physical barriers (i.e„ skin or mucosal surfaces); overcoming these defensive barriers depends on both host and microbial factors. When these barriers are broken, numerous other host defensive strategies are activated.
Any situation that disrupts the physical barrier of the skin and mucosa, alters the environmental conditions (e.g., loss of stomach acidity or dryness of skin), changes the functioning of surface cells, or alters the normal flora population can facilitate the penetration of microorganisms past the barriers and into deeper host tissues. Disruptive factors may vary from acddental or intentional (medical) trauma that result in surface destruction to the use of antibiotics that remove normal, protective, colonizing microorganisms (Box 3-4). Importantly, a number of these factors are related to medical activities and procedures.
Once surface barriers have been bypassed, the host responds to microbial presence in the underlying tissue in various ways. Some of these responses are nonspecific because they occur regardless of the type of invading organism, whereas other responses are more specific and involve the host's immune system. Both nonspecific and specific host responses are critical if the host is to survive. Without them, microorganisms would multiply and invade vital tissues and organs unchecked, resulting in severe damage to the host.
Nonspecific Responses. Some nonspecific responses are biochemical; others are cellular. Biochemical factors remove essential nutrients, such as iron, from tissues so that they cannot be used by invading microorganisms. Cellular responses are central to tissue and organ defenses, and the cells involved are known as phagocytes.
In phagolysosome there is release of lysozyme and other toxic substances
O Long-term survival of Q Bacterial destruction Q Destruction of phagocyte bacteria in phagocyte
Figure 3-6 Overview of phagocyte activity and possible outcomes of phagocyte-bacterial interactions.
Phagocytes. Phagocytes are cells that ingest and destroy bacteria and other foreign particles. The two types of phagocytes are polymorphonuclear leukocytes (also known as PMNs or neutrophils) and macrophages. Phagocytes ingest bacteria by a process known as endocytosis and engulf them in a membrane-lined structure called a phagosome (Figure 3-6). The phagosome is then fused with a second structure, the lysosome. When the lysosome, which contains toxic chemicals and destructive enzymes, combines with the phagosome, the bacteria trapped within are neutralized and destroyed. This destructive process must be carried out inside membrane-lined structures; otherwise the noxious substances contained within would destroy the phagocyte itself. This is evident during the course of rampant infections when thousands of phagocytes exhibit "sloppy" ingestion of the microorganisms and toxic substances spill from the cells, thus damaging the surrounding host tissue.
Although both PMNs and macrophages are phagocytes, these cell types differ. PMNs develop in the bone marrow and spend their short lives, usually a day or less, circulating in blood and tissues. Widely dispersed in the body, PMNs usually are the first cells on the scene of bacterial invasion. Macrophages also develop in the bone marrow but first go through a cellular phase when they are called monocytes. During the monocyte stage, the cells circulate in the blood. When deposited in tissue or at a site of infection, monocytes mature into macrophages. In the absence of infection, macrophages usually reside in specific organs, such as the spleen, lymph nodes, liver, or lungs, where they may live for days to several weeks awaiting encounters with invading bacteria. In addition to the ingestion and destruction of bacteria, macrophages play an important role in mediating immune system defenses (see Specific Responses— The Immune System later in this chapter).
In addition to the inhibition of microbial proliferation by phagocytes and by biochemical substances such as lysozyme, microorganisms are "washed" from tissues by the flow of lymph fluid. The fluid carries infectious agents through the lymphatic system, where they are deposited in tissues and organs (e.g., lymph nodes and spleen) heavily populated with phagocytes. This process functions as an efficient filtration system.
BOX 3-5 Components of Inflammation component
Phagocytes (PMNs and macrophages) Complement system (coordinated group of serum proteins)
Coagulation system (wide variety of proteins and other biologically active compounds)
Cytokines (proteins secreted by macrophages and other cells)
Attracts phagocytes to site of infection Helps phagocytes recognize and bind to bacteria Directly kills gram-negative bacteria Attracts phagocytes to site of infection Increases blood and fluid flow to site of infection Walls off site of infection to physically inhibit spread of microorganisms Multiple effects that enhance the activities of many different cells essential to nonspecific and specific defensive responses
Inflammation. Because microbes may survive initial encounters with phagocytes (see Figure 3-6), the inflammatory response plays an extremely important role as a reinforcement mechanism against microbial survival and proliferation in tissues and organs. Inflammation has both cellular and biochemical components that interact in various complex ways (Box 3-5).
The complement system is composed of a coordinated group of proteins that are activated by the immune system or by the mere presence of invading microorganisms. On activation of this system, a cascade of biochemical events occurs that attracts and enhances the activities of more phagocytes. Because PMNs and macrophages are widely dispersed throughout the body, signals are needed to attract and concentrate these cells at the point of invasion. The complement system provides many of these signals.
Protective functions of the complement system also are enhanced by the coagulation system, which works to increase blood flow to the area of infection and can also effectively wall off the infection through the production of barrier substances.
Another key component of inflammation is a group of biochemicals known as cytokines, substances secreted by one type of cell that have substantial effects on the antiinfective activities of other cells.
On a microscopic level, the presence of phagocytes at the infection site is an important observation in diagnostic microbiology. Microorganisms seen associated with these host cells are frequently identified as the cause of a particular infection. An overview of inflammation is shown in Figure 3-7.
SPECIFIC RESPONSES—THE IMMUNE SYSTEM
The immune system provides the human host with the ability to mount a specific protective response to the presence of a microorganism, a customized defense against the invading microorganism. In addition to this specificity, the immune system has a "memory" so that if a microorganism is encountered a second or third time, an immune-mediated defensive response is immediately available. It is important to remember that nonspecific (i.e., phagocytes, inflammation) and specific (i.e„ the immune system) host defensive systems are interdependent in their efforts to limit the spread of infection.
Components of the Immune System
The central molecule of the immune response is the antibody. Antibodies, also referred to as immunoglobulins, are specific proteins produced by certain cells in response to the presence of foreign molecules known as antigens. In the case of infectious diseases, the antigens are components of the invading microorganism's structure that are usually composed of proteins or polysaccharides. Antibodies circulate in the serum portion of the host's blood and are present in secretions such as saliva. These molecules have two active areas: the antigen binding site and the phagocyte binding site (Figure 3-8).
There are five different classes of antibody: IgG, IgA, IgM, IgD, and IgE. Each class has distinctive molecular configurations. IgG, IgM, IgA, and IgE are most involved in combating infections. IgM is the first antibody produced when an invading microorganism is initially encountered; production of the most abundant antibody, IgG, follows. IgA is secreted in various body fluids and primarily protects those body surfaces lined with mucous membranes. Increased IgE is associated with various parasitic infections. As is discussed in Chapter 10, our ability to measure specific antibody production is a valuable tool for the laboratory diagnosis of infectious diseases.
Regarding the cellular components of the immune response, there are three major types of cells: B lymphocytes, T lymphocytes, and natural killer cells. The functions of these cells are summarized in Box 3-6. B lymphocytes originate from stem cells and develop into B cells in the bone marrow before being widely
BOX 3-6 Cells of the Immune System b LYMPHOCYTES (b CELLS)
Residence: Lymphoid tissues (lymph nodes, spleen, gut-
associated lymphoid tissue, tonsils) Function: Antibody-producing cells Subtypes:
B lymphocytes; cells waiting to be stimulated by an antigen Plasma cells; activated B lymphocytes that are actively secreting antibody in response to an antigen B-memory cells; long-lived cells programmed to remember antigens T LYMPHOCYTES (T CELLS)
Residence: Circulate and reside in lymphoid tissues (lymph nodes, spleen, gut-associated lymphoid tissue, tonsils) Functions: Multiple, see different subtypes Subtypes:
Helper T cells (TH); interact with B cells to facilitate antibody production
Cytotoxic T cells (TC); recognize and destroy host cells that have been invaded by microorganisms Suppressor T cells (TS); shut down immune response when no longer needed NATURAL KILLER CELLS (NK CELLS): Function similar to cytotoxic T cells but do not require stimulation by presence of antigen to function distributed to lymphoid tissues throughout the body. These cells primarily function as antibody producers. T lymphocytes also originate from bone marrow stem cells, but they mature in the thymus and either directly destroy infected cells or work with B cells to regulate antibody production. The development of natural killer cells, which destroy infected or malignant host cells, is uncertain. Each of the three cell types is strategically located within lymphoid tissue throughout the body to maximize the chances of encountering invading microorganisms that the lymphatic system drains from the infection site.
Antibody-mediated immunity is centered on the activities of B cells and the production of antibodies. When B cells encounter microbial antigen, they become activated and a series of events are initiated. These events are mediated by the activities of helper T cells and the release of cytokines. Cytokines mediate an explosion in the number of B cells that recognize the antigen and the maturation of B cells into plasma cells that produce tremendous amounts of antibodies
1, Clonal expansion = multiplication of B cells that specifically recognize antigen that stimulated activation
Ffgm 3-9 Overview of B-cell activation that is central to antibody-mediated immunity.
specific for the antigen. The process also results in the production of B-memory cells (Figure 3-9).
Because a population of activated specific B cells usually is not ready for all microbial antigens, antibody production is delayed when the host is first exposed to an infectious agent. This delay in the primary antibody response underscores the importance of nonspecific response defenses, such as inflammation, that work to hold the invading organisms in check while antibody production begins. This also emphasizes the importance of B-memory cell production. By virtue of this memory, any subsequent exposure to the same microorganism will result in a rapid, overwhelming production of protective antibodies so the body is spared the delays that are characteristic of the primary exposure.
Some antigens, such as bacterial capsules and outer membranes, activate B cells to produce antibodies without the intervention of helper T cells. However, this activation does not result in production of B-memory cells so that on reexposure to the same bacterial antigens, there will be no rapid memory response on the part of the host.
The primary cells that mediate cell-mediated immunity are T lymphocytes that recognize and destroy human host cells infected with microorganisms. This function is extremely important for the destruction and elimination of infecting microorganisms (e.g„ viruses, tuberculosis, some parasites, and fungi) that are able to survive within host cells where they are "hidden" from antibody action. Therefore, antibody-mediated immunity targets microorganisms outside of human cells while cell-mediated immunity targets microorganisms inside human cells. However, in many instances these two arms of the immune system overlap and work together.
Like B cells, T cells must be activated. Activation is accomplished by T-cell interactions with other cells that process microbial antigens and present them on their surface (e.g., macrophages and B cells). The responses of activated T cells are very different and depend on the subtype of T cell (Figure 3-10), Activated helper T cells work with B cells for antibody production (see Figure 3-9) and facilitate inflammation by releasing cytokines. Cytotoxic T cells directly interact with and destroy host cells that contain microorganisms. The T-cell subset, helper or cytotoxic cells, that is activated is controlled by an extremely complex series of molecular and genetic events known as the major histocompatibility complex, or MHC, which is a part of cells that present antigens to the T cells.
In summary, the host presents a spectrum of challenges to invading microorganisms, from the physical barriers of skin and mucous membranes to the interactive cellular and biochemical components of inflammation and the immune system. All these systems work together to minimize microbial invasion
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