IMMUNE FUNCTION: DEFENSES AND RESPONSES There are two general types of immunity: natural (innate) and acquired

(adaptive). Natural immunity is a nonspecific immunity present at birth. Acquired or specific immunity develops after birth. Natural immune responses to a foreign invader are very similar from one encounter to the next regardless of the number of times the invader is encountered; in contrast, acquired responses increase in intensity with repeated exposure to the invading agent (Delves & Roitt, 2000a). Although each type of immunity plays a distinct role in defending the body against harmful invaders, the various components usually act in an interdependent manner. Natural Immunity Natural (innate) immunity provides a nonspecific response to any foreign invader, regardless of the invaders composition. The basis of natural defense mechanisms is the ability to distinguish between friend and foe or self and nonself. Such natural mechanisms include physical and chemical barriers, the action of WBCs, and inflammatory responses. PHYSICAL AND CHEMICAL BARRIERS Physical surface barriers include intact skin and mucous membranes, which prevent pathogens from gaining access to the body, and the cilia of the respiratory tract along with coughing and sneezing responses, which act to filter and clear pathogens from the upper respiratory tract before they can invade the body further. Chemical barriers, such as acidic gastric secretions, mucus, enzymes in tears and saliva, and substances in sebaceous and sweat secretions, act in a nonspecific way to destroy invading bacteria and fungi. Viruses are countered by other means, such as interferon. Interferon, one type of biologic response modifier, is a nonspecific viricidal protein naturally produced by the body that is capable of activating other components of the immune system. WHITE BLOOD CELL ACTION

WBCs, or leukocytes, participate in both the natural and the acquired immune responses. Granular leukocytes, or granulocytes (so called because of granules in their cytoplasm), fight invasion by foreign bodies or toxins by releasing cell mediators, such as histamine, bradykinin, and prostaglandins, and engulfing the foreign bodies or toxins. Granulocytes include neutrophils, eosinophils, and basophils. Neutrophils (also called polymorphonuclear leukocytes, or PMNs, because their nuclei have multiple lobes) are the first cells to arrive at the site where inflammation occurs. Eosinophils and basophils, other types of granulocytes, increase in number during allergic reactions and stress responses. Nongranular leukocytes include monocytes or macrophages (referred to as histiocytes when they enter tissue spaces) and lymphocytes. Monocytes also function as phagocytic cells, engulfing, ingesting, and destroying greater numbers and quantities of foreign bodies or toxins than granulocytes. Lymphocytes, consisting of B cells and T cells, play major roles in humoral and cellmediated immune responses. About 60% to 70% of lymphocytes in the blood are T cells, and about 10% to 20% are B cells (Porth, 2002). INFLAMMATORY RESPONSE The inflammatory response is a major function of the natural (nonspecific or innate) immune system elicited in response to tissue injury or invading organisms. Chemical mediators assist this response by minimizing blood loss, walling off the invading organism, activating phagocytes, and promoting formation of fibrous scar tissue and regeneration of injured tissue. Dysfunction of the natural immune system can occur when the immune components are inactivated or when they remain active long after their effects are beneficial. Immunodeficiencies are characterized by inactivation or impairment of immune components, and disorders with an inflammatory component (eg, asthma, allergy, arthritis) are characterized by persistent

inflammatory responses (Medahitov & Janeway, 2000). The immune systems recognition of ones own tissues as foreign rather than as self is the basis for many autoimmune disorders. Acquired Immunity Acquired (adaptive) immunityimmunologic responses acquired during life but not present at birthusually develops as a result of prior exposure to an antigen through immunization (vaccination) or by contracting a disease, both of which generate a protectiveimmune response. Weeks or months after exposure to the disease or vaccine, the body produces an immune response that is sufficient to defend against the disease upon re-exposure to it. The two types of acquired immunity are known as active and passive. In active acquired immunity, the immunologic defenses are developed by the persons own body. This immunity generally lasts many years or even a lifetime. Passive acquired immunity is temporary immunity transmitted from another source that has developed immunity through previous disease or immunization. For example, immune globulin and antiserum, obtained from the blood plasma of people with acquired immunity, are used in emergencies to provide immunity to diseases when the risk for contracting a specific disease is great and there is not enough time for a person to develop adequate active immunity. For example, immune globulin may be administered to those exposed to hepatitis. Immunity resulting from the transfer of antibodies from the mother to an infant in utero or through breastfeeding is another example of passive immunity. Active and passive acquired immunity involve humoral and cellular (cell-mediated) immunologic responses (described later in this chapter) (Ada, 2001). Response to Invasion When the body is invaded or attacked by bacteria, viruses, or other pathogens, it has three means of defending itself: The phagocytic immune response The humoral or antibody immune response The cellular immune response

The first line of defense, the phagocytic immune response, involves the WBCs (granulocytes and macrophages), which have the ability to ingest foreign particles. These cells move to the point of attack, where they engulf and destroy the invading agents. Phagocytes also remove the bodys own dying or dead cells. Cells in necrotic tissue that are dying release substances that trigger an inflammatory response. Apoptosis, or programmed cell death, is the bodys way of destroying unwanted cells such as cancer cells or cells that die a natural death. Apoptosis involves the digestion of DNA by endonucleases, resulting in the cells being targeted for phagocytosis (Delves & Roitt, 2000a). Unlike macrophages, eosinophils are only weakly phagocytic. On activation, eosinophils probably kill parasites by releasing specific chemical mediators into the extracellular fluid. Additionally, they secrete leukotrienes, prostaglandins, and various cytokines. A second protective response, the humoral immune response (sometimes called the antibody response), begins with the B lymphocytes, which can transform themselves into plasma cells that manufacture antibodies. These antibodies, highly specific proteins, are transported in the bloodstream and attempt to disable the invaders. The third mechanism of defense, the cellular immune response, also involves the T lymphocytes, which can turn into special cytotoxic (or killer) T cells that can attack the pathogens themselves. The part of the invading or attacking organism that is responsible for stimulating antibody production is called an antigen (or an immunogen). For example, an antigen can be a small patch of proteins on the outer surface of the microorganism. Not all antigens are naturally immunogenic and must be coupled to other molecules to stimulate the immune response. A single bacterium, even a single large molecule, such as a toxin (diphtheria or tetanus toxin), may have several such antigens, or markers, on its surface, thus inducing the body to produce a number of different antibodies. Once produced, an antibody is released into the bloodstream and carried to the attacking organism. There it

combines with the antigen, binding with it like an interlocking piece of a jigsaw puzzle (Fig. 50-4). There are four well-defined stages in an immune response: recognition, proliferation, response, and effector. RECOGNITION STAGE Recognition of antigens as foreign, or nonself, by the immune system is the initiating event in any immune response. The body must first recognize invaders as foreign before it can react to them. The body accomplishes recognition using lymph nodes and lymphocytes for surveillance. Lymph nodes are widely distributed internally throughout the body and in the circulating blood, and externally near the bodys surfaces. They continuously discharge small lymphocytes into the bloodstream. These lymphocytes patrol the tissues and vessels that drain the areas served by that node. Lymphocytes recirculate from the blood to lymph nodes and from the lymph nodes back into the bloodstream, in a neverending series of patrols. Some circulating lymphocytes can survive for decades. Some of these small, hardy cells maintain their solitary circuits for the persons lifetime. The exact way in which circulating lymphocytes recognize antigens on foreign surfaces is not known; however, recognition is thought to depend on specific receptor sites on the surface of the lymphocytes. Macrophages play an important role in helping the circulating lymphocytes process the antigens. Both macrophages and neutrophils have receptors for antibodies and complement; as a result, the coating of microorganisms with antibodies, complement, or both enhances phagocytosis. The engulfed microorganisms are then subjected to a wide range of toxic intracellular molecules. When foreign materials enter the body, a circulating lymphocyte comes into physical contact with the surfaces of these materials.

Upon contact, the lymphocyte, with the help of macrophages, either removes the antigen from the surface or in some way picks up an imprint of its structure, which comes into play with subsequent re-exposure to the antigen. In a streptococcal throat infection, for example, the streptococcal organism gains access to the mucous membranes of the throat. A circulating lymphocyte moving through the tissues of the neck comes in contact with the organism. The lymphocyte, familiar with the surface markers on the cells of its own body, recognizes the antigens on the microbe as different (nonself) and the streptococcal organism as antigenic (foreign). This triggers the second stage of the immune response proliferation. PROLIFERATION STAGE The circulating lymphocyte containing the antigenic message returns to the nearest lymph node. Once in the node, the sensitized lymphocyte stimulates some of the resident dormant T and B lymphocytes to enlarge, divide, and proliferate. T lymphocytes differentiate into cytotoxic (or killer) T cells, whereas B lymphocytes produce and release antibodies. Enlargement of the lymph nodes in the neck in conjunction with a sore throat is one example of the immune response. RESPONSE STAGE In the response stage, the changed lymphocytes function either in a humoral or a cellular fashion. The production of antibodies by the B lymphocytes in response to a specific antigen begins the humoral response. Humoral refers to the fact that the antibodies are released into the bloodstream and so reside in the plasma (fluid fraction of the blood). With the initial cellular response, the returning sensitized lymphocytes migrate to areas of the lymph node (other than those areas containing lymphocytes programmed to become plasma cells). Here, they stimulate the residing lymphocytes to become cells that will attack microbes directly rather than through the action of antibodies. These

transformed lymphocytes cytotoxic (killer) T cells.

are

known

as

foreign substance antibodies.

and

in

producing

The T stands for thymus, signifying that during embryologic development of the immune system, these T lymphocytes spent time in the thymus of the developing fetus, where they were genetically programmed to become T lymphocytes rather than the antibodyproducing B lymphocytes. Viral rather than bacterial antigens induce a cellular response. This response is manifested by the increasing number of T lymphocytes (lymphocytosis) seen in the blood smears of people with viral illnesses, such as infectious mononucleosis. (Cellular immunity is discussed in further detail later in this chapter.) Most immune responses to antigens involve both humoral and cellular responses, although one usually predominates. For example, during transplantation rejection, the cellular response predominates, whereas in the bacterial pneumonias and sepsis, the humoral response plays the dominant protective role (Chart 50-1). EFFECTOR STAGE In the effector stage, either the antibody of the humoral response or the cytotoxic (killer) T cell of the cellular response reaches and couples with the antigen on the surface of the foreign invader. The coupling initiates a series of events that in most instances results in the total destruction of the invading microbes or the complete neutralization of the toxin. The events involve an interplay of antibodies (humoral immunity), complement, and action by the cytotoxic T cells (cellular immunity). Figure 50-5 summarizes the stages of the immune response. Humoral Immune Response The humoral response is characterized by production of antibodies by the B lymphocytes in response to a specific antigen. Although the B lymphocyte is ultimately responsible for the production of antibodies, both the macrophages of natural immunity and the special T-cell lymphocytes of cellular immunity are involved in recognizing the

ANTIGEN RECOGNITION Several theories exist about the mechanisms by which the B lymphocytes recognize the invading antigen and respond by producing antibodies. This is probably because the B lymphocytes recognize invading antigens in more than one way and respond in several ways as well. Additionally, the B lymphocytes appear to respond to some antigens by triggering antibody formation directly. In response to other antigens, however, they need the assistance of T cells to trigger antibody formation. T cells (or T lymphocytes), part of a surveillance system dispersed throughout the body, recycle through the general circulation, tissues, and lymphatic system. With the assistance of macrophages, the T lymphocytes are believed to recognize the antigen of a foreign invader. The T lymphocyte picks up the antigenic message, or blueprint, of the antigen and returns to the nearest lymph node with that message. Production of B Lymphocytes. B lymphocytes stored in the lymph nodes are subdivided into thousands of clones, each responsive to a single group of antigens having almost identical characteristics. When the antigenic message is carried back to the lymph node, specific clones of the B lymphocyte are stimulated to enlarge, divide, proliferate, and differentiate into plasma cells capable of producing specific antibodies to the antigen. Other B lymphocytes differentiate into Blymphocyte clones with a memory for the antigen. These memory cells are responsible for the more exaggerated and rapid immune response in a person who is repeatedly exposed to the same antigen. ROLE OF ANTIBODIES Antibodies are large proteins called immunoglobulins because they are found in the globulin fraction of the plasma proteins. All immunoglobulins are glycoproteins and contain a certain amount of carbohydrate. The

carbohydrate concentration, which ranges from approximately 3% to 13%, is dependent upon the class of the antibody. Each antibody molecule consists of two subunits, each of which contains a light and a heavy peptide chain (Fig. 50-6). The subunits are held together by a chemical link composed of disulfide bonds. Each subunit has a portion that serves as a binding site for a specific antigen referred to as the Fab fragment. This site provides the lock portion that is highly specific for an antigen. An additional portion, known as the Fc fragment, allows the antibody molecule to take part in the complement system. Antibodies defend against foreign invaders in several ways, and the type of defense employed depends on the structure and composition of both the antigen and the immunoglobulin. The antibody molecule has at least two combining sites, or Fab fragments. One antibody can act as a cross-link between two antigens, causing them to bind or clump together. This clumping effect, referred to as agglutination, helps clear the body of the invading organism by facilitating phagocytosis. Some antibodies assist in removing offending organisms through opsonization. In this process, the antigenantibody molecule is coated with a sticky substance that also facilitates phagocytosis. Antibodies also promote the release of vasoactive substances, such as histamine and slow-reacting substance, two of the chemical mediators of the inflammatory response. Antibodies do not function in isolation but rather mobilize other components of the immune system to defend against the invader. Their usual role is to focus components of the natural immune system on the invader. This includes activation of the complement system and activation of phagocytosis (Delves & Roitt, 2000a). Types of Immunoglobulins. The body can produce five different types of immunoglobulins. (Immunoglobulins are commonly designated by the abbreviation

Ig.) Each of the five types, or classes, is identified by a specific letter of the alphabet (IgA, IgD, IgE, IgG, and IgM). Classification is based on the chemical structure and biologic role of the individual immunoglobulin. The following list summarizes major characteristics of the immunoglobulins: IgG (75% of Total Immunoglobulin) Appears in serum and tissues (interstitial fluid) Assumes a major role in bloodborne and tissue infections Activates the complement system Enhances phagocytosis Crosses the placenta IgA (15% of Total Immunoglobulin) Appears in body fluids (blood, saliva, tears, breast milk, and pulmonary, gastrointestinal, prostatic, and vaginal secretions) Protects against respiratory, gastrointestinal, and genitourinary infections Prevents absorption of antigens from food Passes to neonate in breast milk for protection IgM (10% of Total Immunoglobulin) Appears mostly in intravascular serum Appears as the first immunoglobulin produced in response to bacterial and viral infections Activates the complement system IgD (0.2% of Total Immunoglobulin) Appears in small amounts in serum Possibly influences B-lymphocyte differentiation, but role is unclear IgE (0.004% of Total Immunoglobulin) Appears in serum Takes part in allergic and some hypersensitivity reactions Combats parasitic infections