Diseases of the Immune System

Receptors of Innate Immunity

Pattern recognition receptors are located in all the cellular compartments where pathogens may be present: plasma membrane receptors detect extracellular pathogens, endosomal receptors detect ingested microbes, and cytosolic receptors detect microbes in the cytoplasm ( Fig. 5.2 ). Several classes of these receptors have been identified.

Reactions of Innate Immunity

The innate immune system provides host defense by two main reactions:

• Inflammation. Cytokines and products of complement activation, as well as other mediators, are produced during innate immune reactions and trigger the vascular and cellular components of inflammation ( Chapter 2 ). The recruited leukocytes destroy pathogens and ingest and eliminate damaged cells.

• Antiviral defense. Type I interferons produced in response to viruses act on infected and uninfected cells and activate enzymes that degrade viral nucleic acids and inhibit viral replication.

In addition to these defensive functions, the innate immune system generates signals that stimulate the subsequent, more powerful adaptive immune response. Some of these signals are described later.

T Lymphocytes

T lymphocytes, so called because they mature in the thymus, develop into the effector cells of cellular immunity following their activation and also stimulate B cells to produce antibodies against protein antigens. T cells constitute 60% to 70% of the lymphocytes in peripheral blood and are the major lymphocyte population in splenic periarteriolar sheaths and lymph node interfollicular zones. T cells cannot recognize free or circulating antigens; instead, the vast majority (>95%) of T cells see only peptide fragments of intracellular proteins displayed by molecules of the major histocompatibility complex (MHC), discussed in more detail later.

There are two major classes of T cells that are distinguished by the expression of CD4 or CD8 on their surfaces. CD4+ T cells are called helper T cells because they secrete soluble molecules (cytokines) that stimulate (help) B cells to produce antibodies and help macrophages to destroy phagocytosed microbes. The central role of CD4+ helper cells in immunity is highlighted by the severe immune defects that result from destruction of these cells by human immunodeficiency virus (HIV) infection (described later). The most important function of CD8+ T cells is to directly kill virus-infected cells and tumor cells; hence, they are called cytotoxic T lymphocytes (CTLs) .

Peptide antigens presented by MHC molecules are recognized by the T-cell receptor (TCR), a heterodimer that in most T cells is composed of disulfide-linked α and β protein chains ( Fig. 5.4A ). Each chain has a variable region that participates in binding a particular peptide antigen and a constant region that interacts with associated signaling molecules. The sequence diversity of the antigen-binding portions is a consequence of the rearrangement and assembly of a multitude of TCR gene segments into functional TCR genes. T cells also express a number of other molecules that serve important functions in immune responses. The CD3 complex is noncovalently associated with the TCR and initiates activating signals following TCR recognition of antigen. During antigen recognition, CD4 molecules on T cells bind to invariant portions of class II MHC molecules (described later) on selected APCs; in an analogous fashion, CD8 binds to class I MHC molecules. CD4 is expressed on 60% to 70% of T cells, whereas CD8 is expressed on about 30% to 40% of T cells. Other important invariant proteins on T cells include CD28, which functions as the receptor for molecules called costimulators that are induced on APCs by microbes, and various adhesion molecules that strengthen the bond between the T cells and APCs and control the migration of the T cells to different tissues.

T cells that function to suppress immune responses are called regulatory T lymphocytes . This cell type is described later, when we discuss immunologic tolerance.

Major Histocompatibility Complex Molecules: The Peptide Display System of Adaptive Immunity

MHC molecules are fundamental to T-cell recognition of antigens, and genetic variations in MHC molecules are associated with graft rejection and autoimmune diseases; hence, it is important to review the structure and function of these molecules. The MHC was discovered on the basis of studies of graft rejection and acceptance (tissue, or “histo,” compatibility). The normal function of MHC molecules is to display peptides for recognition by CD4+ and CD8+ T lymphocytes. In each individual, T cells recognize only peptides displayed by that person’s MHC molecules, which, of course, are the only MHC molecules that the T cells normally encounter. This property of T-cell antigen recognition is called MHC restriction . Because T cells recognize MHC molecules, variations in these molecules among individuals elicit strong immune responses. This is the basis of graft rejection, described later.

The human MHC, known as the human leukocyte antigen (HLA) complex, consists of a cluster of genes on chromosome 6 ( Fig. 5.5 ). On the basis of their chemical structure, tissue distribution, and function, MHC gene products fall into two main categories:

• Class I MHC molecules are expressed on all nucleated cells and are encoded by three closely linked loci, designated HLA-A, HLA-B, and HLA-C. Each of these molecules consists of a polymorphic α chain noncovalently associated with an invariant β ₂ -microglobulin polypeptide (encoded by a separate gene on chromosome 15). The extracellular portion of the α chain contains a cleft where the polymorphic residues are located and where foreign peptides bind to MHC molecules for presentation to T cells, and a conserved region that binds CD8, ensuring that only CD8+ T cells can respond to peptides displayed by class I molecules. Class I MHC molecules bind and display peptides derived from protein antigens present in the cytosol of the cell (e.g., viral and tumor antigens).

• Class II MHC molecules are encoded by genes in the HLA-D region, which contains three subregions: DP, DQ, and DR. Class II molecules are heterodimers of noncovalently linked α and β subunits. Unlike class I MHC molecules, which are expressed on all nucleated cells, expression of class II MHC molecules is restricted to a few cell types, mainly APCs (notably, dendritic cells), macrophages, and B cells. The extracellular portion of class II MHC molecules contains a cleft for the binding of antigenic peptides and a region that binds CD4. In general, class II MHC molecules bind peptides derived from extracellular proteins, for example, from microbes that are ingested and then broken down inside the cell. This property allows CD4+ T cells to recognize the presence of extracellular pathogens.

HLA genes are highly polymorphic; that is, there are alternative forms (alleles) of each gene at each locus (estimated to number over 10,000 for all HLA genes and over 3500 for HLA-B alleles alone). Each individual expresses only one set of HLA genes, and each MHC molecule can display only one peptide at a time. The many MHC variants in the population evolved to display the multitude of microbial peptides that could be encountered in the environment. As a result of this polymorphism, a vast number of combinations of HLA molecules exist in the population. HLA genes are closely linked, so they are passed from parent to offspring en bloc and behave like a single locus with respect to their inheritance patterns. Each set of maternal and paternal HLA genes is referred to as an HLA haplotype . Because of this mode of inheritance, the probability that siblings will inherit the same HLA alleles is 25%. By contrast, the probability that an unrelated donor will share the same HLA genes is very low. The implications of HLA polymorphism for transplantation are obvious; because each person has HLA alleles that differ to some extent from those of every other unrelated individual, grafts from unrelated donors will elicit immune responses in the recipient and be rejected unless the T cell response is suppressed (see discussion later). Only identical twins can accept grafts from one another without fear of rejection.

The inheritance of particular MHC alleles influences both protective and harmful immune responses. The ability of any given MHC allele to bind the peptide antigens generated from a particular pathogen will determine whether a specific individual’s T cells can recognize and mount a protective response to that pathogen. Conversely, if the antigen is an allergen and the response is an allergic reaction, inheritance of some HLA alleles may make individuals susceptible to the allergic reaction. Many autoimmune diseases are associated with particular HLA alleles. We return to a discussion of these associations when we consider autoimmunity.

B Lymphocytes

B lymphocytes, so-called because they mature in the bone marrow, are the cells that produce antibodies, the mediators of humoral immunity. B cells make up 10% to 20% of lymphocytes in the blood. They are also present in bone marrow and in the follicles of secondary (peripheral) lymphoid organs.

B cells recognize antigens by means of membrane-bound antibody of the immunoglobulin M (IgM) class, expressed on the surface together with signaling molecules to form the B-cell receptor (BCR) complex (see Fig. 5.4B ). Whereas T cells recognize only MHC-associated peptides, B cells recognize and respond to many more chemical structures, including soluble or cell-associated proteins, lipids, polysaccharides, nucleic acids, and small chemicals, without requiring the MHC. As with TCRs, each antibody has a unique amino acid sequence in its antigen-binding site. B cells express several invariant molecules, such as Igα and Igβ, that are responsible for signal transduction and activation following antigen recognition by the BCR.

After stimulation, B cells differentiate into plasma cells, which secrete large amounts of antibodies. There are five classes, or isotypes, of immunoglobulins that differ in their constant regions: IgG, IgM, and IgA constitute more than 95% of circulating antibodies (IgG being at the highest concentration); IgA is the major isotype in mucosal secretions; IgE is present in the circulation at very low concentrations and is found attached to the surfaces of tissue mast cells; and IgD is expressed on the surfaces of B cells but is virtually undetectable in the blood. These isotypes differ in their ability to activate complement and recruit inflammatory cells and thus have different roles in host defense and disease states.

Natural Killer Cells

Natural killer (NK) cells are lymphocytes that arise from the same common lymphoid progenitor that gives rise to T lymphocytes and B lymphocytes. NK cells are innate immune cells, as they are functional without prior activation and do not express highly variable receptors for antigens. The activation of NK cells is regulated by signals from two types of receptors. Inhibitory receptors recognize self class I MHC molecules, which are expressed on all healthy cells, whereas activating receptors recognize molecules that are expressed at high levels on stressed or infected cells. Normally, signals from inhibitory receptors dominate over those of activating receptors, preventing spontaneous activation of the NK cells and killing of normal host cells. Infections (especially viral infections) and stress are associated with reduced expression of class I MHC molecules and increased expression of proteins that engage activating receptors, resulting in activation of NK cells and elimination of the infected or stressed cells. NK cells also secrete cytokines such as interferon-γ (IFN-γ), thus providing early defense against intracellular microbial infections.

Innate lymphoid cells (ILCs) are lymphocytes related to NK cells that are not cytotoxic but produce many of the same cytokines that helper T cells do. ILCs do not express antigen receptors but respond to cytokines produced as a result of cell injury and stress. Because ILCs are always present in tissues, they may be early responders to microbes that damage tissues. However, their role in host defense in humans is not established.

Dendritic Cells

Dendritic cells (DCs) are the most important antigen-presenting cells (APCs) for initiating T-cell responses against protein antigens. These cells have numerous fine cytoplasmic processes that resemble dendrites, from which they derive their name. Several features of DCs account for their key role in antigen capture and presentation.

• DCs are located at the right place to capture antigens—under epithelia, the common site of entry of microbes and foreign antigens, and in the interstitia of all tissues, where antigens may be produced. DCs within the epidermis are called Langerhans cells.

• DCs express receptors for capturing and responding to microbes (and other antigens), including TLRs and C-type lectin receptors.

• In response to microbes, DCs migrate to the T-cell zones of lymphoid organs, where they are ideally positioned to present antigens to T cells.

• DCs express high levels of MHC and other molecules needed for antigen presentation and activation of T cells.

Other Antigen-Presenting Cells

Macrophages present antigens of phagocytosed microbes to T cells, which then activate the phagocytes to destroy the microbes. This is a central reaction of cell-mediated immunity. B lymphocytes present endocytosed antigens to helper T cells and receive activating signals from the T cells in humoral immune responses. All nucleated cells can present antigens of cytosolic viruses or tumor antigens to CD8+ T cells and are killed by these T cells. A specialized fibroblast with dendritic morphology, called the follicular dendritic cell (FDC), is present in the germinal centers of lymphoid follicles in the spleen and lymph nodes. These cells bear Fc receptors for IgG and receptors for C3b and can trap antigen bound to antibodies or complement proteins. These cells display antigens to B lymphocytes in lymphoid follicles and promote antibody responses but are not involved in capturing antigens for display to T cells.

Secondary Lymphoid Organs

The secondary lymphoid organs are organized to concentrate antigens, APCs, and lymphocytes in a way that optimizes interactions among these cells and the development of adaptive immune responses. Most of the body’s lymphocytes are located in these organs ( Table 5.1 ).

• Lymph nodes are encapsulated, organized collections of lymphocytes, dendritic cells, and macrophages that are located along lymphatic channels throughout the body ( Fig. 5.6A ). As lymph passes through lymph nodes, resident APCs are able to sample antigens that are carried to the node in lymph from the interstitial fluids of tissues. In addition, DCs transport antigens from nearby epithelial surfaces and tissues by migrating through lymphatic vessels to the lymph nodes. Thus, antigens (e.g., of microbes that enter through epithelia or colonize tissues) become concentrated in draining lymph nodes.

  

• The spleen is organized into white pulp, which is where lymphocytes reside, and red pulp, which contains a network of sinusoids (through which blood flows). It plays an important role in immune responses to bloodborne antigens. Blood entering the spleen flows through the sinusoids where bloodborne antigens are trapped by resident DCs and macrophages.

• The cutaneous and mucosal lymphoid systems are located under the epithelia of the skin and the gastrointestinal and respiratory tracts, respectively. They respond to antigens that enter through breaches in the epithelium. Pharyngeal tonsils and Peyer’s patches of the intestine are two anatomically defined mucosal lymphoid tissues. The large number of lymphocytes in mucosal organs (second only to lymph nodes) reflects the huge surface area of these organs.

In the secondary lymphoid organs, T lymphocytes and B lymphocytes are segregated into different regions ( Fig. 5.6B, C ). In lymph nodes, the B cells are concentrated in discrete structures, called follicles, located at the periphery, or cortex, of each node. If the B cells in a follicle have recently responded to an antigen, the follicle develops a central pale-staining region called a germinal center . T lymphocytes are concentrated in the parafollicular cortex. The follicles contain the FDCs that are involved in the activation of B cells, and the paracortex contains the DCs that present antigens to T lymphocytes. In the spleen, T lymphocytes are concentrated in periarteriolar lymphoid sheaths surrounding small arterioles, and B cells reside in the follicles.

Cytokines: Messenger Molecules of the Immune System

Cytokines are secreted proteins that mediate immune and inflammatory reactions. Molecularly defined cytokines are called interleukins, a name implying a role in communication between leukocytes. Most cytokines have a wide spectrum of actions, and some are produced by several different cell types. The majority of cytokines act on the cells that produce them or on neighboring cells, but some (like IL-1) also have systemic effects.

Different cytokines contribute to specific types of immune responses.

• In innate immune responses, cytokines are produced rapidly after microbes and other stimuli are encountered, and function to induce inflammation and inhibit virus replication. These cytokines include TNF, IL-1, IL-12, type I IFNs, IFN-γ, and chemokines ( Chapter 2 ). They are produced primarily by macrophages, DCs, ILCs, and NK cells but can also be secreted by endothelial and epithelial cells.

• In adaptive immune responses, cytokines are produced principally by CD4+ T lymphocytes activated by antigen and other signals. They function to promote lymphocyte proliferation and differentiation and to activate effector cells. The main cytokines in this group are IL-2, IL-4, IL-5, IL-17, and IFN-γ; their roles in immune responses are described later. Some cytokines serve mainly to limit and terminate immune responses; these include TGF-β and IL-10.

• Other cytokines stimulate hematopoiesis and are called colony-stimulating factors because they stimulate formation of blood cell colonies from bone marrow progenitors ( Chapter 10 ), which increases leukocyte numbers during immune and inflammatory responses and replaces leukocytes that are consumed during such responses. They are produced by marrow stromal cells, T lymphocytes, macrophages, and other cells. Examples include IL-3, IL-7, and granulocyte-colony-stimulating factor.

The knowledge gained about cytokines has numerous practical therapeutic applications. Inhibiting cytokine production or actions can control the harmful effects of inflammation. For example, patients with rheumatoid arthritis often show dramatic responses to TNF antagonists. Other cytokine antagonists are now used to treat various inflammatory disorders. Conversely, administration of cytokines is used to boost reactions that are normally dependent on these proteins, such as hematopoiesis (e.g., following stem cell transplantation).

Sequence of Events in Immediate Hypersensitivity Reactions

Most immediate hypersensitivity reactions follow a stereotypic sequence of cellular responses ( Fig. 5.10 ):

• Activation of Th2 cells and production of IgE antibody. Only a subset of individuals exposed to common environmental antigens make strong Th2 and IgE responses. The factors that contribute to this propensity are discussed later. Th2 cells secrete several cytokines, including IL-4, IL-5, and IL-13, which are responsible for the reactions of immediate hypersensitivity. IL-4 and IL-13 stimulate allergen-specific B cells to undergo heavy-chain class switching to IgE. IL-5 activates eosinophils that are recruited to the reaction, and IL-13 stimulates mucus secretion from epithelial cells. Th2 cells are often recruited to the site of allergic reactions in response to locally produced chemokines; one of these chemokines, eotaxin, also recruits eosinophils to the same site.

• Sensitization of mast cells by IgE antibody. Mast cells are derived from precursors in the bone marrow and widely distributed in tissues, often residing near blood vessels and nerves and in subepithelial locations. Mast cells express a high-affinity receptor for the Fc portion of the ε heavy chain of IgE, called FcεRI. Although the serum concentration of IgE is very low (in the range of 0.1 to 10 μg/mL), the affinity of the mast cell FcεRI receptor is so high that the receptors are always occupied by IgE. These antibody-bearing mast cells are sensitized to react if the specific antigen (the allergen) binds to the antibody molecules. Basophils, circulating cells that resemble mast cells, also express FcεRI, may be recruited into tissues, and may contribute to immediate hypersensitivity reactions.

• Activation of mast cells and release of mediators. When a person who has been sensitized by exposure to an allergen is reexposed to that allergen, the allergen binds to antigen-specific IgE molecules on mast cells, usually at or near the site of allergen entry. Cross-linking of these IgE molecules triggers a series of biochemical signals from the associated FcεRI receptor that culminate in the secretion of various mediators from the mast cells.

Three groups of mediators are important in different immediate hypersensitivity reactions:

• Vasoactive amines released from granule stores. The granules of mast cells contain histamine , which is released within seconds or minutes of activation. Histamine causes vasodilation, increased vascular permeability, smooth muscle contraction, and increased mucus secretion. Other rapidly released mediators include neutral proteases (e.g., tryptase), which may damage tissues and also generate kinins and cleave complement components to produce additional chemotactic and inflammatory factors (e.g., C5a) ( Chapter 2 ). The granules also contain acidic proteoglycans (e.g., heparin, chondroitin sulfate), which seem to serve as a storage matrix for the amines.

• Newly synthesized lipid mediators. Mast cells synthesize and secrete prostaglandins and leukotrienes by the same pathways as do other leukocytes ( Chapter 2 ). These lipid mediators have several actions that are important in immediate hypersensitivity reactions. Prostaglandin D2 (PGD ₂ ) is the most abundant mediator generated by the cyclooxygenase pathway in mast cells. It causes intense bronchospasm as well as increased mucus secretion. The leukotrienes LTC ₄ and LTD ₄ are the most potent vasoactive and spasmogenic agents known; on a molar basis, they are several thousand times more active than histamine in increasing vascular permeability and in causing bronchial smooth muscle contraction. LTB ₄ is highly chemotactic for neutrophils, eosinophils, and monocytes.

• Cytokines. Activated mast cells secrete several cytokines that are important for the late-phase reaction. These include TNF and chemokines, which recruit and activate leukocytes ( Chapter 2 ).

The reactions of immediate hypersensitivity did not evolve to cause human discomfort and disease. The Th2 response plays an important protective role in combating parasitic infections, mainly by destruction of helminths by eosinophil granule proteins. Mast cells are also involved in defense against bacterial infections and animal venoms.

Development of Allergies

Susceptibility to immediate hypersensitivity reactions is genetically determined. An increased propensity to develop immediate hypersensitivity reactions is called atopy . Atopic individuals tend to have higher serum IgE levels and more IL-4–producing Th2 cells than does the general population. A positive family history of allergy is found in 50% of atopic individuals. Genes that are implicated in susceptibility to asthma and other atopic disorders include those encoding HLA molecules (which may confer immune responsiveness to particular allergens), cytokines (which may control Th2 responses), a component of the FcεRI receptor, and ADAM33, a metalloproteinase that may be involved in tissue remodeling in the airways.

Environmental factors are also important in the development of allergic diseases. Exposure to environmental pollutants, all too common in industrialized societies, is an important predisposing factor for allergy. Dogs and cats living in the same environment as humans can develop allergies, whereas chimps living in the wild do not despite their much closer genetic similarity to humans. This simple observation suggests that environmental factors may be more important in the development of allergic disease than genetics. Viral infections of the airways are important triggers for bronchial asthma, an allergic disease affecting the lungs ( Chapter 11 ). Bacterial skin infections are strongly associated with atopic dermatitis.

It is estimated that 20% to 30% of immediate hypersensitivity reactions are triggered by nonantigenic stimuli such as temperature extremes and exercise and do not involve Th2 cells or IgE. It is believed that in these cases of nonatopic allergy, mast cells are abnormally sensitive to activation by various nonimmune stimuli.

The incidence of many allergic diseases is increasing in higher-income countries, perhaps related to a decrease in infections during early life. This observation has led to an idea, called the hygiene hypothesis, that early childhood and even prenatal exposure to microbial antigens educates the immune system such that subsequent pathologic responses against common environmental allergens are prevented. Thus, too little exposure to potential allergens and, perhaps, microbes in childhood may predispose individuals to allergies later in life. This idea has received support from clinical studies demonstrating that exposing infants to peanuts reduces the incidence of peanut allergy later in life.

Clinical and Pathologic Manifestations of Allergic Diseases

Often, the IgE-triggered reaction has two well-defined phases ( Fig. 5.11 ).

• The immediate response, usually evident within 5 to 30 minutes after exposure to an allergen and subsiding by 60 minutes, is stimulated by mast cell granule contents and lipid mediators. It is characterized by vasodilation, vascular leakage, and smooth muscle spasm.

• A second, late-phase reaction usually begins 2 to 8 hours later and may last for several days. It is stimulated mainly by cytokines and is characterized by inflammation as well as tissue injury, such as mucosal epithelial cell damage. The dominant inflammatory cells in the late-phase reaction are neutrophils, eosinophils, and lymphocytes, especially Th2 cells. Neutrophils are recruited by various chemokines; their roles in inflammation were described in Chapter 2 . Eosinophils, which are recruited by eotaxin and other chemokines released from epithelium, produce granule proteins that are toxic to epithelial cells as well as leukotrienes and other factors that promote inflammation. Th2 cells produce cytokines that have multiple actions, as described earlier. These recruited leukocytes can amplify and sustain the injurious inflammatory response, even in the absence of continuous allergen exposure. Because inflammation is a major component of many allergic diseases, notably asthma and atopic dermatitis, therapy includes antiinflammatory drugs such as corticosteroids.

Immediate hypersensitivity reactions may occur as systemic disorders or as local reactions ( Table 5.3 ). The route of antigen exposure often determines the nature of the reaction. Exposure to protein antigens (e.g., in bee venom) or drugs (e.g., penicillin) that enter the circulation may result in systemic anaphylaxis . Within minutes of the exposure in a sensitized host, itching, urticaria (hives), and skin erythema appear, followed rapidly by profound respiratory difficulty caused by pulmonary bronchoconstriction and hypersecretion of mucus. Laryngeal edema may exacerbate matters by causing upper airway obstruction. In addition, the musculature of the entire gastrointestinal tract may be affected, with resultant vomiting, abdominal cramps, and diarrhea. Without immediate intervention, there may be systemic vasodilation with a fall in blood pressure (anaphylactic shock), and the patient may progress to circulatory collapse and death within minutes.

Local reactions generally occur when the antigen is confined to a particular site, such as the skin (following contact), the gastrointestinal tract (following ingestion), or the lung (following inhalation). Atopic dermatitis (eczema), food allergies, allergic rhinitis (hay fever), and certain forms of asthma are examples of localized allergic reactions. However, ingestion or inhalation of allergens also can trigger systemic reactions if the allergen is absorbed into the circulation, as happens in cases of peanut allergy. Sometimes, infants develop atopic dermatitis, followed, later in life, by allergic rhinitis and asthma. These three disorders are grouped under the atopic triad , and their sequential development has been called the atopic march .

Therapy for allergies relies on corticosteroids (to reduce inflammation) and agents to counteract the effects of mediators (such as antihistamines, leukotriene antagonists, bronchodilators for asthma, and epinephrine to correct the drop in blood pressure in anaphylaxis). Antibodies that block Th2 cytokines or their receptors or neutralize IgE are now used for the treatment of asthma, atopic dermatitis, and peanut allergy.

Mechanisms of Antibody-Mediated Diseases

In type II hypersensitivity, antibodies cause disease by targeting cells for phagocytosis, activating the complement system, or interfering with normal cellular functions ( Fig. 5.12 ). The antibodies that are responsible are typically high-affinity IgG and IgM antibodies capable of activating complement and, for IgG, binding to phagocyte Fc receptors.

• Opsonization and phagocytosis. When circulating cells, such as red cells or platelets, are coated (opsonized) with autoantibodies, with or without complement proteins, the cells become targets for phagocytosis by neutrophils and macrophages (see Fig. 5.12A ). These phagocytes express receptors for the Fc tails of IgG antibodies and for breakdown products of the C3 complement protein and use these receptors to bind and ingest opsonized particles. Opsonized blood cells are usually eliminated by macrophages in the spleen, which is why splenectomy is of clinical benefit in some antibody-mediated diseases.

• Antibody-mediated cell destruction occurs in the following clinical situations: (1) transfusion reactions, in which cells from an incompatible donor react with preformed antibody in the host ( Chapter 10 ); (2) hemolytic anemia of the fetus and newborn (erythroblastosis fetalis), in which IgG anti–red cell antibodies from the mother cross the placenta and cause destruction of fetal red cells ( Chapter 4 ); (3) autoimmune hemolytic anemia, neutropenia, and thrombocytopenia, in which individuals produce antibodies to their own blood cells ( Chapter 10 ); and (4) certain drug reactions, in which a drug attaches to plasma membrane proteins of red cells and antibodies are produced against the drug-protein complex.

• Inflammation. Antibodies bound to tissue antigens activate the complement system by the classical pathway (see Fig. 5.12B ). Products of complement activation serve several functions ( Chapter 2 ), one of which is to recruit neutrophils and monocytes, triggering inflammation in tissues. Leukocytes may also be activated by engagement of Fc receptors, which recognize the bound antibodies. Antibody-mediated inflammation is responsible for tissue injury in some forms of glomerulonephritis, vascular rejection in organ grafts, and other disorders.

• Antibody-mediated cellular dysfunction. In some cases, antibodies directed against an essential protein impair or dysregulate important functions without directly causing cell injury or inflammation. In pernicious anemia, antibodies against intrinsic factor, which is required for absorption of vitamin B ₁₂ in the stomach, lead to a deficiency of this vitamin and abnormal hematopoiesis; antibody-mediated damage to gastric epithelial cells may also contribute. Previously, it was thought that in myasthenia gravis, antibodies specific for the acetylcholine receptor in neuromuscular junctions of motor end plates of skeletal muscles inhibited neuromuscular transmission, resulting in muscle weakness, but without injury. However, recent clinical studies have shown benefit with complement inhibition therapies, suggesting that antibody- and complement-mediated damage to motor end plates may be involved in disease pathogenesis. Antibodies can also stimulate excessive cellular responses; e.g., in Graves disease, antibodies against the thyroid-stimulating hormone receptor stimulate thyroid epithelial cells to secrete thyroid hormones, resulting in hyperthyroidism (see Fig. 5.12C ).

Systemic Immune Complex Disease

Much of what we know about systemic immune complex disease is derived from studies of acute serum sickness, which was once a complication of the administration of large amounts of foreign protein (e.g., in serum from immunized horses used for protection against diphtheria). In modern times, the disease is infrequent and is usually seen in individuals who receive antibodies from other individuals or species, e.g., horse or rabbit antithymocyte globulin administered to deplete T cells in recipients of organ grafts.

Acute serum sickness induced by administration of a single large dose of antigen is characterized by fever, rash, and arthritis; the lesions tend to resolve as the complexes are cleared by phagocytes. A form of chronic serum sickness results from repeated or prolonged exposure to an antigen. This occurs in several diseases, such as systemic lupus erythematosus (SLE), which is associated with persistent antibody responses to autoantigens. In many diseases, the morphologic changes and other findings suggest immune complex deposition, but the inciting antigens are unknown. Included in this category are several vasculitides, such as polyarteritis nodosa.

Local Immune Complex Disease (Arthus Reaction)

A model of local immune complex diseases is the Arthus reaction, in which an area of tissue necrosis appears as a result of acute immune complex vasculitis. The reaction is produced experimentally by injecting an antigen into the skin of a previously immunized animal. Immune complexes form as the antigen diffuses into the vascular wall at the site of injection and binds to preformed antibody, triggering the same inflammatory reaction and histologic appearance as in systemic immune complex disease. Within a few hours, the injection site develops edema and hemorrhage, occasionally followed by ulceration.

CD4+ T Cell–Mediated Inflammation

In CD4+ T cell–mediated hypersensitivity reactions, cytokines produced by the T cells induce inflammation that may be chronic and destructive. The prototype of T cell–mediated inflammation is delayed-type hypersensitivity (DTH), a tissue reaction to antigens given to individuals who are already sensitized. In this setting, an antigen administered into the skin results in a detectable cutaneous reaction within 24 to 48 hours (hence the term delayed, in contrast to immediate hypersensitivity).

As described earlier, naïve T cells are activated in secondary lymphoid organs by recognition of peptide antigens displayed by dendritic cells and the T cells differentiate into effector cells. Classical T cell–mediated hypersensitivity is a reaction of Th1 effector cells, but Th17 cells also may contribute, especially when neutrophils are prominent in the inflammatory infiltrate. Th1 cells secrete cytokines, mainly IFN-γ, which are responsible for many of the manifestations of delayed-type hypersensitivity. IFN-γ–activated (so-called classically activated, or M1) macrophages produce substances that destroy microbes and damage tissues and mediators that promote inflammation ( Chapter 2 ). Activated Th17 cells secrete cytokines that recruit neutrophils and monocytes.

Clinical Examples of CD4+ T Cell–Mediated Inflammatory Reactions

The classic example of DTH is the tuberculin reaction (known in clinical medicine as the PPD skin test ), which is produced by the intracutaneous injection of purified protein derivative (PPD, also called tuberculin ), containing protein antigens of the Mycobacterium tuberculosis bacillus. In a previously exposed individual, reddening and induration of the site appear in 8 to 12 hours, reach a peak in 24 to 72 hours, and then slowly subside. Morphologically, delayed-type hypersensitivity is characterized by the accumulation of mononuclear cells, mainly CD4+ T cells and macrophages, around venules, producing perivascular “cuffing” ( Fig. 5.15 ). Prolonged DTH reactions against persistent microbes or other stimuli may result in a special pattern of reaction called granulomatous inflammation ( eFig. 5.1 ), described in Chapter 2 . The release of IFN-γ from blood cells stimulated with mycobacterial antigens in vitro is another widely used test for tuberculosis.

Contact dermatitis is a common example of tissue injury resulting from DTH reactions. It may be evoked by contact with urushiol, the antigenic component of poison ivy and poison oak, and presents as a vesicular dermatitis. It is thought that in these reactions, the environmental chemical binds to and structurally modifies self proteins, and peptides derived from these modified proteins are recognized by T cells that elicit the reaction. The same mechanism is responsible for many drug reactions, among the most common hypersensitivity reactions of humans. The responsible drug (often a reactive chemical) alters self proteins, including MHC molecules, and these neoantigens are recognized as foreign by T cells, leading to cytokine production and inflammation. Drug reactions often manifest as skin rashes.

CD4+ T cell–mediated inflammation is the basis of tissue injury in many organ-specific and systemic autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, as well as diseases probably caused by uncontrolled reactions to bacterial commensals, such as inflammatory bowel disease (see Table 5.6 ).

CD8+ T Cell–Mediated Cytotoxicity

In this type of T cell–mediated reaction, CD8+ CTLs kill antigen-expressing target cells. Tissue destruction by CTLs may be a component of some T cell–mediated diseases, such as type 1 diabetes. CTLs directed against cell surface histocompatibility antigens play an important role in organ transplant rejection, which is discussed later. They also play a role in reactions against viruses. In a virus-infected cell, viral peptides are displayed by class I MHC molecules and the complex is recognized by the TCR of CD8+ T lymphocytes. The killing of infected cells leads to elimination of the infection but, in some cases, causes cell damage (e.g., in viral hepatitis). CD8+ T cells also produce cytokines, notably IFN-γ, and are involved in inflammatory reactions resembling DTH, especially following virus infections and exposure to some contact sensitizing agents.

Now that we have described how the immune system can cause tissue damage, we turn to autoimmune disorders, which are the result of failure of tolerance to self antigens and in which disease is caused by hypersensitivity reactions.