To establish an infection, an invading microorganism must first overcome many surface barriers, such as skin, degradative enzymes and mucus.
These surface barriers have either direct antimicrobial activity or inhibit attachment of the microorganism to the host. Any microorganism that penetrates these barriers encounters two levels of resistance: nonspecific resistance mechanisms and the specific immune response.
The term immunity (Latin immunis, free of burden) refers to the general ability of a host to resist infection or disease. There are two interdependent components of the immune response to invading microorganisms and foreign material. They are non-specific immune response or innate immunity or natural immunity and specific immune response or acquired immunity or adaptive immunity.
Innate immunity refers to those general defence mechanisms that are inherited as part of the innate structure and function of each animal (such as skin, mucus and lysozyme). Innate immunity is the first line of defence against any microorganism or foreign material encountered by the vertebrate host. Innate immunity defends against foreign invaders equally and lacks immunological memory.
Acquired immunity refers to the type of specific immunity that develops after exposure to a suitable antigen. The effectiveness of acquired immunity increases on repeated exposure to foreign agents such as viruses, bacteria or toxins. So acquired immunity has memory. The innate immunity and acquired immunity work together to eliminate pathogenic microorganisms and other foreign agents. Although innate systems predominate immediately upon initial exposure to foreign substances, multiple bridges occur between innate and acquired immune system components (Figure 13.17).
A potential microbial pathogen invading a human host immediately confronts a vast array of nonspecific defence mechanisms. Many direct factors (nutrition, physiology, fever, age, genetics) and equally as many indirect factors (personal hygiene, socioeconomic status, living conditions) influence all host microbe relationships. In addition to these direct and indirect factors, a vertebrate host has the following four non specific defence mechanisms.
A. Physical barriers
B. Chemical mediators
Intact skin contributes greatly to host resistance. It forms a very effective mechanical barrier to microbial invasion. Its outer layer consists of thick, closely packed cells called keratinocytes, The skin is slightly acidic (around pH 5-6) due to skin oil, secretion from sweat glands and organic acids produced by commensal Staphylococci. It also contains a high concentration of sodium chloride and is subject to periodic drying.
The mucous membranes of the eye (conjunctiva), the respiratory, digestive and urogenital systems withstand microbial invasion. The intact stratified squamous epithelium and mucus secretions form a protective covering that resists penetration and traps many microorganisms. Many mucosal surfaces are bathed in specific antimicrobial secretions. One antibacterial substance in these secretions is lysozyme, an enzyme that lyses bacteria. Mucous secretions possess the iron binding protein, lactoferrin. Lactoferrin sequesters iron from the plasma reducing the amount of iron available to invading microbial pathogens and prevents their ability to multiply. Mucous membranes produce lactoperoxidase, an enzyme that catalyzes the production of superoxide radicals, reactive oxygen intermediate that is toxic to many microorganisms.
The mammalian respiratory system has strong defense mechanisms. The average person inhales at least eight microorganisms a minute or 10,000 each. Microbes larger than 10μm are trapped by hairs and cilia lining the nasal cavity. The cilia in the nasal cavity beat toward the pharynx, so that mucus with its trapped microorganisms is moved toward the mouth and expelled. Microbes smaller than 10μm pass through the nasal cavity and are trapped by the mucociliary blanket and the trapped microbes are transported by ciliary action that moves them away from lungs. Coughing and sneezing reflexes clear the respiratory system of microorganisms by expelling air forcefully from the lungs through the mouth and nose, respectively. Salivation also washes microorganisms from the mouth and nasopharyngeal areas into the stomach.
Most microorganisms that reach the stomach are killed by gastric juice. (pH 2-3). However, organisms embedded in food particles are protected from gastric juice and reach the small intestine. There microorganisms are damaged by various pancreatic enzymes, bile, enzymes in intestinal secretions and GALT system. Normal microbiota of the large intestine is important in preventing the establishment of pathogens. The mucous membranes of the intestinal tract contain paneth cells. These cells produce lysozyme and cryptins (toxic for bacteria).
Under normal circumstances, the kidneys, ureters and urinary bladder of mammals are sterile. Urine within the urinary bladder is also sterile. In addition to removing microbes by flushing action, urine kills some bacteria due to its low pH and the presence of urea and other metabolic end products (uric acid, hippuric acid, indican, fatty acids, mucin, and enzymes). The acidic environment (pH 3-5) of the vagina is unfavorable to most microbes.
The conjunctiva is specialized mucus secreting epithelial membrane that lines the interior surface of each eyelid and the exposed surface of the eye ball. It is kept moist by the continuous flushing action of tears. Tears contain large amounts of lysozyme, lactoferrin, and antibody and thus provide chemical as well as physical protection (Figure 13.18).
They are low molecular weight proteins that exhibit broad spectrum antimicrobial activity toward bacteria.
Cationic peptides are found in humans. There are three generic classes of cationic peptides that have the ability to damage bacterial plasma membrane.
Bacteriocins are produced by gram negative and gram positive bacteria. For example, Escherichia coli synthesize bacteriocins called colicins. Colicins causes cell lysis.
Cytokines are proteins made by cells that affect the behavior of other cells. When released from mononuclear phagocytes, they are called monokines. When released from T lymphocytes they are called lymphokines. When released from leukocytes they are called interleukins. Cytokines are required for regulation of both the nonspecific and specific immune responses. Interferons (IFNS) are a group of cytokines produced by virus infected cells. Several classes of interferons are recognized. IFN γ is synthesized by virus infected leukocytes, antigen stimulated T cells and natural killer cells. IFN α / β is derived from virus infected fibroblasts. Interferons prevent viral replication and assembly, thereby limiting viral infection.
Another group of noteworthy cytokines are endogenous pyrogens which elicit fever in the host. Examples of endogenous pyrogens include interleukin – 1, Interleukin – 6 and tissue necrosis factor. All are produced by host macrophages in response to pathogens.
The complement system is a part of the immune system, consists of a series of proteins that interact with one another in a highly regulated manner, in order to eliminate pathogens. Complements are soluble proteins and glycoproteins mostly produced by hepatocytes. More than 20 types of complements are present in serum found circulating normally in human body in inactive forms (called as zymogens or proenzymes). Complement activation is triggered by an antibody when it is bound to the antigen. It can also be triggered by some components of innate immunity. Thus the complement system works in both innate and acquired immunity.
The complement activation occurs via three pathways which are:
1. Classical pathway
2. Alternative pathway
3. Lectin pathway (or mannose binding lectin pathway)
Classical pathway, activated by antigen-antibody reaction, Alternative pathway, activated on microbial cell surfaces, and Mannose binding Lectin pathway, activated by a plasma lectin that binds to mannose residues on microbes (Figure 13.19).
Some major functions of complements are:
· Opsonization and phagocytosis
· Cell lysis
· Activation of mast cells and basophils and enhancement of inflammation
· Production of antibodies
· Immune clearance and inflamma-tion by attracting macrophages and neutrophils.
i. Phagocytosis is the ingestion by phagocytic cells of invading foreign particles such as bacteria. After ingestion, the foreign particle is entrapped in a phagocytic vacuole (phagosome), which fuses with lysosomes forming the phagolysosome. The lysosomes release their powerful lytic enzymes which digest the particle. (Figure 13.20). Phagocytosis is conducted by blood monocytes, neutrophils and tissue macrophages. Phagocytosis may be enhanced by a variety of factors collectively referred to as opsonins which consist of antibodies and various serum components of complement.
ii. Phagocytic cells use two basic mechanisms for the recognition of microorganisms. Opsonin dependent and opsonin independent
iii. Phagocytesuse pathogen recognition receptors to detect pathogen associated molecular patterns on microorganisms. Toll like receptors are a distinct class of pathogen recognition receptors.
Tissue damage caused by a wound or by an invading pathogenic microorganism induces a complex sequence of events collectively known as inflammatory response. Inflammation can either be acute or chronic. The gross features were described over 2000 years ago and are still known as the cardinal signs of inflammation: redness (rubor), warmth (calor), pain (dolor), swelling (tumor), and loss of function (functiolaesa)
The cardinal signs of inflammation reflect the three major events of an inflammatory response.
1. Vasodilation (an increase in the diameter of blood vessels) of nearby capillaries occurs as the vessels that carry blood away from the affected area constrict. This results in engorgement of the capillary network. The engorged capillaries are responsible for tissue redness (erythema) and an increase in temperature.
2. An increase in capillary permeability facilitates an influx of fluid and cells from the engorged capillaries into the tissue. The fluid that accumulates (exudate) has much higher protein content. Accumulation of exudate contributes to tissue swelling (edema)
3. Influx of phagocytes from the capillaries into the tissues is facilitated by increased capillary permeability. As phagocytic cells accumulate at the site and begin to phagocytoses bacteria, they release lytic enzymes, which can damage nearby healthy cells. The accumulation of dead cells, digested material and fluid forms substances called pus.
Lower animal forms possessso called innate or non-specific immune mechanisms such as phagocytosis of bacteria by specialized cells. Higher animals have evolved an adaptive or acquired immune response. This acquired immune response provides a flexible, specific and more effective reaction to different infections.
Acquired (adaptive)immunity refers to the type of specific immunity that a host develops after exposure to a suitable antigen.
This is the immunity one develops throughout life time. Adaptive or acquired immunity has four important features namely (1) Memory (2) Specificity diversity and (4) discrimination between self and non self.
We rarely suffer twice from diseases such as measles, mumps, chicken pox, whooping cough and so on. The first contact with an infectious organism clearly imprints some memory so that the body is effectively prepared to repel any later invasion by that organism.
By following the production of antibody on the first and second contact with antigen, we can know the basis for the development of immunity. For example, when we inject a bacterial product such as staphylococcal toxoid into a rabbit, several days elapse before antibodies can be detected in the blood. These reach a peak and then fall. If we now allow the animal to rest and then give a second injection of staphylococcal toxoid, the cause of events is dramatically altered. Within two to three days the antibody level in the blood raises steeply to reach much higher values than were observed in the primary response. This secondary response is characterized by a more rapid and more abundant production of antibody. This explosive production of antibodies is due to the tuning up of the antibody forming system to provide a population of memory cells after first exposure to antigen. The principle of memory is involved in vaccination.
The establishment of immunity by one organism does not provide protection against another unrelated organism. After an attack of measles we are immune to further infection but are susceptible to polio or mumps viruses. Thus the body can differentiate specifically between the two organisms.
The immune system is able to generate an enormous diversity of molecules such as cellular receptors and soluble proteins, including antibodies that recognize trillions of different foreign substances.
The specific immune system almost responds selectively to non self and produces specific responses against the stimulus. This is possible because host cells express a unique protein on their surface, making them as residents of that host or as self. Thus the introduction of materials lacking that unique self marker results in their attack by the host.
Two branches or arms of specific immunity are recognized: humoral (antibody mediated) immunity and cellular (cell mediated) immunity (Figure 13.21).
The antigen specific arm of the humoral immunity consists of the B cells. Each B cell expresses a unique antigen binding receptor on its membrane. The B cell receptor (BCR) is membrane bound antibody molecule. When a naive B cell first encounters the antigen that matches its membrane bound antibody, the binding of the antigen to the antibody causes the cell to divide rapidly. Its progeny differentiate into memory B cells and antibody secreting plasma cells. A single plasma cell can secrete more than 2000 molecules of antibody per second. Circulating antibodies bind to microorganisms, toxins and extracellular viruses, neutralizing them or tagging them for destruction by phagocytes and other mechanisms.
The cellular (cell mediated) immunity consists of the T cells. Each T cell expresses antigen receptors called T cell receptors (TCRS). Unlike membrane bound antibody on B cells, which can recognize antigen alone, T cell receptors can recognize only antigen that is bound to MHC molecules. There are two major types of MHC molecules. Class I MHC molecules are expressed by all nucleated cells. Class II MHC molecules are expressed only by antigen presenting cells such as dendritic cells, macrophages and B cells. When a naive T cell encounters antigen combined with an MHC molecule on a cell, the T cell proliferates and differentiates into memory T cells and various effector T cells (helper T cells, cytotoxic T cells and regulatory T cells). Specific kinds of T cells directly attack target cells infected with viruses or parasites, transplanted cells or organs and cancer cells. T cells can induce target cell suicide (apoptosis), lyse targets cells, or release chemicals (cytokines) that enhance specific immunity and non specific defences such as phagocytosis and inflammation.
Specific immunity can be acquired by natural means actively through infection or passively through receipt of preformed antibodies as through colostrum. Specific immunity can be acquired by artificial means actively through immunization or passively through receipt of preformed antibodies as with antisera.