CHAPTER 17 Inflammation and Immunity

Acquiring Antibody-Mediated Immunity

Active immunity occurs when antigens enter a person's body and it responds by making specific antibodies against the antigen. This type of IMMUNITY is active because the body takes an active part in making antibodies. Active immunity occurs under natural or artificial conditions. Natural active IMMUNITY occurs when an antigen enters the body naturally without human assistance and the body responds by actively making antibodies against that antigen. Natural active immunity is the most effective and the longest lasting. Artificial active IMMUNITY is the protection developed by vaccination or immunization. Small amounts of specific antigens are placed as a vaccination into a person. The person's immune system responds by actively making antibodies against the antigen. Artificial active immunity lasts many years, although repeated but smaller doses of the original antigen are required as a "booster". Passive IMMUNITY occurs when the antibodies against an antigen are transferred to a person's body after first being made in the body of another person or animal. Because these antibodies are foreign to the receiving person, they are recognized as non-self and eliminated quickly. For this reason, passive immunity provides only immediate, short-term protection against a specific antigen. Artificial passive immunity may be used to prevent disease or death for patients exposed to rabies, tetanus, and poisonous snake bites. Natural passive IMMUNITY occurs when antibodies are passed from the mother to the fetus via the placenta or to the infant through colostrum and breast milk. AMI works with INFLAMMATION to protect against infection. However, AMI can provide the most effective long-lasting IMMUNITY only when its actions are combined with those of cell-mediated immunity.

Acute Rejection

Acute rejection first occurs within 1 week to 3 months after transplantation and may occur sporadically after that. Two mechanisms are responsible. The first mechanism is antibody mediated and results in vasculitis within the transplanted organ. This reaction differs from hyperacute rejection in that blood vessel necrosis (not occlusion) leads to organ destruction. The second mechanism is cellular. The recipient's cytotoxic/cytolytic T-cells and NK cells enter the transplanted organ through the blood, penetrate the organ cells, start an inflammatory response, and cause lysis of the organ cells. Diagnosis of acute rejection is made by laboratory tests that show impaired function of the donated organ and by biopsy. When acute rejection occurs in a transplanted kidney, the patient usually has some tenderness in the kidney area and may have other general manifestations of INFLAMMATION. An episode of acute rejection after solid organ transplantation does not automatically mean that the patient will lose the new organ. Drug management of the recipient's immune responses at this time may limit the damage to the organ and allow the graft to be maintained.

Antibody Classification

All antibodies are immunoglobulins, also called gamma globulins. Because antibodies are globular proteins, they are "globulins." The term immunoglobulin is used for antibodies because they are globular proteins that provide IMMUNITY. Antibodies also are called gamma globulins because all free antibodies in the plasma separate out in the gamma fraction of plasma proteins during electrophoresis. On first exposure to an antigen, the newly sensitized B-cell produces the IgM antibody type against the antigen. IgM is special because it forms itself into a five-member group. Each IgM group, then, has ten antigen binding sites. So, even though antibody production is slow on first exposure, the antibody type produced forms groups that are very efficient at antigen binding. This process ensures that the initial illness, like influenza A, lasts only 5 to 10 days. On re-exposure to the same antigen, the already sensitized B-cell makes large amounts of the IgG type of antibody against that antigen. Although IgG does not form groups of five, the enormous amounts produced make IgG antibodies efficient at clearing the antigen and protecting

Antibody-Mediated Immunity

Antibody-mediated immunity (AMI), also known as humoral immunity, involves antigen-antibody interactions to neutralize, eliminate, or destroy foreign proteins. Antibodies are produced by sensitized B-lymphocytes (B-cells). B-cells become sensitized to a specific foreign protein (antigen) and produce antibodies directed specifically against that protein. The antibody, rather than the actual B-cell, then causes one of several actions to neutralize, eliminate, or destroy that antigen. Macrophages and T-lymphocytes work with B-cells to start and complete antigen-antibody interactions. B-cells start as stem cells in the bone marrow, the primary lymphoid tissue, that commit to the lymphocyte pathway and are then restricted in development. The lymphocyte stem cells are released from the bone marrow into the blood. They then migrate into many secondary lymphoid tissues to mature. The secondary lymphoid tissues for B-cell maturation are the spleen, parts of lymph nodes, tonsils, and the mucosa of the intestinal tract.

Antigen-Antibody Interactions 2

B-cell divides and forms two types of B-lymphocytes: One new cell becomes a plasma cell, which starts immediately to produce antibodies against the sensitizing antigen. The other new cell becomes a memory cell. The memory cell is a sensitized B-cell but does not produce antibodies until the next exposure to the same antigen. Antibody production and release allow the antibodies to search out specific antigens. Antibodies are produced by plasma cells, and each plasma cell can make as many as 300 molecules of antibody per second. Each plasma cell produces antibody specific only to the antigen that originally sensitized the parent B-cell. The antibody is in body fluids (or body "humors") and is separate from the B-cells, this type of IMMUNITY is sometimes called humoral immunity. Circulating antibodies can be transferred from one person to another to provide the receiving person with immediate immunity of short duration. Antibody-antigen binding is needed for anti-antigen actions. Antibodies are Y-shaped molecules (Fig. 17-9). The tips of the short arms of the Y recognize the specific antigen and bind to it. Because each antibody molecule has two tips (Fab fragments, or arms), each antibody can bind either to two separate antigens or to two areas of the same antigen. The stem of the Y is the "Fc fragment." This area can bind to Fc receptor sites on white blood cells (WBCs). The WBC then not only has its own means of attacking antigens but also has the added power of having surface antibodies that can stick to antigens.

Basophils

Basophils come from myeloid stem cells and cause the manifestations of INFLAMMATION. Basophil function acts on blood vessels with basophil chemicals (vasoactive amines), which include heparin, histamine, serotonin, kinins, and leukotrienes. Basophils have sites that bind the base portion of immunoglobulin E (IgE) molecules, which binds to and is activated by allergens. When allergens bind to the IgE on the basophil, the basophil membrane opens and releases the vasoactive amines into the blood. Heparin inhibits blood and protein clotting. Histamine constricts small veins, inhibiting blood flow and decreasing venous return. This effect causes blood to collect in capillaries and arterioles. Kinins dilate arterioles and increase capillary permeability. These actions cause blood plasma to leak into the interstitial space (vascular leak syndrome). Thus basophils stimulate both general INFLAMMATION and the inflammation of allergy and hypersensitivity reactions.

Overview

Body defenses to prevent organisms from entering include intact skin and mucous membranes, skin surface normal flora, and natural chemicals that inhibit bacterial growth. The purpose of INFLAMMATION and IMMUNITY is to provide protection by neutralizing, eliminating, or destroying organisms that invade the body. To protect without harming the body, immune system cells exert these actions only against non-self proteins and cells.

Cell Types Involved in Cell-Mediated Immunity 1

CMI include several specific T-lymphocytes (T-cells) along with a special population of cells known as natural killer (NK) cells. Most T-cells have more than one antigen on their cell membrane. For example, all mature T-cells contain T1, T3, T10, and T11 proteins. The three T-lymphocyte subsets that are critically important for the development and continuation of CMI are helper/inducer T-cells, suppressor T-cells, and cytotoxic/cytolytic T-cells. An additional cell, the natural killer cell, although not a true T-cell, also contributes to CMI. Helper/inducer T-cells have the T4 protein. Called T4+ cells or TH cells. The most correct name for helper/inducer T-cells is CD4+ (cluster of differentiation 4). Helper/inducer T-cells easily recognize self cells versus non-self cells. When they recognize non-self (antigen), helper/inducer T-cells secrete cytokines that can enhance the activity of other WBCs and increase overall immune function. These cytokines increase bone marrow production of stem cells and speed up their maturation. Thus helper/inducer T-cells act as organizers in "calling to arms" various squads of WBCs involved in inflammatory, antibody, and cellular protective actions. Suppressor T-cells have the T8-lymphocyte antigen. Called T8+ cells, CD8+ cells, or TS-cells. Suppressor T-cells help regulate CMI. Suppressor T-cells prevent hypersensitivity (immune overreactions) on exposure to non-self cells or proteins. This function is important in preventing the formation of antibodies directed against normal, healthy self cells. The suppressor T-cells secrete cytokines that have an overall inhibitory action on most cells of the immune system. Suppressor T-cells have the opposite action of helper/inducer T-cells. Balance occurs when the helper/inducer T-cells outnumber the suppressor T-cells by a ratio of 2 : 1. When this ratio increases, indicating that helper/inducer T-cells vastly outnumber the suppressor cells, overreactions can occur, some of which are tissue damaging as well as unpleasant. When the helper/suppressor ratio decreases, indicating fewer-than-normal helper/inducer T-cells, IMMUNITY is suppressed and the person's risk for infections increases.

Protection Provided by Cell-Mediated Immunity

Cell-mediated IMMUNITY (CMI) helps protect the body through the ability to differentiate self from non-self. The non-self cells most easily recognized by CMI are cancer cells and those self cells infected by organisms that live within host cells, especially viruses. CMI watches for and rids the body of self cells that might potentially harm the body. CMI is important in preventing the development of cancer and metastasis after exposure to carcinogens.

Cell-Mediated Immunity

Cell-mediated IMMUNITY (CMI), or cellular immunity, involves many white blood cell (WBC) actions and interactions. CMI is another type of adaptive or acquired true immunity that is provided by lymphocyte stem cells that mature in the secondary lymphoid tissues of the thymus and pericortical areas of lymph nodes.

Cytokines

Cytokines are small protein hormones produced by the many WBCs (and some other tissues). Cytokines made by the macrophages, neutrophils, eosinophils, and monocytes are called monokines. Those produced by T-cells are called lymphokines. Cytokines work like hormones: one cell produces a cytokine, which in turn exerts its effects on other cells of the immune system and on other body cells. Cytokines act like "messengers" that tell specific cells how and when to respond. The cells that change their activity when a cytokine is present are "responder" cells. For a responder cell to respond to the presence of a cytokine, the responder cell must have a specific receptor. Cytokines include the interleukins (ILs), interferons (IFNs), colony-stimulating factors, tumor necrosis factors (TNFs), and transforming growth factors (TGFs). The interleukins are the largest group of cytokines, with interleukin-33 (IL-33) being the most recently defined. Some are considered "proinflammatory" and increase the actions of natural immunity (INFLAMMATION). These currently include TNF-α, IL-1, IL-10, IL-12, and interferons (α [alpha], β [beta], and γ [gamma]). Other cytokines have a major influence on AMI and CMI activities. These include IL-2, IL-4, IL-5, IL-10, TGF-β, and IFN-γ. Although there are many cytokines, not all their functions are known or clinically useful at this time.

Cell Types Involved in Cell-Mediated Immunity 2

Cytotoxic/cytolytic T-cells are also called TC-cells. Because they have the T8 protein present on their surfaces, they are a subset of suppressor cells. Cytotoxic/cytolytic T-cells destroy cells that contain a processed antigen's human leukocyte antigens (HLAs). This activity is most effective against self cells infected by parasites, such as viruses or protozoa. Parasite-infected self cells have both self HLA proteins (universal product code) and the parasite's antigens on the cell surface. This allows the person's immune system cells to recognize the infected self cell as abnormal, and the cytotoxic/cytolytic T-cell can bind to it, punch a hole, and deliver a "lethal hit" of enzymes to the infected cell, causing it to lyse and die. Natural killer (NK) cells are also known as CD16+ cells and are very important in providing CMI. The actual site of NK cell differentiation and maturation is unknown, and it is not a true T-cell. NK cells have direct cytotoxic effects on some non-self cells without first being sensitized. They conduct "seek and destroy" missions in the body to eliminate non-self cells. NK cells are most effective in destroying unhealthy or abnormal self cells. The non-self cells most often harmed by NK cells are cancer cells and virally infected body cells.

Eosinophils

Eosinophils come from the myeloid line and contain many vasoactive chemicals. Eosinophil function is very active against infestations of parasitic larvae and also limits inflammatory reactions. The eosinophil granules contain many different substances. Some are enzymes that degrade the vasoactive chemicals released by other leukocytes. This is why the number of circulating eosinophils increases during an allergic response.

Hyperacute Rejection

Hyperacute rejection begins immediately on transplantation and is an antibody-mediated response. Antigen-antibody complexes form in the blood vessels of the transplanted organ. The recipient's (host's) blood has pre-existing antibodies to one or more of the antigens (including blood group antigens) present in the donated organ. The antigen-antibody complexes adhere to the lining of blood vessels and activate complement. The activated complement in the blood vessel linings triggers the blood clotting cascade, causing small clots to form throughout the new organ. Widespread clotting occludes blood vessels and leads to ischemic necrosis, INFLAMMATION with phagocytosis of the necrotic blood vessels, and release of lytic enzymes into the new organ. Occurs mostly in transplanted kidneys but is less common now. Greatest risk for hyperacute rejection are those who have received donated organs of an ABO blood type different from their own, have received multiple blood transfusions at any time in life before transplantation, have a history of multiple pregnancies, or have received a previous transplant. The manifestations of hyperacute rejection are apparent within minutes of attachment of the donated organ to the recipient's blood supply. The process cannot be stopped once it has started, and the rejected organ is removed as soon as hyperacute rejection is diagnosed.

Immunity

IMMUNITY is an adaptive internal protection that results in long-term resistance to the effects of invading microorganisms. The body has to learn to generate specific immune responses when it is infected by or exposed to specific organisms. Lymphocytes develop actions and products that provide the protection of true immunity.

Inflammation

INFLAMMATION, also called innate-native immunity or natural immunity, provides immediate protection. It can be a barrier to prevent organisms from entering the body or can be an attacking force that eliminates organisms that have already entered the body. The inflammatory responses are part of innate IMMUNITY. Other parts of innate immunity include skin, mucosa, antimicrobial chemicals on the skin, complement, and natural killer cells. INFLAMMATION differs from AMI and CMI in two important ways: • Inflammatory protection is immediate but short-term. It does not provide true immunity on repeated exposure to the same organisms. • Inflammation is a nonspecific body defense to invasion or injury and can be started quickly by almost any event, regardless of where it occurs or what causes it. Inflammation also helps start both antibody-mediated and cell-mediated actions to activate full IMMUNITY.

Infection

Infection is usually accompanied by inflammation; however, inflammation can occur without infection. Examples of inflammation without infection include joint sprain injuries, myocardial infarction, and blister formation. Examples of inflammation caused by noninfectious invasion include allergic rhinitis, contact dermatitis, and other allergic reactions. Inflammations from infection include otitis media, appendicitis, and viral hepatitis, among many others. Inflammation does not always mean that an infection is present.

Macrophages

Macrophages come from the committed myeloid stem cells in the bone marrow and form the mononuclear-phagocyte system. The stem cells first form monocytes, which are released into the blood at this stage. Until they mature, monocytes are limited. Monocytes move from the blood into body tissues, where they mature into macrophages. Some macrophages become "fixed" in position within the tissues, whereas others can move within and between. Macrophages in various tissues have slightly different appearances and names. Macrophage function: important in immediate inflammatory responses and also stimulate the longer-lasting immune responses of antibody-mediated IMMUNITY (AMI) and cell-mediated IMMUNITY (CMI). Macrophage functions include phagocytosis, repair, antigen presenting/processing, and secretion of cytokines for immune system control. The inflammatory function of macrophages is phagocytosis. Macrophages can easily distinguish between self and non-self, and their large size makes them very effective at trapping invading cells. They have long life spans.

Management of Transplant Rejection

Maintenance therapy is the continuous immunosuppression used after a solid organ transplant. The drugs used for routine therapy after solid organ transplantation are combinations of a calcineurin inhibitor, a corticosteroid, and an antiproliferative agent. Which drugs are used depends on the transplant type and other patient-specifics. All oral agents and must be taken for the life of the transplanted organ. All are immunosuppressive to some degree, and the dosage is adjusted to the immune response of each patient. Treatment with these agents increases the risk for bacterial and fungal infections and for cancer development. Rescue therapy is used to treat acute rejection episodes. The drug categories for this purpose are the monoclonal and polyclonal antibodies (see Chart 17-2). The drugs used for maintenance are often also used during rejection episodes at much higher dosages than for maintenance.

Organization of the Immune System

Most immune system cells come from the bone marrow. Some cells mature in the bone marrow; others leave the bone marrow and mature in different body sites. The bone marrow is the source of all blood cells, including most immune system cells. The bone marrow produces immature, undifferentiated cells called stem cells. Stem cells are pluripotent, meaning that each cell has more than one potential. Erythropoietin is a growth factor for red blood cells (erythrocytes [RBCs]). When immature stem cells are exposed to erythropoietin, they commit to the erythrocyte pathway. White blood cells (leukocytes [WBCs]) protect the body from the effects of invasion by organisms. The leukocytes provide protection through these defensive actions: • Recognition of self versus non-self • Destruction of foreign invaders, cellular debris, and unhealthy or abnormal self cells • Production of antibodies directed against invaders • Complement activation • Production of cytokines that stimulate increased formation of leukocytes in bone marrow and increase specific leukocyte activity The three processes needed for human protection through IMMUNITY are (1) INFLAMMATION, (2) antibody-mediated immunity (AMI), and (3) cell-mediated immunity (CMI). Full immunity (immunocompetence) requires the function and interaction of all three processes.

Transplant Rejection

Natural killer (NK) cells and cytotoxic/cytolytic T-cells also destroy cells from other people or animals; it is also responsible for rejection of tissue grafts and transplanted organs (also termed grafts). Without intervention, the recipient's immune system starts inflammatory and immunologic actions to destroy or eliminate these non-self cells. This activity causes rejection of the transplanted organ. Rejection can be hyperacute, acute, or chronic.

Neutrophils

Neutrophils come from the stem cells and complete the maturation process in the bone marrow (Fig. 17-5). They are also called granulocytes because of the large number of granules. Mature neutrophils are also called segmented neutrophils ("segs") or polymorphonuclear cells ("polys," PMNs) because of their segmented nucleus. Less mature neutrophils are called band neutrophils ("bands" or "stabs") because of their nuclear shape. Growth of a stem cell into a mature neutrophil requires 12 to 14 days. This time is shortened by the presence of specific growth factors (cytokines), such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF). The life span of each neutrophil is short—about 12 to 18 hours. Neutrophil function provides protection after invaders, especially bacteria, enter the body. This powerful army of small cells destroys invaders by phagocytosis and enzymatic digestion. Mature neutrophils are the only stage of this cell capable of phagocytosis. This cell type is responsible for continuous, instant, nonspecific protection against organisms, the percentage and actual number of mature circulating neutrophils are used to measure a patient's risk for infection: the higher the numbers, the greater the resistance to infection. This measurement is the absolute neutrophil count (ANC), also called the absolute granulocyte count or total granulocyte count. Problems, such as sepsis, cause the neutrophils in the blood to change from being mostly segmented neutrophils to being less mature forms. This situation is termed a left shift or bandemia because the segmented neutrophil are the new minority. Instead, more of the circulating cells are bands—the less mature cell type found farther left on the neutrophil pathway. A left shift indicates that the patient's bone marrow cannot produce enough mature neutrophils to keep pace with the continuing infection and is releasing immature neutrophils into the blood. These immature cells are of no benefit because they are not capable of phagocytosis.

Self Versus Non-Self

Non-self proteins and cells include infected body cells, cancer cells, cells from other people, and invading organisms. Recognizing self versus non-self, which is necessary to prevent healthy body cells from being destroyed along with the invaders, is called self-tolerance. Unique proteins, known as human leukocyte antigens (HLAs), are found on the surface of all body cells of that person and serve as a "universal product code" for that person. Because the cell-surface proteins are non-self to another person's immune system, they are antigens, which are proteins capable of stimulating an immune response. They are a normal part of the person and determine the tissue type of a person. Other names for these HLAs are human histocompatibility antigens and class I antigens. There are many different human major HLAs that are determined by a set of genes called the major histocompatibility complex (MHC). However, each human expresses only six of the major HLAs.

Chart 17-1 Nursing Focus on the Older Adult Changes in Immune Function Related to Aging

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TABLE 17-1 Immune Functions of Specific Leukocytes

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TABLE 17-2 Values of a White Blood Cell Differential for Peripheral Blood Representing a Normal Count

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TABLE 17-3 Tissue Macrophages

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FIG. 17-7 B-lymphocyte and T-lymphocyte differentiation, maturation, and function.

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FIG. 17-8 Sequence of the seven steps required to stimulate antibody-mediated immunity.

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TABLE 17-4 Antibody Classification

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TABLE 17-5 Activity of Selected Cytokines

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Chart 17-2 Common Examples of Drug Therapy Transplant Rejection

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Phagocytosis

Phagocytosis, the engulfing and destruction of invaders, which also rids the body of debris after tissue injury. Neutrophils and macrophages are most efficient at phagocytosis. Phagocytosis involves the seven steps. Exposure and invasion occur as the first step in response to injury or invasion. For phagocytosis to start, the body must first be invaded by organisms, foreign proteins, or debris. Attraction is needed as the second step because phagocytosis can occur only when the WBC comes into direct contact with the target (antigen, invader, or foreign protein). Damaged tissues secrete chemotaxins that attract neutrophils and macrophages and release debris that can combine with the surface of invaders. Adherence allows the phagocytic cell to bind to the surface of the target. Opsonins are substances that increase contact of the cell with its target by coating the target cell (antigen or organism). During INFLAMMATION, coating the target makes it easier for phagocytic cells to stick. Opsonins: particles from dead neutrophils, antibodies, and activated (fixated) complement components. Complement activation and fixation are part of opsonization. When stimulated, each complement protein(20) is activated, joins other activated complement proteins, surrounds an antigen, and "fixes" or sticks to the antigen. Recognition occurs when the phagocytic cell sticks to the target cell and "recognizes" it as non-self. Cellular ingestion is needed because phagocytic destruction occurs inside the cell. The target cell is brought inside the phagocytic cell by phagocytosis (engulfment). Phagosome formation occurs when the phagocyte's granules break and release enzymes that attack the ingested target. Degradation is the final step.

Antigen-Antibody Interactions 1

Seven steps are needed to produce a specific antibody directed against a specific antigen whenever the person is exposed to that antigen. Exposure or invasion is needed because antibody actions occur inside the body or on a few body surfaces. Invasion by the antigen must occur in such large numbers that some of the antigen evades detection by the body's natural nonspecific defenses or overwhelms the ability of the inflammatory response. Antigen recognition is the next step to begin making antibodies against an antigen. The unsensitized B-cell must first recognize the antigen as non-self. B-cells need the help of macrophages and helper/inducer T-cells to recognize an antigen. After the antigen surface has been altered by opsonization, the macrophage recognizes the invading antigen as non-self and attaches itself to the antigen. This attachment allows the macrophage to "present" the attached antigen to the helper/inducer T-cell. Then the helper/inducer T-cell and the macrophage together process the antigen to expose the antigen's recognition sites (universal product code). After processing the antigen, the helper/inducer T-cell brings the antigen into contact with the B-cell so that the B-cell can recognize the antigen as non-self. Sensitization occurs when the B-cell recognizes the antigen as non-self and is now "sensitized" to this antigen. A single unsensitized B-cell can become sensitized only once and only that antigen. Sensitizing allows this B-cell to respond to any substance that carries the same antigens (codes) as the original antigen. All cells produced by that sensitized B-cell also are already pre-sensitized to that same specific antigen.

Sequence of Inflammation 2

Stage II is the cellular exudate part of the response. In this stage, neutrophilia (an increased number of circulating neutrophils) occurs. Exudate in the form of pus occurs, containing dead WBCs, necrotic tissue, and fluids that escape from damaged cells. Active cells in stage II are the neutrophils, basophils, and tissue mast cells. Under the influence of cytokines, the neutrophil count can increase hugely. Neutrophils attack and destroy organisms and remove dead tissue through phagocytosis. Basophils and tissue mast cells continue or sustain the initial responses. WBCs and inflamed tissues secrete cytokines, which allow tissue macrophages to increase and trigger bone marrow production of monocytes. This reaction begins slowly, but its effects are long lasting. The arachidonic acid cascade starts to increase the inflammatory response. This action begins by the conversion of fatty acids in plasma membranes into arachidonic acid (AA). The enzyme cyclooxygenase (COX) converts AA into many chemicals that are further processed into the substances (mediators) that promote the continued inflammatory response in the tissues. These mediators include histamine, leukotrienes, prostaglandins, serotonin, and kinins. Many anti-inflammatory drugs, including NSAIDs, stop this cascade by preventing cyclooxygenase from converting AA into inflammatory mediators.

Antigen-Antibody Interactions 4

Sustained immunity (memory) provides us with long-lasting IMMUNITY to a specific antigen. Sustained immunity results from memory B-cells made during the lymphocyte sensitization stage. On re-exposure to the same antigen, the memory cells rapidly respond by first dividing and forming new sensitized blast cells and plasma cells. The blast cells continue to divide, producing many more sensitized plasma cells. These new sensitized plasma cells rapidly make large amounts of the antibody specific for the sensitizing antigen. This ability of the memory cells to respond on re-exposure to the same antigen that originally sensitized the B-cell allows a rapid and large immune response (anamnestic response) to the antigen. Because so much antibody is made, often the invading organisms are removed completely and the person does not become ill. This process prevents people from becoming ill with chickenpox or any infectious disease more than once.

Antigen-Antibody Interactions 3

The binding of antibody to antigen may not be lethal to the antigen. Instead, antibody-antigen binding starts other actions that neutralize, eliminate, or destroy the antigen. Antibody-binding actions are triggered by binding of antibody to antigen. The resulting reactions of agglutination, lysis, complement fixation, precipitation, and inactivation can then neutralize, eliminate, or destroy the bound antigen. Agglutination is a clumping action that results from the antibody linking antigens together, forming large and small immune complexes (Fig. 17-10). Agglutination slows the movement of the antigen in body fluids. Also, the irregular shape of the antigen-antibody complex (see Fig. 17-10) increases the actions of macrophages and neutrophils. Lysis is cell membrane destruction, and it occurs now because of antibody binding to membrane-bound antigens of some invaders. The actual binding makes holes in the invader's membrane, weakening the invader(usually requires that complement be activated and "fixed" to the immune complex). Complement activation and fixation are actions triggered by the IgG and IgM classes of antibodies that can remove or destroy antigen. Binding of either IgG or IgM to an antigen provides a binding site for the first component of complement. Cascading complement system. Precipitation, antibody molecules bind so much antigen that large antigen-antibody complexes are formed. These complexes cannot stay in suspension in the blood, they form a large precipitate, which then can be acted on by neutrophils and macrophages. Inactivation (neutralization) is the process of making an antigen harmless without destroying it. Usually only a small area of the antigen, the active site, causes the harmful effects. When an antibody binds to an antigen's active site, covering it up, the antigen is made harmless.

Cell Types Involved in Inflammation

The leukocytes (white blood cells [WBCs]) involved in INFLAMMATION are neutrophils, macrophages, eosinophils, and basophils. An additional cell type important in inflammation is the tissue mast cell. Neutrophils and macrophages destroy and eliminate foreign invaders. Basophils, eosinophils, and mast cells release chemicals that act on blood vessels to cause tissue-level responses that help neutrophil and macrophage actions.

Chronic Rejection

The origin of chronic rejection is similar to chronic INFLAMMATION and scarring. The smooth muscles of blood vessels overgrow and occlude the vessels. The donated organ tissues are replaced with fibrotic, scarlike tissue. Because this fibrotic tissue is not organ tissue, the transplanted organ's function is reduced in proportion. Long-standing and occurs continuously as a response to chronic ischemia caused by blood vessel injury. The results of chronic rejection are unique to different transplanted organs. For example, in transplanted lungs, chronic rejection thickens small airways. In transplanted livers, chronic rejection destroys bile ducts. In transplanted hearts, this process is called accelerated graft atherosclerosis (AGA) and is the major cause of death. The process probably occurs to some degree with all transplanted solid organs obtained from donors who are not identical siblings of the recipients. Because the fibrotic changes are permanent, there is no cure for chronic graft rejection. When the fibrosis increases to the extent that the transplanted organ can no longer function, the only recourse is retransplantation.

Sequence of Inflammation 1

Three-stage sequence. The sequence is the same regardless of the trigger. Responses at the tissue level cause the five cardinal manifestations of inflammation: warmth, redness, swelling, pain, and decreased function. Stages may overlap. Stage I is the vascular part of the inflammatory response. Injured tissues and the leukocytes and tissue mast cells in this area secrete histamine, serotonin, and kinins that constrict the small veins and dilate the arterioles in the area of injury. These blood vessel changes cause redness and warmth of the tissues. This increased blood flow increases delivery of nutrients. Blood flow to the area increases (hyperemia), and swelling (edema). Capillary leak also occurs, allowing blood plasma to leak into the tissues. This response causes swelling and pain. Protects the area from further injury by creating a cushion of fluid. The macrophage is the major cell involved in stage I of INFLAMMATION. The action is rapid because macrophages are already in place at the site. To enhance the inflammatory response, the tissue macrophages secrete several cytokines. One cytokine is colony-stimulating factor (CSF), which triggers the bone marrow to shorten the time needed to produce white blood cells (WBCs) from 14 days to a matter of hours. Some cytokines cause neutrophils from the bone marrow to move to the site of injury or invasion.

Tissue Mast Cells

Tissue mast cells look like and have functions very similar to basophils and eosinophils. They differentiate and mature in tissues, especially those near blood vessels, nerves, lung tissue, skin, and mucous membranes. Like basophils, mast cells have binding sites for the base of IgE molecules and are involved in hypersensitivity reactions. Some mast cells also respond to the inflammatory products made and released by T-lymphocytes. The tissue mast cells have important roles in maintaining and prolonging inflammatory and hypersensitivity reactions.

Sequence of Inflammation 3

When an infection stimulating INFLAMMATION lasts longer than just a few days, the bone marrow begins to release immature neutrophils. Stage III features tissue repair and replacement. This stage is completed last, and it begins at the time of injury. WBCs involved in INFLAMMATION start the replacement of lost tissues or repair of damaged tissues by inducing the remaining healthy cells to divide. In tissues that cannot divide, WBCs trigger new blood vessel growth and scar tissue formation. Degree of function lost depends on how much normal tissue is replaced by scar. (Remember that heart muscle is non-dividing tissue and the heart cannot replace these muscle cells.) The scar tissue serves only as a patch; it does not contract or act in any way like heart muscle. INFLAMMATION alone cannot provide IMMUNITY. Inflammatory cells must interact with lymphocytes to provide long-lasting immunity. Long-lasting immune actions develop through antibody-mediated immunity (AMI) and cell-mediated immunity (CMI).

Key Points: Physiological Integrity

• INFLAMMATION and IMMUNITY are provided through the actions and products of white blood cells (WBCs), also called leukocytes. • Different types of WBCs provide different types of immune or inflammatory protection. • The differential of the WBC count can be used to determine the patient's risk for infection, the presence or absence of infection, the presence or absence of an allergic reaction, and whether an infection is bacterial or viral. • WBCs are the only body cells able to recognize non-self cells and to attack them. • Self-tolerance is the special ability of WBCs to recognize healthy self cells and not attempt to attack or destroy them. • Human leukocyte antigens (HLAs) are a person's tissue type and are inherited from parents. • Immunocompetence requires that all three parts of INFLAMMATION and IMMUNITY have optimal functioning. • INFLAMMATION is a general, nonspecific protective response also known as innate immunity. • The five cardinal manifestations of INFLAMMATION are redness, warmth, swelling, pain, and loss of function. • INFLAMMATION and infection are not the same thing. Infection almost always is accompanied by inflammation, but inflammation often occurs without infection. • The tissue responses to INFLAMMATION are helpful if confined to the area of invasion or infection and do not extend beyond the acute phase. • Chronic INFLAMMATION can damage tissues and reduce function. • The cells and actions of cell-mediated IMMUNITY control and coordinate the entire inflammatory and immune responses. • Inflammatory protection cannot be transferred from one person to another. • Immune function declines with age, making the older adult at increased risk for infection and cancer development. • Antibody-mediated IMMUNITY (also known as humoral immunity) can be transferred from one person or animal to another. • Antibodies transferred from one person into another person have a short-term effect. • Natural, active IMMUNITY is the most beneficial and long-lasting type of immunity. • Vaccinations cause artificial active IMMUNITY and require "boosting" for best long-term effects. • A person's normal membrane proteins would be antigens in another person. • Transplant rejection is a normal response of the immune system that can damage or destroy the transplanted organ. • Patients who receive transplanted organs (unless from an identical sibling) need to take immunosuppressive drugs daily to prevent transplant rejection. • Patients who take immunosuppressive drugs have an increased risk for infection and cancer development.