Chapter 41

The Immune System and Anesthesia

The field of immunology addresses the body’s defense mechanisms against pathogens, such as bacteria and viruses that have the potential to trigger tissue injury and disease. Protection from infection and disease depends on the functions of particular leukocytes, the phagocytes and lymphocytes, with the assistance of auxiliary cells such as mast cells, basophils, and platelets (Table 41-1).^1–3 Immune responses involve not only these various cell types, but also soluble mediator molecules secreted by the cells. These soluble mediators include cytokines, a superfamily of peptide molecules that regulate the actions of immune system cells (Box 41-1).

BOX 41-1 Cytokines

• Cytokines are peptide molecules that regulate the actions of immune system cells.

• The cytokine superfamily includes interferons (IFNs), interleukins (ILs), tumor necrosis factor-alpha (TNF-α), colony-stimulating factors (CSFs), and chemokines (chemotactic cytokines).

• IFNs have antiviral activity and act to suppress spread of viral infection; IFN-α and IFN-β are produced by cells already infected by virus, and IFN-γ is produced by activated NK cells and T_H1 lymphocytes.

• IL-1 and IL-6 are produced by several cell types, including lymphocytes and macrophages.

• IL-2 is produced by T_H1 lymphocytes and promotes proliferation and function of T lymphocytes, B lymphocytes, and natural killer (NK) cells.

• IL-4 and IL-10 are produced by T_H2 lymphocytes; IL-4 activates B lymphocytes.

• IL-6 stimulates hepatocytes to release acute phase proteins such as C-reactive protein (CRP).

• IL-12 is produced by antigen-presenting cells (APCs) and promotes differentiation of T_H0 lymphocytes into T_H1 lymphocytes.

• TNF-α is released from activated macrophages and T_H1 lymphocytes.

• IFN-γ, IL-1, IL-6, IL-12, and TNF-α are important proinflammatory cytokines.

• IL-4 and IL-10 are important antiinflammatory cytokines.

• Granulocyte, monocyte, and granulocyte-monocyte CSFs are released from activated macrophages and vascular endothelial cells and stimulate bone marrow to release PMNs and monocytes into the circulation.

• Chemokines are produced by venule endothelial cells and activated macrophages and act to attract leukocytes to an area of infection.

Adapted from Rang HP, et al. Rang and Dale’s Pharmacology. 7th ed. Edinburgh: Churchill Livingstone; 2012.

TABLE 41-1

Cellular Components of Immunity

Two components of immunity provide defense against invading pathogens: the innate immune system and the adaptive (acquired) immune system. This chapter highlights immune system physiology and pathology, including the effects of human immunodeficiency virus (HIV) on the immune system, with particular consideration of the effects of anesthesia on immune function.

The Immune System

Innate Immune System

Innate immunity is nonspecific, that is, it provides defense against a very large number of pathogens, rather than being directed at one specific microorganism or type of microorganism. Components of innate immunity include physical barriers such as the skin and lung alveoli, the pathogen-hostile environment of the gastrointestinal tract, leukocytes whose primary function is phagocytosis and destruction of invading pathogens, and soluble molecules such as interferons and the complement system.1–3

Phagocytes

Polymorphonuclear neutrophils (PMNs) and macrophages are the primary phagocytes of the immune system. Polymorphonuclear neutrophils and monocytes, the cellular precursors of tissue macrophages, are generated from pluripotent hematopoietic stem cells in the bone marrow (Figure 41-1). Both cell types are continually released to the blood, and many are stored in the marrow until mobilized for defense. Chemical substances known as colony-stimulating factors that enter the circulation from an area of infection are transported to the marrow to stimulate production and release of PMNs and monocytes. Colony-stimulating factors are members of the cytokine superfamily (see Box 41-1).

FIGURE 41-1 All immune cells originate from hematopoietic stem cells. Polymorphonuclear cells and monocytes are released from bone marrow to the circulation and then pass into tissues. B cells mature in the fetal liver and postnatal bone marrow, and T cells mature in the thymus gland. These lymphocytes are released into the circulation and pass into tissues. Other cells that originate from hematopoietic stem cells include mast cells, platelets, antigen-presenting cells (APCs), and natural killer (NK) cells. (From Male D, et al. Immunology. 8th ed. Philadelphia: Saunders; 2013:18.)

After release from bone marrow, PMNs and monocytes circulate for a short time (less than 24 hours) in the blood before moving either directly across, or through pores between, venule endothelial cells to enter tissues. This process is known as diapedesis. Transendothelial movement of PMNs and monocytes and their subsequent movement within tissue to a site of inflammation are not random events, but rather are orchestrated by numerous chemotactic substances that include chemokines produced by endothelial cells, bacterial and viral components, and products C3a and C5a of the blood complement system (Figure 41-2). Production of endothelial-cell chemokines and adhesion molecules, which permit leukocytes to “stick” to the endothelium prior to diapedesis, is stimulated by proinflammatory cytokines, in particular, tumor necrosis factor-alpha (TNF-α) produced by activated macrophages (Figure 41-3).

FIGURE 41-2 Infection or tissue injury causes inflammation and release of inflammatory mediators, some of which stimulate chemotaxis of phagocytes to the site of inflammation. Chemokines stimulate phagocytes to stick to the venular endothelium and undergo migration across the vessel wall (diapedesis). Phagocytes then move to the site of inflammation in response to a concentration gradient of chemotactic molecules such as complement product C5a. (From Male D, et al. Immunology. 8th ed. Philadelphia: Saunders; 2013:14.)

FIGURE 41-3 The cytokine TNF-α plays a central role in inflammation. Among its proinflammatory actions, it promotes clotting, leukocyte adhesion and diapedesis, macrophage activation, and cytokine production by other cells. (From Male D, et al. Immunology. 8th ed. Philadelphia: Saunders; 2013:112.)

The primary function of PMNs and macrophages is phagocytosis of pathogens such as bacteria and viruses. In this process, the phagocyte engulfs and destroys the foreign agent. Of critical importance is the ability of the phagocyte to distinguish between what is foreign and what is self. To this end, phagocytes have receptors that recognize carbohydrate and lipid moieties, known as pathogen-associated molecular patterns (PAMPs), present on cell surfaces of many pathogens but typically not on cells of the host. An example of a microbial PAMP is lipopolysaccharide in the cell walls of gram-negative bacteria. Phagocyte recognition of PAMPs permits the phagocyte to bind directly to the pathogen.

Phagocyte selectivity also can be provided by the process of opsonization, in which serum components bind to the pathogen and permit indirect recognition by phagocytes. Antibodies directed against a pathogen (and produced as part of acquired immunity) act as opsonins by binding to the pathogen and subsequently to antibody receptors on the phagocyte cell membrane (Figure 41-4). Alternatively, the complement product C3b may act as an opsonin, with subsequent binding of C3b to its receptors on phagocyte cell membranes. Phagocyte binding to a pathogen is followed by endocytosis of the pathogen and its intracellular destruction by lysosomal enzymes and products of the phagocyte respiratory burst, which include superoxide ion, hydrogen peroxide, and nitric oxide (Figure 41-5).

FIGURE 41-4 Phagocytes have some intrinsic ability to bind and phagocytize pathogens (1). Phagocytosis is enhanced if the pathogen has been opsonized by complement product C3b (2) or antibody (3). Phagocytes have C3b and Fc receptors that bind opsonized pathogens. Phagocytosis is greatly enhanced if both C3b and antibody opsonize the pathogen (4). (From Male D, et al. Immunology. 8th ed. Philadelphia: Saunders; 2013:10.)

FIGURE 41-5 Mechanism of phagocyte killing of pathogen. Opsonized pathogen undergoes phagocytosis, triggering the respiratory (oxidative) burst and fusion of the phagocytic granule with intracellular lysosomes, which digest the pathogen. (From Nairn R, Helbert M. Immunology for Medical Students. 2nd ed. Philadelphia: Mosby; 2007.)

Although some macrophages are mobile and migrate through tissues in response to chemotactic signals, many are fixed within tissues for long periods of time (resident macrophages) as part of the mononuclear phagocyte system (also called the reticuloendothelial system; Figure 41-6). This system includes the network of monocytes, mobile macrophages, and fixed macrophages that provides phagocytic function in body tissues. The resident macrophages are particularly important in those tissues potentially exposed to large amounts of pathogens, that is, skin, lymph nodes, lung alveoli, liver sinusoids, and the spleen. When these macrophages encounter a pathogen, a number of responses are rapidly set into play: (1) phagocytosis of the pathogen, which provides a first line of defense against infection, (2) secretion of chemotactic mediators that promote infiltration of leukocytes to the site of infection, (3) secretion of colony-stimulating factors that mobilize PMNs and monocytes from the bone marrow, and (4) secretion of proinflammatory cytokines such as TNF-α and interleukin-1 (IL-1). Neutrophil infiltration provides a rapid second line of defense against the pathogen, while a delayed but potent third line of defense occurs as infiltrating monocytes mature into macrophages, and lymphocytes migrate to the area of infection.

FIGURE 41-6 Cells of the mononuclear phagocyte system are located in many tissues and organs. These cells all derive from blood monocytes that originate from hematopoietic stem cells in the bone marrow. (From Male D, et al. Immunology. 8th ed. Philadelphia: Saunders; 2013:5.)

Phagocytosis and breakdown of pathogens also permits macrophages to present chemical components (e.g., peptide fragments) of pathogens to cells of the acquired immune system. In this way, macrophages behave as “antigen-presenting cells” to recruit the acquired immune system and greatly augment the body’s defense responses to pathogens.

Natural Killer Cells

Another cellular component of the innate immune system is the natural killer (NK) cell. These cells have some morphologic resemblance to lymphocytes, and hence are also referred to as large granular lymphocytes (see Table 41-1). NK cells develop in the bone marrow (see Figure 41-1), though the exact mechanism of their differentiation from precursor cells is not well understood. NK cells are potent killers of virus-infected “self” cells. Although leukocytes known as cytotoxic T lymphocytes (CTLs; discussed later) destroy many virus-infected cells, some viruses (e.g., herpes simplex virus [HSV]) evade detection by these lymphocytes. Fortunately, NK cells can recognize and kill HSV-infected cells. The mechanism by which NK cells kill virus-infected cells is the same as that by which CTLs destroy infected self-cells and foreign cells. The NK cell binds to the infected cell, secretes a pore-producing protein known as perforin into the infected cell membrane, and then releases cytotoxic proteolytic enzymes into the infected cell.

Natural killer cells have other key functions. They are the main immune cells of the pregnant uterus, where they act to protect the uterus and the fetus from viral infections during pregnancy. NK cells are very important in the surveillance of tumor cells (i.e., transformed self-cells) and can destroy some tumor cells. They also release cytokines that influence the immune response to pathogens. One key cytokine released by NK cells is interferon-gamma (IFN-γ).

Interferons

As noted in Box 41-1, the interferons (IFNs) are cytokines with antiviral activity. Indeed, the name interferon derives from the ability of these substances to “interfere” with viral replication. There are two main IFN families: type I and type II. Type I IFNs include IFN-α and IFN-β, which are released from many cell types within hours after initiation of viral infection. These cytokines act on neighboring noninfected cells in a paracrine fashion to prevent spread of the viral infection. In addition, type I IFNs promote proliferation and activation of NK cells, which can bind to and destroy virus-infected cells. Synthetic IFN-α produced by recombinant technology is used to treat hepatitis B infection and some neoplasms. Recombinant IFN-β has been used successfully to reduce nervous system inflammation in some patients with multiple sclerosis.

Type II IFN is IFN-γ released from activated NK and T lymphocytes. Like the type I IFNs, IFN-γ can exert protective antiviral activity in noninfected cells, but more importantly it serves to activate macrophages, promote further NK-cell activity, and stimulate differentiation of T lymphocytes. Synthetic IFN-γ is used for treatment of chronic granulomatous disease (discussed later).

Complement

The complement system is a collection of plasma proteins produced mainly by the liver; it plays a key role in both innate and acquired immunity. When the complement system is activated, a cascade of reactions occurs in which a particular complement component catalyzes the production of the next component in the cascade and so on until the final product is produced. The main proteins of the complement system are labeled C1 through C9. The complement cascade can be triggered by an antigen-antibody reaction that activates C1 (the classical pathway) or by direct microorganism interaction with C3 (the alternative and lectin pathways). In either case, activation of the complement cascade generates products that cause opsonization, chemotaxis, and activation of mast cells and basophils. The final product of the cascade is a complex of five complement factors—C5b6789—that acts as a membrane attack complex by inserting cytolytic pores into pathogen cell membranes (Figure 41-7).

FIGURE 41-7 Three pathways can serve to activate the complement cascade. Antigen-antibody reaction typically activates the classical pathway. The alternative and lectin pathways do not require antibody and are directly activated by chemical groups on the pathogen surface. Thus the alternative and lectin pathways serve innate immunity, whereas the classical pathway is linked to the adaptive immune system. All three pathways convert C3 to C3b as the central event of the complement cascade. C3b can then promote the formation of the membrane attack complex. (From Male D, et al. Immunology. 8th ed. Philadelphia: Saunders; 2013:72.)

Acquired Immune System

Acquired, or adaptive, immunity is specific, that is, the immune responses are directed against a particular antigen, which is usually a component of a microorganism or foreign tissue.1–3 In some cases, though, a “self” antigen may generate an autoimmune response that results in tissue injury. By one definition, an antigen is a chemical substance with a molecular weight greater than or equal to 8000 Da, and thus antigens are typically polypeptides or large polysaccharides.³ Acquired immunity directed against a particular antigen is usually directed at one or more small regions, known as epitopes, within the antigen structure.^1–3

Acquired immunity depends fundamentally on lymphocytes, which comprise approximately 30% of circulating leukocytes. There are two main families of lymphocytes: B lymphocytes (B cells) and T lymphocytes (T cells). B lymphocytes are responsible for humoral immunity, which is provided by soluble antibodies directed against a particular antigen. T lymphocytes are responsible for cell-mediated immunity directed against a particular antigen.

Maturation of lymphocytes occurs in primary lymphoid tissues: the thymus gland, fetal liver, and bone marrow. Initially, some pluripotent hematopoietic stem cells differentiate to become lymphoid progenitor cells, which in turn differentiate to become either pre-T cells (thymocytes) or pre-B cells (Figures 41-1 and 41-8). Pre-T cells migrate from the marrow to the thymus gland, where they are processed to become mature T cells directed against specific antigens. T-cell maturation is characterized in part by the appearance of T-cell receptors (TCRs) on the cell membranes. Specificity of a particular T cell for an antigen reflects the specificity of its TCRs to recognize and bind that antigen. As a critical part of thymic processing, T cells that recognize and bind self-antigens undergo programmed cell death, known as apoptosis, whereas T cells that recognize foreign antigens expand and migrate to secondary lymphoid tissues—lymph nodes, adenoids, and tonsils; submucosal lymph tissue; and the spleen. Literally thousands of different T-cell clones develop in the thymus gland, each clone having TCRs directed against a particular antigen.

FIGURE 41-8 Development of B cells, T cells, and natural killer (NK) cells from a common lymphoid progenitor. B cells begin maturation in the bone marrow, and T cells mature in the thymus gland. NK cells develop in the bone marrow, although the mechanism of their differentiation is unclear. (From Nairn R, Helbert M. Immunology for Medical Students. 2nd ed. Philadelphia: Mosby; 2007.)

Distinct populations of T cells are produced during thymic maturation. The two main populations are CD4⁺ T cells, also known as helper T (Th) cells, and CD8⁺ T cells, also known as cytotoxic T lymphocytes (CTLs). (The abbreviation CD refers to “cluster of differentiation” and indicates a particular cell-membrane marker molecule that can be used to identify the hematopoietic cell type.) Naive helper T cells (Th0 cells) have not been exposed to antigen and can differentiate into several subsets, including Th1 and Th2 cells, based on the nature of an ongoing immune response and cytokines present in the local environment (Figure 41-9). Th1 cells promote the function of the mononuclear phagocytes, whereas Th2 cells promote the function of B lymphocytes.

FIGURE 41-9 Differentiation of T helper subsets. When a naive, mature T helper cell is presented antigen by an antigen-presenting cell (APC), it becomes “primed” to differentiate into either a Th1 or Th2 cell. Preference of differentiation is driven by the nature of the infection and the local cytokine environment. After differentiation, Th1 cells secrete interferon-gamma (IFN-γ) and promote cellular immunity, and Th2 cells secrete interleukin (IL)-4 and -5 and promote humoral immunity. Th1 = T_H1 and Th2 = T_H2. (From Nairn R, Helbert M. Immunology for Medical Students. 2nd ed. Philadelphia: Mosby; 2007.)

Development of B cells begins in the fetal and postnatal bone marrow and is completed in secondary lymphoid tissues such as the spleen and lymph nodes (Figure 41-10). As maturation proceeds, B cells that recognize self-antigens undergo apoptosis and are not released into the blood. Those B cells that do leave the bone marrow and migrate to secondary lymphoid tissue acquire two types of immunoglobulin (Ig) molecules on the cell surface, IgM and IgD. These surface-bound Ig molecules are functionally analogous to the TCRs on surfaces of mature T cells, that is, they recognize and bind specific antigens. Other Ig molecules that may be expressed on B-cell surfaces include IgA, IgG, and IgE. Similar to the situation for T cells, thousands of different B-cell clones are produced, each clone having surface Ig molecules directed against a particular antigen.

FIGURE 41-10 Stages of B-cell development. After B-cell release from the bone marrow, maturation is completed in the periphery. When activated by exposure to antigen, mature B cells differentiate into antibody-secreting plasma cells and proliferate to form memory B cells that provide for clonal expansion. (From Nairn R, Helbert M. Immunology for Medical Students. 2nd ed. Philadelphia: Mosby; 2007.)

Humoral Response to Antigen

When a mature B cell encounters and binds antigen, it proliferates and differentiates into plasma cells that secrete soluble antibodies directed against the antigen. In addition, memory B cells are produced that expand the clone of B cells directed against that antigen. The secreted antibodies are Ig molecules and are members of the gamma globulin fraction of serum proteins. Five main classes of Ig molecules exist, which differ substantially in molecular size and charge: IgA, IgD, IgE, IgG, and IgM. Immunoglobulin G comprises approximately 70% of serum immunoglobulins, whereas IgA and IgM comprise approximately 20% and 10%, respectively. Normally, serum levels of IgD and IgE are very low. Rather, IgD is located primarily on B-cell surfaces, where it serves to bind antigen, whereas IgE is found primarily on the surfaces of tissue mast cells and circulating basophils and plays a role in hypersensitivity reactions.

An Ig molecule consists of two or more pairs of light chain–heavy chain polypeptide combinations. The variable, or Fab, regions of an Ig molecule are regions in which the amino acid sequence permits specific, high-affinity binding to antigen (hence, the variable regions “vary” in amino acid sequence among antibody molecules). The constant, or Fc, portion of Ig molecules has a relatively “constant” amino acid sequence that can bind to Fc receptors on phagocyte cell membranes (Figure 41-11).

FIGURE 41-11 The Fab region of an antibody binds to a small portion (epitope) of an antigen on the pathogen surface. The “stem” of the antibody is its Fc region, which binds to phagocyte Fc receptors to promote phagocytosis. (From Male D, et al. Immunology, 8th ed. Philadelphia: Saunders; 2013:10.)

Antibodies promote antigen removal by different mechanisms, including activation of the classical complement pathway, opsonization of a pathogen for phagocytosis, and binding to a pathogen to permit recognition by NK cells. Recently, monoclonal antibodies (mAbs) (i.e., antibodies with very high specificity for antigen) have been developed by recombinant technology for treatment of diseases such as rheumatoid arthritis, Crohn’s disease, and breast cancer, as well as for other applications (Box 41-2). Adalimumab and infliximab are mAbs directed against the proinflammatory mediator TNF-α.

BOX 41-2 Monoclonal Antibodies

The monoclonal antibodies (mAbs) are genetically engineered immunoglobulins (IgGs) that react with specific molecular targets. They may be part mouse/part human (termed chimeric or humanized, depending on the degree of mouse Ig sequences) or fully human. In chimeric and humanized mAbs, antigen-recognizing portions of mouse antibodies are joined to the framework of a human IgG molecule.

• Abciximab: Chimeric mAb against the clotting receptor GpIIb-IIIa on platelets; used to prevent clotting in patients undergoing coronary angioplasty.

• Adalimumab: Humanized mAb against the cytokine TNF-α; used for rheumatoid arthritis.

• Alemtuzumab: Humanized mAb against an antigen on T and B lymphocytes; used to treat B-cell leukemia.

• Basiliximab: Chimeric mAb against the receptor for the cytokine interleukin-2 on activated T cells; used in acute rejection of kidney transplants.

• Daclizumab: Humanized mAb against the receptor for the cytokine interleukin-2 on activated T cells; used in acute rejection of kidney transplants.

• Etanercept: Fusion protein for the tumor necrosis factor used in therapy for rheumatoid arthritis.

• Infliximab: Chimeric mAb against the cytokine TNF-α; used for rheumatoid arthritis and Crohn’s disease.

• Omalizumab: Humanized mAb against the binding of IgE to the high-affinity IgE receptor on the surface of mast cells and basophils; used for the treatment of asthma.

• Palivizumab: Humanized mAb against a protein of respiratory syncytial virus (RSV); used to treat RSV infection in children.

• Rituximab: Humanized mAb against the cytokine CD20 receptor on B cells; used in non-Hodgkin lymphoma.

• Trastuzumab: mAb against HER2; used for breast cancer treatment.

Adapted from Rang HP, et al. Rang and Dale’s Pharmacology. 7th ed. Edinburgh: Churchill Livingstone; 2012.

Antibodies can provide effective defense against toxins or pathogens in the extracellular compartment. However, many pathogens exist within cells of the host, and defense against these pathogens requires a second component of the adaptive immune response—cell-mediated immunity provided by T lymphocytes.

T-Lymphocyte Response to Antigen

Cell-mediated immunity requires “presentation” of antigen to T lymphocytes by infected cells or antigen-presenting cells (APCs) such as dendritic cells, macrophages, and B lymphocytes. What is actually presented to the T cell is a small portion of the parent antigen that has been processed, or degraded, by the presenting cell. The antigen fragment is presented bound to a major histocompatibility (MHC) molecule on the presenting cell surface. T-cell receptors on T cells directed against the antigen then recognize and bind the antigen-MHC complex (Figure 41-12).

FIGURE 41-12 General mechanism of antigen presentation to T cells. A surface major histocompatibility complex (MHC) molecule presents a peptide portion of pathogen in an infected cell. The T-cell receptor recognizes and binds the MHC molecule/peptide combination. (From Male D, et al. Immunology. 8th ed. Philadelphia: Saunders; 2013:10.)

The MHC is a collection of genes that serve immune recognition in all mammals. There are two types of MHC molecules that function in immune recognition. Class I molecules are present on the surfaces of all nucleated cells, and class II molecules are present on the surfaces of APCs. In humans, the MHC is known as the human leukocyte antigen (HLA). Three regions, or loci, on the HLA encode for MHC class I molecules found on nucleated cell surfaces. Collectively, these three regions comprise more than 100 genes and are known as HLA-A, HLA-B, and HLA-C. A separate region on the HLA, known as HLA-D, encodes for MHC class II molecules found on APCs. Within this region are three loci, known as HLA-DP, HLA-DQ, and HLA-DR. A key characteristic of the HLA is the high degree of polymorphism of the MHC molecules for which it encodes. An individual’s HLA type (haplotype) is determined by the MHC molecules expressed on that person’s cell membranes. Genetic variability in HLA type influences susceptibility to infection and autoimmune disease and rejection of transplanted tissue. Tissue typing prior to organ transplantation involves characterization of the HLA types of donor and recipient to determine whether an acceptable “match” is present.

MHC class I molecules present antigen derived from an intracellular pathogen, such as a virus, that has infected the cell. The antigen-MHC class I complex is presented to CTLs, which bind the complex and destroy the infected cell. MHC class II molecules present antigen derived from pathogens that have undergone phagocytosis and subsequent processing. The antigen-class II complex is presented to Th0 cells, which can then differentiate into several subsets of Th cells, two of which are Th1 and Th2 cells (see Figure 41-9). The Th1/Th2 ratio is determined by the nature of the immune response and the local cytokine environment. Interleukin-12 produced by APCs favors Th1 differentiation. Th1 cells secrete IFN-γ, which activates mononuclear phagocytes. Th2 cells secrete IL-4 and IL-5, which promote conversion of B lymphocytes to antibody-secreting plasma cells and stimulate mast cells to release inflammatory mediators. Activation of T cells in response to antigen also promotes T-cell production of IL-2, which acts locally to promote T-cell proliferation and augment the immune response to the antigen.

Vaccination

A key characteristic of the immune response to antigen is clonal expansion of specific B and T lymphocytes directed at the antigen. Clonal expansion allows a more rapid and vigorous immune response on subsequent exposure to the antigen. Vaccination is a process that produces acquired immunity against specific diseases by deliberate exposure of an individual to particular antigens. Vaccination against diseases such as typhoid, cholera, pertussis, and influenza is accomplished by administration of dead organisms that have retained their chemical antigens (epitopes), yet cannot cause an actual disease state. Toxoid vaccines are chemical modifications of toxins produced by pathogens such as tetanus and diphtheria. Attenuated microorganisms are mutated pathogens that themselves do not readily produce disease, but may be used to produce immunity against diseases such as poliomyelitis, measles, rubella, and smallpox.

Passive immunity is produced by administering preformed antibody to provide protection against an invasive pathogen or toxin, often as a lifesaving maneuver. For example, passive immunity may be a maneuver used to treat botulism, diphtheria, or snake-bite. Preformed antibodies are obtained from human or animal blood after immunization against a particular antigen.

Inflammation

Inflammation is the collective response to tissue injury, which can be caused by invasion of infectious microorganisms, toxins, or trauma. The inflammatory response consists of several components: localized vasodilation and increased blood flow; increased capillary permeability and extravasation of plasma proteins, including complement and coagulation factors; and chemotactic movement of leukocytes to the site of injury. The clinical manifestations of inflammation include erythema, localized edema, and pain.1,2

Both the innate and acquired immune systems participate in the production of inflammation. Communication between the two immune systems is provided by a network of peptide mediators known as cytokines (see Box 41-1). Normally these substances act locally to regulate the immune response and may exert synergistic or inhibitory interactions in the regulation of immune cell activity. If produced in high amounts during an exuberant inflammatory response, though, some cytokines may demonstrate measurable blood levels and exert adverse systemic effects.

When resident macrophages encounter a pathogen, they become activated to phagocytize the pathogen and secrete proinflammatory cytokines such as TNF-α, IL-1, IL-6, and IL-12. Among its various actions, TNF-α stimulates the production of endothelial-cell adhesion molecules and chemokines, which are necessary for leukocyte infiltration to the site of infection (see Figure 41-3). Overproduction of TNF-α can have deleterious local and systemic effects. Indeed, high circulating levels of TNF-α are characteristic of chronic major illness and systemic inflammatory response syndrome.

Like TNF-α, IL-1 stimulates endothelial-cell adhesion molecule production. It also has other actions, one of which is to alter the hypothalamic core temperature set-point and produce fever. One important consequence of increased body temperature is more rapid lymphocyte proliferation to combat infectious microorganisms. IL-1 also activates T lymphocytes, thereby recruiting those cell types against the infection. IL-12 promotes preferential differentiation of Th0 cells to the Th1 subtype and activates NK cells. Both Th1 cells and NK cells release IFN-γ, which enhances NK-cell activity and inhibits Th2 cell function. IL-6 stimulates B lymphocytes and may play a role in wound healing. In addition, a recent study in mice has provided evidence that IL-6 can directly stimulate adrenocortical secretion of glucocorticoids, providing a unique mechanism by which the inflammatory response can provoke stress hormone secretion.⁴

TNF-α, IL-1, and IL-6 stimulate production of acute-phase proteins.1,2 These serum proteins are produced by hepatocytes, and their serum levels increase rapidly with the onset of infection. One acute-phase protein of particular importance is C-reactive protein (CRP), which derives its name from its affinity for the C protein of pneumococci. Indeed, CRP serves to opsonize pneumococci and promote their phagocytosis by macrophages. The serum CRP level is often used as a clinical measure of inflammation and may have particular prognostic significance. A number of large, prospective studies have demonstrated the serum CRP level to be an independent predictor of cardiovascular risk.^5,6 It has also been suggested that elevated serum CRP levels might be predictive of perioperative morbidity. One recent study found an association between elevated CRP level and increased length of hospital stay in patients with medium cardiovascular risk undergoing orthopedic procedures.⁷

If the immune response is successful in clearing the pathogen and allowing recovery of tissue function, the inflammatory response is termed acute inflammation.1,2 In some situations, though, the initial immune response does not completely remove the pathogen, and infection persists, causing chronic inflammation to develop. Chronic inflammation is characterized by greater numbers of macrophages and CTLs, compared with the leukocyte population seen with acute inflammation. One concern with chronic inflammation is that it can cause significant injury to host tissues. Chronic bacterial infection, such as occurs with tuberculosis, can lead to the formation of granulomas. These structures are composed of a central core of macrophages and epithelioid cells (produced from activated macrophages) surrounded by infiltrating T lymphocytes. TNF-α is a key cytokine responsible for granuloma formation. Chronic viral infections can also cause tissue injury, such as occurs with chronic hepatitis B virus infection.

Auxiliary cells, such as tissue mast cells, circulating basophils, and platelets, play a key role in inflammation and mobilization of immune responses (see Table 41-1). Mast cells and basophils can be activated by allergens that cross-link antibody molecules bound to the cell surface (to be discussed), by complement products C3a and C5a, by particular drugs such as codeine, morphine, and vancomycin, and by radiocontrast media. Once activated, mast cells and basophils undergo rapid release of proinflammatory substances such as histamine and serotonin and slower de novo production and release of leukotriene D₄ (a powerful bronchoconstrictor) and cytokines TNF-α and IL-4 (Figure 41-13).

FIGURE 41-13 Release of proinflammatory mediators after binding of antigen to IgE molecules on mast cell membranes. Preformed mediators such as histamine are rapidly released, whereas de novo synthesis delays release of other mediators such as leukotrienes and cytokines. Mast cells can also be directly activated by agents such as opioids, vancomycin, radiocontrast media, and complement products C3a and C5a. Similar events occur in response to activation of circulating basophils. (From Male D, et al. Immunology. 8th ed. Philadelphia: Saunders; 2013:381.)

Blood platelets can be activated in several ways, including contact with damaged endothelial cells, by IgG immune complexes, and by platelet-activating factor released from activated macrophages. Activated platelets can aggregate and help to “wall off” an area of inflammation. In addition, activated platelets release serotonin, which acts to increase capillary permeability.

Immune System Pathology

Hypersensitivity and Allergic Reactions

In some cases, the immune response to antigen is greatly exaggerated, a situation referred to as hypersensitivity.1,2 In 1963, Coombs and Gell classified hypersensitivity reactions into types I, II, III, and IV (Figure 41-14). Recently, however, it has been recognized that this classification system is somewhat artificial, as there are overlapping mechanisms of action in types I, II, and III.

FIGURE 41-14 The Coombs and Gell classifications of the four types of hypersensitivity reactions. Type I reactions are immediate hypersensitivity reactions, and type IV reactions are delayed-type hypersensitivity reactions. See discussion in text for characteristics of each type of reaction. (From Male D, et al. Immunology. 8th ed. Philadelphia: Saunders; 2013:372.)

Type I Hypersensitivity

Type I hypersensitivity is a rapidly developing reaction that results from antigen-antibody interaction in an individual who has been previously exposed and sensitized to the antigen. The responsible antigen, referred to as an allergen, reacts with specific IgE antibodies on tissue mast cells and circulating basophils to trigger mediator release (see Figure 41-13) and an allergic response. A key mediator of allergic symptoms is histamine (Box 41-3). Chemically, allergens are usually proteins, and a multitude of environmental factors, including grass, pollen, dust, mites, molds, and animal dander, can generate type I hypersensitivity reactions.

BOX 41-3 Histamine

• Histamine is a basic amine stored in granules within mast cells and basophils and secreted when allergen interacts with membrane-bound IgE or when complement components C3a and C5a interact with specific membrane receptors.

• Histamine produces symptoms of allergic reactions by acting on H₁ or H₂ receptors on target cells.

• The main actions of histamine in humans (via the receptors involved) are:

• Vasodilation (H₁)

• Increased vascular permeability (H₁)

• Contraction of most smooth muscle other than that of blood vessels (H₁)

• Cardiac stimulation (H₂)

• Stimulation of gastric secretion (H₂)

• Intradermal injection of histamine causes the cutaneous “triple response”: erythema from local vasodilation, wheal from increased vascular permeability and protein and fluid extravasation, and flare from an “axon” reflex in sensory nerves that releases a peptide mediator.

• The pathophysiologic effects of histamine can be blocked by H₁-receptor antagonists (diphenhydramine, hydroxyzine, cyclizine, loratadine) and H₂-receptor antagonists (cimetidine, ranitidine, famotidine)

Adapted from Rang HP, et al. Rang and Dale’s Pharmacology. 7th ed. Edinburgh: Churchill Livingstone; 2012.

Allergic reactions present with symptoms such as rhinitis, conjunctivitis, urticaria, pruritus, and possibly anaphylaxis. The term anaphylaxis refers to a severe, generalized, immediate hypersensitivity reaction that includes pruritus, urticaria, angioedema (especially laryngeal edema), hypotension, wheezing and bronchospasm, and direct cardiac effects, including arrhythmias. A shocklike state can develop from hypotension secondary to systemic vasodilation and extravasation of protein and fluid. Clinical manifestations of an allergic reaction can present in various combinations and usually occur within minutes of exposure to the precipitating antigen(s). In some cases, though, the onset of signs and symptoms may be delayed for an hour or longer. Signs and symptoms can be protracted and variably responsive to treatment. Biphasic anaphylaxis also can occur, in which early signs and symptoms clear, either spontaneously or after acute therapy, and then symptoms recur several or many hours later. Generally, the severity of an anaphylactic event relates to the suddenness of its onset and to the magnitude of the challenge, that is, the bigger the provocative stimulus, the more severe the reaction. However, anaphylaxis can occur after exposure to minute amounts of allergen in highly sensitive individuals.

Anaphylactoid reactions are caused by mediator release from basophils and mast cells in response to a non–IgE-mediated triggering event. Such reactions present with similar clinical manifestations as those with anaphylaxis, though symptoms may be less severe than those associated with IgE-mediated reactions.⁸

Tryptase is a marker for mechanistic delineation of an allergic response. It is an enzyme released from mast cells, along with histamine and other inflammatory mediators, during an allergic response. Tryptase has a half-life of several hours and is stable at room temperature. It demonstrates a positive predictive value of 92.6% and a negative predictive value of 54.6% as an indicator of an immunologically mediated event. Thus a significantly elevated tryptase level (greater than 25 mcg/L) strongly suggests an allergic mechanism. The presence of a normal tryptase level, however, does not exclude an immunologic reaction because elevated tryptase levels are not found in almost one third of anaphylactic cases. Although diagnosis of anaphylaxis should not rely on a single test, the high positive predictive value of tryptase makes it useful medicolegally and for subsequent patient management.8,9

Type II Hypersensitivity

Type II hypersensitivity reactions result from IgG and IgM antibodies binding to antigens on cell surfaces or extracellular tissue components such as basement membrane (see Figure 41-14).^1,2 The antigen-antibody reaction activates the complement cascade, causing production of C3a and C5a, which attract PMNs and macrophages, and production of the C5b5789 membrane attack complex that inserts into target cell membranes. Examples of type II hypersensitivity reactions include transfusion reactions, autoimmune hemolytic anemia, myasthenia gravis, and Goodpasture syndrome.