IMMUNE FUNCTION: DEFENSES AND RESPONSES
There are two general types of immunity: natural (innate) and ac-quired (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 re-sponses increase in intensity with repeated exposure to the in-vading 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 inter-dependent manner.
Natural (innate) immunity provides a nonspecific response to any foreign invader, regardless of the invader’s 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 surface barriers include intact skin and mucous mem-branes, 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 fur-ther. 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 bac-teria and fungi. Viruses are countered by other means, such as in-terferon. 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.
WBCs, or leukocytes, participate in both the natural and the ac-quired 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 his-tamine, 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 ba-sophils, other types of granulocytes, increase in number during allergic reactions and stress responses. Nongranular leukocytes in-clude 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 granulo-cytes. Lymphocytes, consisting of B cells and T cells, play major roles in humoral and cell-mediated immune responses. About 60% to 70% of lymphocytes in the blood are T cells, and about 10% to 20% are B cells (Porth, 2002).
The inflammatory response is a major function of the natural (non-specific or innate) immune system elicited in response to tissue in-jury or invading organisms. Chemical mediators assist this response by minimizing blood loss, walling off the invading organism, acti-vating 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 char-acterized 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 system’s recognition of one’s own tissues as “foreign” rather than as self is the basis for many autoimmune disorders.
Acquired (adaptive) immunity—immunologic responses acquired during life but not present at birth—usually develops as a result of prior exposure to an antigen through immunization (vaccination) or by contracting a disease, both of which generate a protective immune 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 person’s own body. This immunity gener-ally lasts many years or even a lifetime.
Passive acquired immunity is temporary immunity transmit-ted from another source that has developed immunity through previous disease or immunization. For example, immune globu-lin and antiserum, obtained from the blood plasma of people with acquired immunity, are used in emergencies to provide immu-nity to diseases when the risk for contracting a specific disease is great and there is not enough time for a person to develop ade-quate 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 im-munity. Active and passive acquired immunity involve humoral and cellular (cell-mediated) immunologic responses (Ada, 2001).
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 body’s 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 body’s 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 spe-cific chemical mediators into the extracellular fluid. Additionally, they secrete leukotrienes, prostaglandins, and various cytokines (Delves & Roitt, 2000a).
A second protective response, the humoral immune response (sometimes called the antibody response), begins with the B lym-phocytes, which can transform themselves into plasma cells that manufacture antibodies. These antibodies, highly specific pro-teins, are transported in the bloodstream and attempt to disable the invaders. The third mechanism of defense, the cellular im-mune response, also involves the T lymphocytes, which can turninto special cytotoxic (or killer) T cells that can attack the patho-gens themselves.
The part of the invading or attacking organism that is respon-sible 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 anti-gens 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 teta-nus toxin), may have several such antigens, or markers, on its sur-face, 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 com-bines 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 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 dis-tributed internally throughout the body and in the circulating blood, and externally near the body’s surfaces. They continuously discharge small lymphocytes into the bloodstream. These lym-phocytes 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 never-ending series of patrols. Some circulating lymphocytes can sur-vive for decades. Some of these small, hardy cells maintain their solitary circuits for the person’s lifetime.
The exact way in which circulating lymphocytes recognize antigens on foreign surfaces is not known; however, recogni-tion is thought to depend on specific receptor sites on the sur-face 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 lym-phocyte, with the help of macrophages, either removes the anti-gen 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 strepto-coccal 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, rec-ognizes 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.
The circulating lymphocyte containing the antigenic message re-turns to the nearest lymph node. Once in the node, the sensitized lymphocyte stimulates some of the resident dormant T and B lym-phocytes to enlarge, divide, and proliferate. T lymphocytes dif-ferentiate 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.
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 lym-phocytes 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 ac-tion of antibodies. These transformed lymphocytes are known as cytotoxic (killer) T cells. 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 lympho-cytes rather than the antibody-producing B lymphocytes. Viral rather than bacterial antigens induce a cellular response. This re-sponse is manifested by the increasing number of T lymphocytes (lymphocytosis) seen in the blood smears of people with viral ill-nesses, such as infectious mononucleosis.
Most immune responses to antigens involve both humoral and cellular responses, although one usually predominates. For exam-ple, during transplantation rejection, the cellular response pre-dominates, whereas in the bacterial pneumonias and sepsis, the humoral response plays the dominant protective role (Chart 50-1).
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 re-sults in the total destruction of the invading microbes or the com-plete 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.
The humoral response is characterized by production of anti-bodies by the B lymphocytes in response to a specific antigen. Although the B lymphocyte is ultimately responsible for the pro-duction of antibodies, both the macrophages of natural immu-nity and the special T-cell lymphocytes of cellular immunity are involved in recognizing the foreign substance and in producing antibodies.
Several theories exist about the mechanisms by which the B lym-phocytes recognize the invading antigen and respond by produc-ing 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 di-rectly. In response to other antigens, however, they need the assis-tance of T cells to trigger antibody formation.
T cells (or T lymphocytes), part of a surveillance system dis-persed throughout the body, recycle through the general circu-lation, 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 anti-genic message, or “blueprint,” of the antigen and returns to the nearest lymph node with that message.
B lymphocytes stored in thelymph nodes are subdivided into thousands of clones, each re-sponsive 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 lymphocytes differentiate into B-lymphocyte 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.
Antibodies are large proteins called immunoglobulins because they are found in the globulin fraction of the plasma proteins. All im-munoglobulins 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 anti-body. 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 disul-fide bonds. Each subunit has a portion that serves as a binding site for a specific antigen referred to as the Fab fragment. This site pro-vides 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 frag-ments. One antibody can act as a cross-link between two anti-gens, causing them to bind or clump together. This clumping effect, referred to as agglutination, helps clear the body of the in vading organism by facilitating phagocytosis. Some antibodies as-sist in removing offending organisms through opsonization. In this process, the antigen–antibody 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 chem-ical 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).
The body can produce five differ-ent types of immunoglobulins. (Immunoglobulins are com-monly 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 chemi-cal structure and biologic role of the individual immunoglobu-lin. 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 genitouri-nary 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
The portion of the antigen involved in binding with the antibody is referred to as the antigenic determinant. The binding of the Fab fragment (antibody-binding site) to the antigenic determi-nant can be likened to a lock-and-key situation (Fig. 50-7). The most efficient immunologic responses occur when the antibody and antigen fit exactly. Poor fit can occur with an antibody that was produced in response to a different antigen. This phenome-non is known as cross-reactivity. For example, in acute rheumatic fever, the antibody produced against Streptococcus pyogenes in the upper respiratory tract may cross-react with the patient’s heart tis-sue, leading to heart valve damage.
Whereas the B lymphocytes are responsible for humoral immu-nity, the T lymphocytes (or T cells) are primarily responsible for cellular immunity. Stem cells continuously migrate from the bone marrow to the thymus gland, where they develop into T cells. T cells continue to develop in the thymus gland, despite partial degen-eration of the thymus gland that occurs at puberty (Delves & Roitt, 2000a). By spending time in the thymus, these cells are programmed to become T cells rather than antibody-producing B lymphocytes. Several types of T cells exist, each with designated roles in the defense against bacteria, viruses, fungi, parasites, and malignant cells. T cells attack foreign invaders directly rather than by producing antibodies.
Cellular reactions are initiated by the binding of an antigen with an antigen receptor located on the surface of a T cell. This may occur with or without the assistance of macrophages. The T cells then carry the antigenic message, or blueprint, to the lymph nodes, where the production of other T cells is stimulated. Some T cells remain in the lymph nodes and retain a memory for the antigen. Other T cells migrate from the lymph nodes into the general circulatory system and ultimately to the tissues, where they remain until they either come in contact with their respec-tive antigens or die.
Two major categories of effector T cells are helper T cells and cytotoxic T cells. These cells participate in destroying foreign organisms. Other T cells include suppressor T cells and memory T cells. T cells interact closely with B cells, indicating that hu-moral and cellular immune responses are not separate, unrelated processes but rather branches of the immune response that can and do affect each other.
Helper T cells are activated upon recognition of antigens andstimulate the rest of the immune system. When activated, helper T cells secrete cytokines that attract and activate B cells, cytotoxic T cells, natural killer cells, macrophages, and other cells of the im-mune system. Separate subpopulations of helper T cells produce different types of cytokines and determine whether the immune re-sponse will be the production of antibodies or a cell-mediated immune response. Helper T cells produce lymphokines, one category of cytokines. These lymphokines activate other T cells (interleukin-2 [IL-2]), natural and cytotoxic T cells (interferon-gamma), and other inflammatory cells (tumor necrosis factor). Helper T cells produce IL-4 and IL-5, lymphokines that activate B cells to grow and differentiate (Table 50-2).
Cytotoxic T cells (killer T cells) attack the antigen directly byaltering the cell membrane and causing cell lysis (disintegration) and releasing cytolytic enzymes and cytokines. Lymphokines can recruit, activate, and regulate other lymphocytes and WBCs. These cells then assist in destroying the invading organism. Delayed-type hypersensitivity is an example of an immune reaction that protects the body from antigens through the production and re-lease of lymphokines and is discussed in more detail later.
Another type of cell, the suppressor T cell, has the ability to decrease B-cell production, thereby keeping the immune response at a level that is compatible with health (eg, sufficient to fight in-fection adequately without attacking the body’s healthy tissues). Memory cells are responsible for recognizing antigens from pre-vious exposure and mounting an immune response (Table 50-3).
Null lymphocytes and natural killer (NK) cells are other lympho-cytes that assist in combating organisms. These are distinct from B cells and T cells and lack the usual characteristics of B cells and T cells. Null lymphocytes, a subpopulation of lymphocytes, de-stroy antigens already coated with antibody. These cells have spe-cial Fc receptor sites on their surfaces that allow them to couple with the Fc end of antibodies (antibody-dependent, cell-mediated cytotoxicity).
Natural killer cells, another subpopulation of lymphocytes,defend against microorganisms and some types of malignant cells. NK cells are capable of directly killing invading organisms and producing cytokines. The helper T cells contribute to the differ-entiation of null and NK cells.
Circulating plasma proteins, which are made in the liver and ac-tivated when an antibody couples with its antigen, are known as complement. These proteins interact sequentially with one an-other in a cascade or “falling domino” effect. This complement cascade alters the cell membranes on which antigen and antibody complex forms, permitting fluid to enter the cell and leading eventually to cell lysis and death. In addition, activated comple-ment molecules attract macrophages and granulocytes to areas of antigen–antibody reactions. These cells continue the body’s de-fense by devouring the antibody-coated microbes and by releas-ing bacterial agents.
Complement plays an important role in the immune response. Destruction of an invading or attacking organism or toxin is not achieved merely by the binding of the antibody and antigens; it also requires activation of complement, the arrival of killer T cells, or the attraction of macrophages. Complement has three major phys-iologic functions: defending the body against bacterial infection, bridging natural and acquired immunity, and disposing of im-mune complexes and the byproducts associated with inflammation (Walport, 2001a). Complement-mediated immune responses are summarized in Table 50-4.
There are several ways to activate the complement system: the classic pathway, the alternate pathway, and the lectin pathway (Delves & Roitt, 2000a).
The classic pathway (the first method discovered) is activated by antigen–antibody complexes; it begins when antibody binds to a cell surface and ends with lysis of the cell. It involves the reaction of the first of the circulating complement proteins (C1) with the receptor site of the Fc portion of an antibody molecule after for-mation of an antigen–antibody complex. The activation of the first complement component then activates all the other compo-nents in the following sequence: C4, C2, C3, C5, C6, C7, C8, and C9. (The components are named in the sequence in which they were discovered.)
The alternate and lectin pathways of complement activation are activated without the formation of antigen–antibody complexes. These pathways can be initiated by the release of bacterial prod-ucts, such as endotoxins. When complement is activated with-out the formation of antigen–antibody complexes, the process bypasses the first three components (C1, C4, and C2) and begins with C3. Whatever the method of activation, once activated, the complement destroys cells by altering or damaging the cell mem-brane of the antigen, by chemically attracting phagocytes to the antigen (chemotaxis), and by rendering the antigen more vul-nerable to phagocytosis (opsonization). The complement sys-tem enhances the inflammatory response by releasing vasoactive substances.
Complement components, prostaglandins, leukotrienes, and other inflammatory mediators all contribute to the recruitment of inflammatory cells, as do chemokines, a group of cytokines. The activated neutrophils pass through the vessel walls to accumulate at the site of infection, where they phagocytose complement-coated microbes (Delves & Roitt, 2000a).
This response is usually therapeutic and can be lifesaving if the cell attacked by the complement system is a true foreign invader, such as a streptococcal or staphylococcal organism. If that cell, however, is in reality part of the person—a cell of the brain or liver, the tissue lining the blood vessels, or the cells of a trans-planted organ or skin graft, for example—the result can be dev-astating disease and even death. The result of the immune response—the vigorous attack on any material identified as for-eign, the deadliness of the struggle—is obvious in the purulent material, or pus (the remains of microbes, granulocytes, macro-phages, T-cell lymphocytes, plasma proteins, complement, and antibodies), that accumulates in wound infections and abscesses. In addition, many autoimmune diseases (ie, systemic lupus ery-thematosus) and disorders characterized by chronic infection (ie, hepatitis C, bacterial endocarditis) and necrosis (myocardial infarction, stroke) are thought to be due in part to continued or chronic activation of complement, which in turn causes chronic inflammation (Walport, 2001b).
The red blood cells (erythrocytes) and platelets (thrombo-cytes) also have a role in the immune response. Red blood cells and platelets have complement receptors and as a result play an important role in the clearance of immune complexes that con-sist of antigen, antibody, and components of the complement sys-tem (Delves & Roitt, 2000a).
Biologic response modifiers, such as the interferons, are under investigation to determine their roles in the immune system and their potential therapeutic effects in disorders characterized by dis-turbed immune responses. Interferons have antiviral and antitu-mor properties. In addition to responding to viral infection, they are produced by T lymphocytes, B lymphocytes, and macrophages in response to antigens. They are thought to modify the immune response by suppressing antibody production and cellular immu-nity. They also facilitate the cytolytic role of macrophages and NK cells. Interferons are undergoing extensive testing to evaluate their effectiveness in treating tumors and acquired immunodeficiency syndrome (AIDS). Some interferons are already used to treat immune-related disorders (eg, multiple sclerosis) and chronic inflammatory conditions (eg, chronic hepatitis).