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Nonspecific Defenses of the Host Innate Immunity Nonspecific defenses of the host The ability to ward off disease through our defenses is called resistance. Vulnerability or lack of resistance to disease is called susceptibility. Non-specific defenses are also called innate defenses and they protect us from infections by pathogens in general. This type of innate immunity which one is born with is distinguished from adaptive immunity which protects one from infection against a specific organism and which develops after exposure to that specific organism. Innate versus adaptive immunity As will be seen, the innate and adaptive immune systems do not operate independently of each other, but are very inner-connected in their activities. Innate immunity The first line of defense is intact skin and mucous membranes. Both mechanical and chemical factors are involved in this first line of defense: Mechanical factors Intact skin – consists of the connective tissue the inner dermis and the outer epidermis which is a continuous sheet of closely packed epithelial cells. The top layer contains a waterproofing protein called keratin. This all provides a formidable physical barrier to the entrance of microorganisms. When the epithelial surface is broken, a subcutaneous infection may develop, frequently by Staph. aureus. Intact skin Innate immunity Intact mucous membranes – also consists of outer epithelial and inner connective tissue layers. Mucous membranes line the digestive, respiratory, urinary, and reproductive tracts. Goblet cells in the epithelial layers secrete mucous to prevent the tracts from drying out and the mucous may act to trap microorganisms that enter. Some pathogens (T. pallidum, M. tuberculosis, S. pneumoniae), however, actually survive in these moist secretions and, if present in sufficient numbers, are able to penetrate the membranes. Innate immunity Cilia – the cells of the mucous membranes of the respiratory tract contain cilia which move synchronously to propel inhaled dust and microorganisms that have become trapped in the mucous, upward toward the throat. Ciliated mucous membranes Innate immunity The lacrimal apparatus of the eye manufactures and drains away tears. By its continual washing action it helps keep microorganisms from settling on the surface of the eye. If something irritates the eye, the lacrimal glands will secrete heavily to wash away the irritating substance. Lacrimal apparatus Innate immunity In a similar cleansing action, saliva produced by the salivary glands, washes microorganisms from the teeth and mucous membranes of the mouth. The mucous membranes of the nose has mucous coated hair that filter inspired air and trap microorganisms, dust and pollutants. The epiglottis, which covers the larynx during swallowing, helps to prevent microorganisms from entering the lower respiratory tract. The flow of urine through the urethra provides a mechanical cleansing of the urinary tract. Innate immunity Chemical factors Sebum produced by the oil glands of the skin provides a protective film over the surface of the skin. It contains unsaturated fatty acids which inhibit the growth of certain bacteria and fungi and contribute to the low pH of the skin which is also inhibitory to the growth of microorganisms. What also contributes to the low pH? What is the relationship between sebum and the acne that sometimes occurs, particularly in adolescents? Perspiration produced by the sweat glands contributes to the high salt content of the skin that is osmotically unfavorable for the growth of many microorganisms. Innate immunity Perspiration, tears, saliva, nasal secretions and tissue fluids all contain lysozyme. What is the activity of lysozyme? Gastric juice produced by the stomach is very acidic and will destroy most bacteria and bacterial toxins. Food particles, however, may protect enteric pathogens from the effects of the acid. Defensins - are cysteine rich peptides produced by the skin that have antibacterial activity Cryptocidins – are antimicrobial peptides produced by the epithelium of the intestine The presence of normal flora may protect from colonization by potentially pathogenic bacteria. How? Innate immunity The second line of defense: Phagocytosis – cells in the human body that counter infection by phagocytosing microorganisms are called phagocytes and they are all either types of white blood cells (WBCs) or derivatives of blood cells. Blood= plasma + the formed elements: RBCs are called erythrocytes Platlets are called thrombocytes WBCs are called leukocytes Innate immunity During a bacterial infection, there is often an increase in the number of leukocytes and this is called a leukocytosis. Some diseases cause a decrease in leukocytes and this is called leukopenia. The source of the increase or decrease of of leukocytes can be determined by performing a differential count. The percentage of each type of WBC is determined by counting 100 WBCs. The normal values are: Formed elements of the blood Innate immunity Note that the WBCs are divided into two basic types, granulocytes, which contain granules and agranulocytes which lack granules, both of which may be phagocytic: Innate immunity What are the basic functions of the various WBCs? PMNs are highly phagocytic and can leave the blood to enter infected tissues to destroy foreign substances Basophils release histamine and heparin in the inflammatory response and in hypersensitivity reactions Eosinophils are somewhat phagocytic. They ingest antigenantibody complexes and are increased during parasitic infections and hypersensitivity reactions. Lymphocytes are found mainly in lymphoid tissue, but some are in circulating blood. They are important in antibody production and in modulating the immune response. Monocytes are poorly phagocytic until stimulated by infection. Then they move into the tissues and differentiate into macrophages which are highly phagocytic. Innate immunity During an infection both PMNs and monocytes, which become macrophages, migrate to the infected area. Neutrophils are the first cell type to arrive at the infected site and are the predominant cell found during the initial stage of the infection. In the latter stages of the infection monocytes will predominate (more on this later). Phagocytosis occurs in two stages: Adherence – this refers to the attachment of the phagocytic cell with the surface of the invading microorganism via a receptor on the phagocytic cell that recognizes structures that are characteristic of microbial pathogens and are not present on mammalian cells (pathogen associated molecular patterns or PAMPs). The receptors are called pattern recognition receptors. PAMPs Innate immunity The pattern recognition receptors are also called toll-like receptors because they resemble, both in structure and function, receptors, called toll receptors, that were originally identified in the innate immune response of Drosophila. Binding of a PAMP to a toll-like receptor triggers a signaling cascade in which a transcription factor is translocated into the nucleus leading to the expression of genes involved in the innate response. When this occurs it is said that the phagocytic cell has been activated. LPS is an example of a PAMP which binds to a toll-like receptor to trigger a subsequent signal transduction pathway that leads to expression of genes involved in the innate response. TLRs and signal transduction pathways LPS activation of innate immunity Innate immunity The process of adherence is facilitated by chemotaxis which is the attraction of phagocytes to the microorganisms via chemical factors (cytokines) released by certain WBCs, damaged tissues, microbial products or peptides derived from the complement cascade (more on this later). Adherence of encapsulated microorganisms is difficult and may occur by two mechanisms: Non-immune or surface phagocytosis – the phagocyte traps the microorganism against a rough surface which the microorganism cannot slide away from. Opsonization – the microorganism is first coated by an opsonin which can be either an antibody or a component of the complement cascade. Phagocytic cells may contain receptors for these opsonins which serve to act as a bridge to promote the attachment of the microorganism to the phagocyte. Opsonization Innate immunity Ingestion is the second stage of phagocytosis and it follows adherence and activation of the phagocytic cell. The microorganism is engulfed by pseudopods. Once the microorganism is surrounded, the phagocytic membrane will fold inward enclosing the microorganism in a sac called a phagosome or phagocytic vacuole. The phagosome will pinch off and enter the cytoplasm where it will fuse with a lysosome. The digestive enzymes present in the lysosome may kill the bacteria. It should be noted that not all bacteria are killed by lososomal enzymes. Phagocytosis and intracellular destruction Mechanism of phagocytosis Innate immunity In addition to killing bacteria via the digestive enzymes present in lysosomes, phagocytic cells have two other mechanisms by which they might kill bacteria (both intra and extracellular): Present in the plasma membrane of the phaocytic cell and in the membrane of the phagosome is a phagocytic oxidase enzyme that is activated to produce reactive oxygen intermediates (ROIs) such as the superoxide radical which may be toxic to bacteria. The process by which ROIs are produced is called the respiratory or oxidative burst. There is also a nitric oxidase synthase that may be activated to produce nitric oxide (NO) which can interact with the ROIs to generate a highly toxic peroxynitrite radical. Microbicidal mechanisms of phagocytes Phagocytosis Innate immunity In addition to killing phagocytosed microbes, activated macrophages serve many other functions in defense against infections including leukocyte recruitment and tissue remodeling. Many of these functions are mediated by cytokines. Cytokines are chemicals produced by in innate immunity, mainly by PMNs, macrophages and NK cells (discussed later). Endothelial cells and epithelial cells may also produce cytokines. Cytokines serve to communicate information among inflammatory cells and between inflammatory cells and responsive tissue cells. More second line defense… Inflammation – damage to the bodies’ tissues will trigger an inflammatory response. The four fundamental symptoms of inflammation are redness, pain, heat, and swelling. There is also sometimes loss of function. Inflammation has the following three functions: To destroy the injurious agent, if possible, and to remove it and its by-products from the body. If destruction is not possible, to wall off the injurious agent and its by-products. To repair or replace damaged tissue. More second line defense Inflammation occurs in three stages: Damage to the tissues causes a release of histamine, kinins, and prostoglandins. The release of these substancees causes vasodilation and increased permeability of the blood vessels. Vasodilation (increase in the diameter of blood vessels) in the area of injury causes an increase in blood flow to the injured area. This causes redness and heat. Increased vascular permeability permits defensive substances normally present in the blood to enter the injured area resulting in edema and swelling. Pain from the pressure of swelling as well as from nerve damage and irritation by toxins will occur. More second line defense Clotting elements are also delivered to the injured area. The clots that form prevent the spreading of the microorganisms and result in a localized collection and pus in a cavity formed by the breakdown of body tissues (an abscess forms). Phagocytic migration occurs. Within one hour phagocytes appear on the scene. As the blood flow decreases, the phagocytic cells begin to stick to the lining of the blood vessels (margination), and then the cells squeeze through the walls of the vessels to move to the damaged area (diapodesis). PMN’s arrive first and are attracted to the area by chemotactic factors. Leokocytosis promoting factor released from inflamed tissues causes the production and release of additional PMNs from the bone marrow. More second line defense As the inflammatory response continues monocytes enter the inflamed area and differentiate into macrophages which are much larger than and several times more phagocytic than the PMNs. After PMNs and macrophages engulf large numbers of microorganisms and tissue, they, themselves, die. A collection of dead cells and various tissue fluids is called pus. Pus formation will continue until the infection subsides. Repair is the last stage of the inflammatory process. This is the process by which tissues replace dead or damaged cells. Inflammation Inflammation More second line defense Fever – fever is a systemic response to infection. Body temperature is controlled by the hypothalamus. Certain antigens such as the LPS can cause the phagocytic cells to release leukocyte pyrogen (IL1) that causes the hypothalamus to release prostoglandins that reset the hypothalmic thermostat at a higher temperature. More second line defense Blood vessel constriction, increased rate of metabolism and shivering will all help to increase the temperature of the body. Thus shivering is a definite sign that body temperature is rising. As the infection subsides, heat losing mechanisms such as vasodilation and sweating will occur. Up to a certain point, a fever is beneficial because it inhibits bacterial growth, intensifies the effects of interferon (discussed later), and may help the body tissues to repair themselves more quickly. However, if body temperature gets too high (>450 C) this may be lethal. More second line defense Antimicrobial substances Interferon (IFN) – interferons are substances produced and released from virally infected cells. Interferons bind to receptors on neighboring cells and, though a signal transduction pathway, induce them to produce anti-viral substances that interfere with viral multiplication and thus protect the cell from viral infection. IFN is host specific, but not viral specific, i.e., interferon in humans will not work in dogs (why?), and when made, IFN is made to protect the neighboring cells from viral infections in general. It doesn’t protect only against a specific virus. IFN production and activity More second line defense Complement and properdin – complement and properdin are a group of proteins found in normal blood serum. They are important in both non-specific and specific antigen- antibody defenses against microbial infection. They function to attack and destroy invading microorganisms and to help stimulate the inflammatory response. The proteins act in an ordered sequence or cascade of reactions. In an ordered sequence of steps, the proteins activate one another usually by cleaving the next protein in the series. The fragments of the cleaved proteins have new enzymatic or physiological functions. More second line defense There are three different, interconnected pathways of complement activation: The classical pathway is activated via an antigen-antibody complex which activates the complement components C1 to an activated C1 complex which then activates C4, and C2 to form another activated complex. This complex next activates C3 which is cleaved into C3a and C3b The lectin pathway is initiated by the binding of a serum protein, mannose-binding lectin (MBL) that is produced during inflammation. MBL binds to mannose residues on glycoproteins or carbohydrates that are on the surface of microorganisms. It functions like an activated C1-like complex. More second line defense The alternate or properdin pathway is activated by cell wall polysaccharides that interact with properdin factors B, D, and P as well as circulating C3b to create a complex that also activates C3 by cleavage into C3a and C3b. C3b produced by all three pathways involves components C5 through C9 in a membrane attack complex that punches a hole in an invading microorganism leading to its cytolysis (a process called complement fixation) C3b, when bound to the surface of a microorganism, can interact with receptors on the surface of phagocytes to promate phagocytosis (opsonization) More second line defense C3a and cleavage products from C5, C6, and C7 can contribute to the development of an acute inflammatory response via their activity on mast cells, platlets and basophils (leads to increased permeability of blood vessels) and their ability to act as chemotactic factors for phagocytic cells. Once activated the destructive capabilities of the complement system are quickly inactivated. Complement activation Lectin pathway Complement fixation Results of complement fixation Complement stimulation of inflammation More second line defense Natural killer (NK) cells – NK cells are large, granular lymphocytes that are activated by three types of targets: Antibody coated cells Cells infected by viruses and some intracellular bacteria Cells lacking class I MHC molecules (more on this later). NK cells express inhibitory receptors that recognize class I MHC molecules, and therefore NK cells are inhibited by class I expressing cells and activated by target cells lacking class I molecules. Some viruses are known to down regulate expression of class I molecules. Activated NK cells lyse the target cells by releasing granules that contain perforin that creates pores in the target cells and granzymes that enter the target cells through the pores and induce apoptosis of the target cell. NK activity NK activity with normal cell NK activity with cell lacking MHC class I molecules Summary of components of innate immunity – note how inner-connected these components are Innate stimulation of adaptive immunity Innate defenses play a major role in stimulating adaptive defenses: