedded microbes and particles upwards towards the throat from where they are ejected outside by cough or sneeze. Mucus is secreted by goblet cells of the epithelial layers.
A diagrammatic sketch of a longitudinal view of mucus membrane and ciliary movement is shown in Fig. 10.3:
As the microbes are trapped in the mucus, they are unable to attach to the epithelium which is necessary for entering the body. Thereby, the chance of infection is minimized. Like mucus, saliva secreted in the mouth from salivary glands helps to keep the mouth and teeth relatively free of microbes by continuous washing. The microbes entering through food and drink are washed down into the stomach where most of them are killed, though some organisms, like Helicobacterium pylori, can grow in the stomach.
Although eyes are not protected by mucous membrane, tears produced by tear glands exert a protective role. Like saliva, tears are produced continuously to keep the eye surface moist and wash away dirt and microbes present in air. Tears are passed into the nose through the nasal duct and eliminate foreign matters.
Similarly, urine helps to keep the urinary tract clean by periodic washing. Vaginal secretions likewise protect the female genital tract. The secretions like mucus, saliva and tears besides giving physical protection to the inner tissues of the human body, also contain chemical factors which have antimicrobial properties.
3. Chemical Factors:
One of the potent antibacterial chemical agent which occurs in tears, saliva, nasal secretion and tissue fluids is an enzyme called lysozyme. It can cause hydrolytic cleavage of the muropeptide which forms the backbone of bacterial cell wall, thereby causing lysis of bacteria, specially the Gram-positive ones.
The oil-glands present in skin produces an oily substance called sebum which also has antibacterial activity. Sebum contains, among other ingredients, unsaturated fatty acids which can inhibit microbial growth. Besides, sebum helps to maintain an acidic reaction of the skin surface which discourages microbial proliferation. Sebaceous glands of the ear produces a waxy material called cerumen. This substance forms a coating in the ear-hole and prevents attachment of microorganisms.
The epithelial cells of the GI tract and the respiratory tract elaborate several small peptides having molecular weights of 3,000 to 5,000 Dalton. These peptides also possess antibacterial properties. Among such peptides are cecropins and magainins which have bacteriolytic activity, as also defensins which can make holes in bacterial membrane.
Another group of antibacterial proteins present in mucus and blood are the transferrins. These compounds bind iron by chelation. They inhibit bacterial growth by depriving iron which is required by microbes for synthesis of iron-containing enzymes, like cytochromes.
The environment in the stomach and the small intestine is also not conducive for microbial growth. The stomach acid and enzymes in gastric juice are inhibitory for most microbes. Other enzymes secreted in the small intestine as well as bile destroy most microbes by attacking the structural components of microbial cells, like polysaccharides, proteins and lipids. All these chemical and biochemical factors contribute substantially to protect the body from microbial invaders, each having its own sphere of action.
4. Commensal Organisms:
Skin and the mucous membranes of different passages harbour a microbial flora, characteristic for each. The organisms in these flora under normal conditions, are not only non-pathogenic, but beneficial to the human body. They play an important role in warding off the pathogens, thereby protecting the body in a nonspecific manner. These normally resident micro-flora are known as commensal organisms and the relationship with the host is commensalism.
In general, the commensal organisms — which are mostly bacteria — exert their beneficial effect by competitive elimination of the pathogens. The commensals by virtue of their great number, occupy most of the attachment sites and consume available oxygen and food. The pathogenic invaders which are smaller in number, are thus deprived of space and food.
Beside such passive resistance through competition, commensals may also produce chemical agents which actively antagonize pathogenic microbes. For example, Escherichia coli, which colonize the human colon (large intestine), produces colicins which inhibit the growth of other enterobacteria, such as Salmonella.
Besides colicins, the colon-commensals produce various organic acids by fermentation which are inhibitory to many pathogens. Lactobacilli which are resident in the vaginal tract produce lactic acid fermentation. This keeps the pH acidic enough to prevent growth of protozoans, like Trichomonas vaginalis and yeast, like Candida albicans.
The commensal organisms, which are normally beneficial when they colonize the organ or part of the body where they are best suited, may sometimes turn into opportunistic pathogens. For example, E. coli has a beneficial role so long it grows in the colon, but may be pathogenic when it infects the urinary tract.
5. Cellular Components:
Apart from the physical barriers, chemical factors and deterrent effects of commensal organism, there are several types of cells in the human body which actively participate in the non-specific defense against pathogenic agents. These cells include the different types of phagocytes, the natural killer cells, the mast cells and basophils, and the dendritic cells. The functions of the cells are discussed below. It would be rewarding to have knowledge of the different blood cells and the lymphatic system of the human body.
(i) Blood Cells:
There are three main types of blood cells. These are erythrocytes or red blood cells (RBC), the leucocytes or white blood cells (WBC), and the thrombocytes or platelets. The mature RBC and platelets are without a nucleus, while all types of WBCs are nucleated cells.
The fluid portion of blood in which the cells are suspended is called serum. The serum is an aqueous solution of minerals, proteins and other organic compounds. When the fluid contains the clotting agents, like fibrinogen and prothrombin, it is called plasma.
Among the three main types of blood cells, the leucocytes play important roles in both nonspecific as well as specific defense. Erythrocytes are mainly involved in carrying oxygen to different tissues, while the platelets function in blood clotting.
All types of blood cells are differentiated from the haemopoietic stem cells which are present in the foetal liver spleen and bone-marrow and in adults only in the bone marrow. From the point of view of the body’s defense, the leucocytes are of special importance. These non-pigmented nucleated blood cells are differentiated into five types depending on their nuclear shape, cell inclusions and function.
The different types of leucocytes, their characteristics and their relative number in normal blood are shown in Table 10.1:
(ii) The Lymphatic System:
The fluid that bathes the tissues and cells and fills the intercellular spaces is known as lymph. The liquid fraction of blood filters out of the capillaries and feeds the tissue cells with oxygen and nutrients, as well as it collects the waste products. This fluid is then taken up in tiny vessels (lymph capillaries). From these vessels, the fluid passes into larger vessels called lymphatic’s and finally, the fluid is returned to a vein through which it is channelized into the heart. Thus, the fluid that flows out of the capillaries is returned to the main stream — the cardiovascular system.
The lymph channels have pockets of lymphatic tissues called lymph nodes. Lymph nodes are spherical to ovoid solid structures, measuring 2 to 10 mm in diameter. As the lymph capillaries are very thin-walled, they are permeable and microorganisms can enter them. A major function of the lymph nodes is to act like checkpoints and remove any microbial intruder by the phagocytes present in the lymph nodes.
They also contain the lymphocytes that are actively involved in the specific defense. Lymph nodes are mainly concentrated in certain parts of the human body like the neck, armpits, groins and the mesentery. These nodes sometimes swell due to infection when they are commonly called swollen glands.
A diagrammatic representation of a lymph node is shown in Fig. 10.4:
(iii) Phagocytic Cells & Phagocytosis:
The phagocytes of the human body are of two main types — the neutrophils, belonging to the polymorphonuclear leucocytes (PMNs); and the cells derived from monocytes, like macrophages, Kupffer cells in the liver, microglial cells of brain, mesangial cells of kidney etc.
The neutrophils circulate in the blood stream they are the mobile phagocytic cells of the human body. They constitute some 60 to 65% of the total leucocytes and blood contains about 8 million of them per ml. But they have a short life-span and are continuously regenerated from the stem cells.
Whenever they happen to meet a microbe in course of circulation, they phagocytize and kill it with the help of hydrolytic enzymes contained in their granules. These enzymes include peroxidase and phosphatases. Neutrophils also produce small antibacterial peptides, called defensins.
In contrast to the mobile neutrophils, the phagocytic cells derived from monocytes are stationary in different tissues of the body, although the precursors, i.e. monocytes are mobile in the blood stream. They migrate from blood capillaries into tissues and are transformed into phagocytic cells of different types as named above. The general name of these phagocytes is macrophage which is much larger in size than its precursor and has an irregular shape (Fig. 10.5).
The phagocytic cells derived from monocytes, together with the monocytes, constitute the mononuclear phagocyte system, which was previously called the reticulo-endothelial system. The main function of this system is to eliminate microbial invaders as well as removal of dead body-cells by phagocytosis. The macrophages also play important functions in acquired defense of the body, like processing and presentation of antigens as well as secretion of cytokinin.
Phagocytosis is a natural phenomenon exhibited by many lower organisms, like amebae which engulf solid food particles including microbial cells and digest them inside their body. The process was first observed in 1884 by Metchnikoff (1845-1916), a Russian zoologist working in Pasteur’s laboratory.
Later, he discovered that certain white blood cells behaved in a similar manner. He claimed that phagocytosis was responsible for human defense against pathogenic microbes. The importance of his claim was not appreciated immediately, but recognized later and he was awarded the (with Paul Ehrlich) Nobel Prize in 1908.
From an immunological standpoint, phagocytosis refers to ingestion of a microbe (or a microbe-infected body cell, or a dead body-cell) by a phagocyte of the body leading in most cases to complete destruction. In rare cases, an ingested microbe may withstand killing and may even multiply within a phagocyte. An example of this type of microbe is Mycobacterium tuberculosis.
Phagocytosis occurs in a number of steps. The process begins with migration of phagocytes towards a microbe. This is mediated by chemical attractants (chemo-taxis). The attracting chemicals may be microbial products e.g. muramyl dipeptide, or components of complement (complement is a set of constitutive serum proteins). The phagocytes have specific receptor sites for these attractants on their surface and they migrate towards the site where a microbe has breached the mechanical barrier and has entered the tissue.
The next step consists of attachment of the microbial cell to the phagocyte. In this process, the surface receptors of the phagocyte bind to the surface molecules, like sugars and lipids of the microbial cell. A complement protein (C3b) helps in this binding.
The interaction between the phagocyte and the microbial cell leading to phagocytosis is greatly facilitated by a process known as opsonization in which the microbial cell is coated by complement proteins and by antibodies.
These agents are called opsonins. While complement proteins are constitutive elements of the blood, antibodies are synthesized only in response to antigens. They are constituents of the acquired defense system. Thus, opsonization forms a link between the non-specific innate defense system and the specific acquired defense.
At the next step following attachment, the microbial cell is internalized by the phagocyte through the process of endocytosis. The membrane of the phagocyte folds and surrounds the target cell forming a phagocytic vesicle, called a phagosome. After internalization is completed, the phagosome becomes an intracellular body containing the endocytosed microbial cell. The phagosome membrane next fuses with the membrane of a lysosome present in the phagocyte’s cytoplasm and gives rise to a phagolysosome.
The interior of the phagolysosome contains lytic enzymes which attack the ingested microbe. The pH of the phagolysosome becomes acidic due to active pumping of H+-ions. Lysosomal enzymes that attack bacterial cells include lysozyme which cleaves peptidoglycans of cell wall and a peroxidase which produces superoxide radical (O2–).
Superoxide is highly toxic to bacteria. Another important killer of bacterial cells, nitric oxide (NO), is believed to be involved in destroying the ingested microbe. Most bacteria are killed within 10 to 30 minutes after phagocytosis. After the microbe has been digested, the residual material in the phagolysosome (now it is a residual body) moves towards the periphery of the phagocyte and is released as waste products outside.
The events occurring in phagocytosis are shown in Fig. 10.6:
(iv) Natural Killer Cells:
Natural killer cells, also known as null cells, are also leucocytes which circulate mainly in the blood and lymph, but are present in the tissues as well. They resemble other granulated leucocytes having diameters of 12 to 15 but are not phygocytic.
They are components of the innate defense system and kill virus-infected and cancer cells by a mechanism more or less comparable to that of cytotoxic T-lymphocytes. The latter cells are components of the cell-mediated immunity produced as a result of immune response, i.e. the acquired defense system, whereas natural killer cells are normally present in the body without immune response.
The natural killer cells are able to distinguish the virus-infected body cells or cancer cells from normal body cells by means of specific receptors present on their surface. Although they can bind to both normal body cells as well as to abnormal cells (virus-infected and cancer cells), specific receptors send a signal which prevents destruction of a normal cell.
On the other hand, an abnormal cell is killed through release of cytotoxic molecules from the granules of the killer cell. The cytotoxic molecules include perforins which makes a hole in the membrane of the target cell through which proteolytic enzymes contained in the granules are transmitted resulting in death of the target cell.
Natural killer cells, when they interact with virus-infected body cells, are known to secrete y-interferon (IFNy) which helps to protect neighbouring body cells from virus infection. IFNy has also other functions in acquired defense system.
(v) Other Cells Involved in Non-Specific Defense:
These include the dendritic cells, mast cells, basophils, and eosinophil’s. The dendritic cells (Fig. 10.2) have a highly folded surface. They include the Langerhans cells present in skin, the follicular dendritic cells in the lymphoid tissues, and the interdigitating cells of the lymph nodes.
The main function of these cells is to process and present antigens to lymphocytes which bind to these cells with the help of specific receptors. The dendritic cells are able to recognize the microbial antigens with the help of innate receptors. Thus, the dendritic cells form a link between the innate and acquired defense systems.
Mast cells and basophils are granular leucocytes (granulocytes). On activation, they release the cytoplasmic granules which contain several chemical substances, like histamine and cytokines. These substances cause dilation of the capillaries (vasodilation) and attraction of the phagocytic cells, like neutrophils to an infection site, required for developing inflammation.
Eosinophil’s are also granular leucocytes. They also exhibit some phagocytic activity. But their main function is to kill large parasites, like worms, with the help of toxic substances contained in their cytoplasmic granules. They bind to the antibody-coated parasite and release the lethal cell-contents on the parasite’s body to kill it.
6. Some Proteins Involved in Non-Specific Defense:
Besides the mechanical barriers, chemical factors and the cellular components, there are also some protective proteins which are actively engaged in affording protection of the body against foreign invaders. Among these non-specific proteins, the most important are the complement system, and the interferons. In addition, there are some other proteins which have protective functions.
These are briefly discussed:
(i) Complement:
Complement is a group of more than 20 constitutive serum proteins constituting the complement system. The components of this system are interdependent and activation of the first one leads to activation of the second. This proceeds sequentially to activate all the components of the system. The activated complement takes part both in non-specific and in specific defense systems.
The complement proteins are synthesized by hepatocytes and monocytes, and the proteins circulate in the blood stream forming about 5% of the total serum protein. They are normal constituents of the serum, independent of immune response, but they can participate in both non-specific and specific defense systems. They are known as complement, because they bind to antigen-bound antibody molecules and help or complement their function in acquired immune response. The binding of complement to antigen-antibody complex is known as complement fixation.
The components of complement system are designated as C1, C2, C3, C4, C5, C6, C7, C8 and C9 (C standing for complement). Some of these have subcomponents, e.g. CI has three Clq, Clr and Cls. In addition, there are some other proteins, like factors B, D and P.
The total number of components is at least 20, may be more. The components remain normally in an inactive form. They are activated to become functional. Activation of the complement proteins occurs in an ordered sequence through a cascade of reactions. Except C4, other components are activated according to the numerical sequence.
That is, CI is activated first and the product activates C2, and so on. During such activation, a component is usually cleaved to form subcomponents which have different functions. For example, one subcomponent may act as opsonin helping phagocytosis and another may have an enzymatic activity.
Activation of the complement system may occur through two pathways. One is called the classical pathway and the other is called the alternative pathway. The activation of complement by the classical pathway involves antibodies produced as a consequence of immune response, while the other pathway becomes operative through direct interaction of complement and microorganisms without any involvement of the immune system or antibodies.
Obviously, complement activation by the alternative pathway is part of the innate defense of the body and plays a very important role in destruction of the invading microbes. In fact, the complement is the first line of internal defense which a microbe has to counter when it breaks through the mechanical barriers, specially skin and the mucous membrane. For the present, we shall consider the alternative pathway of complement activation and the consequences of such activation.
Alternative pathway of complement activation:
The alternative pathway does not involve complement components C1, C2 and C4, though they participate in the classical pathway. In both, complement C3 plays a crucial role. On the other hand, the complement proteins called factors B, D and P are involved in the alternative pathway, but not in the classical one.
Complement activation by the alternative pathway occurs by direct interaction with certain surface molecules of microbes, while activation by the classical pathway occurs by interaction with antibodies bound to microbes or any other antigen.
Microorganisms like Gram-negative bacteria have lipopolysaccharides (LPS) in their outer membrane and Gram-positive bacteria possess lipoteichoic (LTA) acid chains on their cell wall. These molecules can interact with the complement. The complement component C3, which is present in considerable amount in serum and body fluids, plays the pivotal role in such interaction with microbial surface molecules.
The C3 protein is cleaved normally at a low level into two fragments, — C3a and C3b. Of them C3b is a highly reactive protein which binds covalently, both with the bacterial surface molecules, such as LPS and LTA on one hand and with the surface receptors of neutrophils (PMNs) on the other.
This helps to bring the phagocyte and the bacterial cell close to each other — facilitating phagocytosis. In this process, the complement subcomponent C3b coats the bacterial surface and acts as opsonin by binding with LPS or LTA. Thus, C3b facilitates phagocytosis by opsonization.
A more important role of the activated complement system is direct killing of microbial cells and other foreign cells by the process of cytolysis. The binding of C3b to an invading cell triggers activation of another complement protein, factor B, leading to its cleavage into two fragment Ba and Bb. The C3b and Bb subcomponents then combine to form a complex C3b-Bb — a proteolytic enzyme.
This enzyme then attacks the component C5 and cleaves it into two subcomponents — C5a and C5b. The latter (C5b) then combines with the components C6, C7, C8 and C9 one by one to form a large complex known as the membrane attack complex. This complex attacks the membrane of the target microbial cell producing a hole or pore with a diameter of about 10 nm. The attacked cell loses its cell contents through the pore and undergoes lysis. The component C9 possibly plays a key role in the formation of such trans membrane pore.
A third consequence of complement activation is that the cleavage products — C3a and C5a — contribute to the development of inflammation another non-specific defense mechanism. C3a and C5a can bind to mast cells, basophils and thrombocytes causing release of histamine which increases vasodilation. This helps migration of phagocytic blood cells from capillaries into tissues. C5a acts also as chemo attractant for guiding the phagocytic cells to the site of infection where complement has been activated by the invading microbes. Thus, complement activation leads to a three-pronged attack on the invading microbes as shown in Fig. 10.7.
The activation of complement by the alternative pathway is shown in Fig. 10.8:
(ii) Interferons:
Interferons are small proteins (M.W. 15,000-30,000 Daltons) synthesized by eukaryotic nucleated cells infected by virus. Interferons themselves are not antiviral, but they protect the neighbouring cells from virus infection by inducing production of antiviral proteins. These antiviral proteins inhibit translation of viral m-RNAs in the host cells and stop viral multiplication (Fig. 10.9).
Interferons are non-specific in the sense that an interferon induced by a particular virus can protect other cells not only from that virus, but also from other viruses. On the other hand, interferons are species specific which means interferons produced only by human cells are effective for humans. Interferons produced by other animals are not effective in humans.
These proteins are produced in very small quantities by many types of cells including macrophages and dendritic cells in response to virus infection and protect adjacent cells. As interferon synthesis is not directly related to the immune system, they are considered as a component of the innate defense system. Besides having antiviral property, interferons also act as signals of communication between cells (cytokines).
Interferons are broadly divided into two types. Type I includes alpha-interferon (IFNα) and beta- interferon (IFNβ). IFNα includes at least 12 different proteins which are closely related to each other. IFNP has only one protein. The genes controlling both IFNα and IFNP are located on human chromosome 9. Type II interferon is represented by gamma-interferon (IFNy). The gene for IFNy is located on human chromosome 12.
Type I interferons are produced by several types of cells, specially by the fibroblasts, leucocytes, dendritic cells and epithelial cells. They function not only as antiviral agents, but also as cytokines for stimulation of the major histocompatibility complex (MHC) Class I genes.
Type II interferon (IFNy) is produced by certain specialized cells, like natural killer cells and T-helper lymphocytes. TFNy, besides having antiviral property, also stimulates expression of MHC Class I and MHC Class II genes and it plays a major role in activation of macrophages, thereby enhancing considerably the killing power of these phagocytes, particularly of the intracellular parasites.
(iii) Other Proteins:
An assortment of different proteins, normally present in the serum, take part in innate defense system. Their concentration in serum increases many-fold during inflammation. Their main functions are to stimulate phagocytosis by acting as opsonins and activate the complement system.
They are commonly known as acute phase proteins, because of their amplification during acute inflammatory response. They include the C-reactive protein which binds to phosphoryl choline of bacterial cells, mannose-binding protein, the serum amyloid protein A etc.
The C-reactive protein acts as an opsonin and it stimulates phagocytosis. The mannose-binding protein binds to mannose residues of bacterial glycoproteins as well as to specific receptors of phagocytes. It also functions as an opsonin and facilitates phagocytosis. The serum amyloid protein activates the complement component Clq and, at the same time, acts as an opsonin. The C-reactive protein also activates complement component Clq.
Another group of proteins involved in the innate defense are the collections. These proteins bind to carbohydrate molecules present on the surface layers of microorganisms. One such protein binds to magnesium on the surface of macrophages and it acts as an opsonin. Conglutinin is another protein of this group. In general, these proteins function as opsonin and play an important role in elimination of microbial invaders by phagocytosis.
7. Inflammation:
Inflammation is a non-specific defensive response triggered by damage to the tissues caused by a variety of agents. Such agents include microbial infection, chemical irritants like corrosive acids or alkalis, radiations like heat, ultraviolet’, trauma like cuts, abrasions, blows etc. An inflammatory response is characterized by four well-known external symptoms viz. swelling of the affected part due to infiltration of plasma (tumor or edema), redness due to accumulation of blood (rubor or erythema), pain due to injury of the nerve-endings (dolor) and heat due to increased blood circulation to the area (calor).
Although these symptoms make a person uncomfortable, the ultimate effect of inflammation is beneficial, because through this process the body attempts to remove the injurious effects of the cause and finally to repair the injured tissues.
As the inflammation subsides, a residual debris consisting of a mixture of fibrin (clots), remains of microbial cells (if the cause is microbial attack), the dead phagocytic cells and tissue cells is left behind at the site of injury. This residual matter is known as pus which may accumulate to form an abscess and may require surgical intervention for removal. An inflammatory response results due to complex interaction of many factors.
The main events occurring in inflammation caused by entry of a microbe through a wound are briefly discussed:
(i) Vasodilation:
As soon as a tissue is damaged by a cut or by other means, the capillary blood vessels in that area increase in diameter making the thin delicate wall (endothelium) more permeable. This is called vasodilation. Due to increased permeability, the fluid portion of the blood diffuses into tissues causing swelling and increased temperature. Flow of blood through dilated capillaries also increases causing redness of the affected part. Pain felt in that part may be due to injured nerves or due to increased pressure produced by swelling.
Vasodilation is mediated by several chemical factors. An important one among these is histamine which is present in a type of basophils in the tissues, called mast cells, as well as in the basophils and platelets of blood. The mast cells play a central role in the development of acute inflammation.
They occur mostly in the connective tissues and close to blood vessels. When the mast cells are activated by complement components C3a and C5a, they release their cytoplasmic granules which contain histamine. Release of histamine from mast cells, basophils and platelets may occur also directly due to injury without intervention of complement components C3a and C5a.
Among the other chemical factors contributing to vasodilation are the small proteins, known as cytokines. There are several cytokines which perform a variety of functions in both innate and acquired defense systems. Among them, interleukin 1 (IL-1) produced by activated macrophages and endothelial cells of blood vessels is an important chemical mediator of inflammation.
It activates vascular endothelium causing vasodilation. The cytokine-producing cells have a specific receptor on their surface (CD 14) which is able to bind surface molecules present on Gram-positive and Gram-negative bacteria, like LTA, LPS and peptidoglycan. The binding of producing cells to bacteria triggers release of cytokines. Other pro-inflammatory substances causing vasodilation include leukotriene’s produced by mast cells and prostaglandins released by damaged body cells. Both of these agents increase vascular permeability.
(ii) Transmigration of Phagocytes from Blood Vessels to Injured Tissue:
Vasodilation resulting in increased permeability of the capillaries is a preparatory step for the next event in the process of inflammation, viz. migration of the phagocytic cells, mainly neutrophils, from the blood vessels to the site of injury. The capillary wall is composed of loosely bound single-layered endothelial cells.
As the blood flows through the capillaries near the damaged tissues, the cytokines diffuse into the vessels through the dilated endothelium. The phagocytic polymorphonuclear leucocytes, like neutrophils as well as the monocytes of blood, are induced to bind to the endothelial cells at specific sites with the help of receptors expressed by the cytokines.
The normally spherical neutrophils become flattened and they are squeezed through the endothelial cells by pushing these cells apart. AS a result, the neutrophils as also monocytes migrate from the capillaries into the tissues at the site of injury (Fig. 10.10). This process of transmigration of blood phagocytic cells is called extravasation.
(iii) Chemo taxis of the Phagocytic Cells:
After extravasation of the neutrophils and monocytes into the tissues, they are chemotactically attracted to the injured tissues. The agents causing such attraction may be products of injured tissue cells themselves or complement component like C5a, or cytokines and leucotrienes. Attracted by these chemical mediators, the phagocytes stream towards the site of injury.
At the beginning of the inflammatory response, the neutrophils appear in the arena, but at a later stage the monocytes also appear in the field. Monocytes are transformed into macrophages and they become the predominant phagocytes. Macrophages are larger in size and have a much greater phagocytic activity.
(iv) Phagocytosis:
The accumulated phagocytic cells — the neutrophils and the macrophages — are then engaged in phagocytosis of not only the invading microbes, but also the damaged tissue cells. Phagocytic process is greatly enhanced by opsonization of the target cells. The cleavage of the complement component C3 into C3a and C3b is triggered by bacteria in the alternative pathway of complement activation.
The C3b fraction acts as an opsonin helping in the ingestion of microbes by the phagocytes. In exerting the killing effect on the ingested microbes, phagocytes themselves are also killed in large numbers. This leads to accumulation of a debris at the site of inflammation containing the remains of microbial cells, dead leucocytes and macrophages, damaged tissue cells, blood clots etc. This accumulated product is called pus which may remain in situ and slowly destroyed, or, sometimes, it may form an abscess. On opening, either naturally or by surgical operation, the pus comes out and the wound is healed.
An overall picture of inflammation is shown diagrammatically in Fig. 10.11:
(v) Healing:
Healing of the damaged tissues following an inflammation begins when the active inflammatory phase subsides and the causal agent has been removed. First of all, the pro-inflammatory chemical mediators have to be neutralized by specific inhibitors and anti-inhibitory cytokines, like interleukin 4 and 10.
Actual repair of the damaged tissues then starts by production of new cells to replace the damaged ones. The repair process depends on the tissue that has been damaged. For example, skin has a high capacity of regeneration. Fibroblasts and macrophages take active part in regeneration of damaged tissues; both of these cells synthesize collagen which is required for repair.
The important components of the innate defense of the human body are summarized in Table 10.12:
