Robbins and Cotran - Chapter 6 Diseases of the Immune System

Adaptive immunity

(also called acquired, or specific, immunity) consists of mechanisms that are stimulated by ("adapt to") exposure to microbes and other foreign substances. It develops more slowly than innate immunity, but is even more powerful in combating infections. By convention, the term immune response usually refers to adaptive immunity. Figure 6.1. The principal components of innate and adaptive immunity. NK, Natural killer.

Innate immunity

(also called natural, or native, immunity) refers to intrinsic mechanisms that are poised to react immediately, and thus constitute the first line of defense. It is mediated by cells and molecules that recognize products of microbes and dead cells and induce rapid protective host reactions. Figure 6.1. The principal components of innate and adaptive immunity. NK, Natural killer.

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. The recruited leukocytes destroy microbes and ingest and eliminate damaged cells. The innate immune response also triggers the repair of damaged tissues. - 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, inducing what has been called an antiviral state. NK cells recognize virus-infected cells, as described above.

Three phases of systemic immune complex disease

1. Formation of immune complexes. The introduction of a protein antigen triggers an immune response that results in the formation of antibodies, typically about 1 week after the injection of the protein. These antibodies are secreted into the blood, where they react with the antigen still present in the circulation and form antigen-antibody complexes. 2. Deposition of immune complexes. In the next phase, the circulating antigen-antibody complexes are deposited in vessels. The factors that determine whether immune complex formation will lead to tissue deposition and disease are not fully understood, but the major influences seem to be the characteristics of the complexes and local vascular alterations. In general, complexes that are of medium size, formed under conditions of slight antigen excess, are the most pathogenic. Organs where blood is filtered at high pressure to form other fluids, like urine and synovial fluid, are sites where immune complexes become concentrated and tend to deposit; hence, immune complex disease often affects glomeruli and joints. 3. Inflammation and tissue injury. Once immune complexes are deposited in the tissues, they initiate an acute inflammatory reaction. During this phase (approximately 10 days after antigen administration), clinical features such as fever, urticaria, joint pain, lymph node enlargement, and proteinuria appear. Wherever complexes deposit, inflammation and tissue injury occur through the antibody-mediated mechanisms that were discussed earlier. The important role of complement in the pathogenesis of the tissue injury is supported by the observations that complement proteins can be detected at the site of injury and, during the active phase of the disease, consumption of complement leads to a decrease in serum levels of C3.

Peripheral Tolerance - Suppression by regulatory T cells

A population of T cells called regulatory T cells functions to prevent immune reactions against self antigens. Regulatory T cells develop mainly in the thymus, as a result of recognition of self antigens, but they may also be induced in peripheral lymphoid tissues. The best-defined regulatory T cells are CD4+ cells that express high levels of CD25, the α chain of the IL-2 receptor, and FOXP3, a transcription factor of the forkhead family. Both IL-2 and FOXP3 are required for the development and maintenance of functional CD4+ regulatory T cells. Regulatory T cells may suppress immune responses by multiple mechanisms. Their inhibitory activity may be mediated in part by the secretion of immunosuppressive cytokines such as IL-10 and TGF-β, which inhibit lymphocyte activation and effector functions. Regulatory T cells prevent immune responses not only against self antigens but also against the fetus and commensal microbes.

Differentiation of CD8+ T lymphocytes

Activated CD8+ T lymphocytes differentiate into CTLs that kill cells harboring microbes in the cytoplasm. By destroying the infected cells, CTLs eliminate the reservoirs of infection. CTLs also kill tumor cells by recognizing tumor-specific antigens derived from mutated or abnormal cytoplasmic proteins.

Lymphocyte Activation and Immune Responses

All adaptive immune responses develop in steps, consisting of: antigen recognition; activation of specific lymphocytes to proliferate and differentiate into effector and memory cells; elimination of the antigen; and decline of the response, with memory cells being the long-lived survivors.

Antibody-Mediated (Type II) Hypersensitivity

Antibodies that react with antigens present on cell surfaces or in the extracellular matrix cause disease by destroying these cells, triggering inflammation, or interfering with normal functions . The antibodies may be specific for normal cell or tissue antigens (autoantibodies) or for exogenous antigens, such as chemical or microbial proteins, that bind to a cell surface or tissue matrix. Figure 6.16. Mechanisms of antibody-mediated injury. (A) Opsonization of cells by antibodies and complement components and ingestion by phagocytes. (B) Inflammation induced by antibody binding to Fc receptors of leukocytes and by complement breakdown products. (C) Antireceptor antibodies disturb the normal function of receptors. In these examples, antibodies to the acetylcholine (ACh) receptor impair neuromuscular transmission in myasthenia gravis, and antibodies against the thyroid-stimulating hormone (TSH) receptor activate thyroid cells in Graves disease.

Antigen receptor diversity

Antigen receptor diversity is generated by somatic recombination of the genes that encode antigen receptors. During lymphocyte maturation (in the thymus for T cells and the bone marrow for B cells), these gene segments are assembled by recombination, and DNA sequence variation is introduced at the sites where the gene segments are joined. This creates many different genes that can be transcribed and translated into antigen receptors with diverse amino acid sequences, particularly in the regions of the receptors that recognize and bind antigen. The enzyme in developing lymphocytes that mediates recombination of these gene segments is the product of RAG-1 and RAG-2 (recombination-activating genes). It is important to note that germline antigen receptor genes are present in all cells in the body, but only T and B cells contain recombined (also called rearranged) antigen receptor genes (the TCR in T cells and Ig in B cells). Hence, the presence of recombined TCR or Ig genes, which can be demonstrated by molecular analysis, is a marker of T- or B-lineage cells . Furthermore, because each T or B cell and its clonal progeny have a unique DNA rearrangement (and hence a unique antigen receptor), it is possible to distinguish polyclonal (nonneoplastic) lymphocyte proliferations from monoclonal (neoplastic) lymphoid tumors by assessing the diversity of antigen receptor rearrangements within a population of lymphocytes.

Immune Complex-Mediated (Type III) Hypersensitivity

Antigen-antibody complexes produce tissue damage mainly by eliciting inflammation at the sites of deposition. The pathologic reaction is usually initiated when antigen combines with antibody in the circulation, creating immune complexes that typically deposit in vessel walls. Less frequently, the complexes may be formed at sites where antigen has been "planted" previously (called in situ immune complexes). The antigens that form immune complexes may be exogenous, such as a foreign protein that is injected or produced by an infectious microbe, or endogenous, if the individual produces antibody against self antigens (autoimmunity). Immune complex-mediated diseases tend be systemic, but often preferentially involve the kidney (glomerulonephritis), joints (arthritis), and small blood vessels (vasculitis).

Autoimmune Diseases

At least three requirements should be met before a disorder is categorized as truly caused by autoimmunity: (1) the presence of an immune reaction specific for some self antigen or self tissue; (2) evidence that such a reaction is not secondary to tissue damage but is of primary pathogenic significance; and (3) the absence of another well-defined cause of the disease.

B-cell antigen receptor complex

B cells recognize antigen via the B-cell antigen receptor complex. Membrane-bound antibodies of the IgM and IgD isotypes, present on the surface of all mature, naïve B cells, are the antigen-binding component of the B-cell receptor (BCR) complex. In addition to membrane Ig, the B-cell antigen receptor complex contains a heterodimer of two invariant proteins called Igα and Igβ. Similar to the CD3 and ζ proteins of the TCR complex, Igα (CD79a) and Igβ (CD79b) are essential for signal transduction in response to antigen recognition. B cells also express several other molecules that are essential for their responses. These include the type 2 complement receptor (CR2, or CD21), which recognizes complement products generated during innate immune responses to microbes, and CD40, which receives signals from helper T cells. Figure 6.7. Structure of antibodies and the B-cell antigen receptor. (A) The B-cell antigen receptor complex is composed of membrane immunoglobulin M ( IgM; or IgD, not shown ), which recognizes antigens, and the associated signaling proteins Igα and Igβ. CD21 is a receptor for a complement component that also promotes B-cell activation. (B) Crystal structure of a secreted IgG molecule, showing the arrangement of the variable (V) and constant (C) regions of the heavy (H) and light (L) chains.

B Lymphocytes

B lymphocytes are the only cells in the body capable of producing antibodies, the mediators of humoral immunity. B lymphocytes develop from precursors in the bone marrow. B cells recognize antigen via the B-cell antigen receptor complex. Membrane-bound antibodies of the IgM and IgD isotypes, present on the surface of all mature, naïve B cells, are the antigen-binding component of the B-cell receptor (BCR) complex. After stimulation by antigen and other signals, B cells develop into plasma cells, veritable protein factories for producing antibodies, as well as long-lived memory cells.

C-type lectin receptors (CLRs)

C-type lectin receptors (CLRs) expressed on the plasma membrane of macrophages and DCs detect fungal glycans and elicit inflammatory reactions to fungi.

T Cell-Mediated (Type IV) Hypersensitivity

Cell-mediated hypersensitivity is caused mainly by inflammation resulting from cytokines produced by CD4+ T cells. CD4+ T cell-mediated hypersensitivity induced by environmental and self antigens is the cause of many autoimmune and other chronic inflammatory diseases. Cell killing by CD8+ cells may also be involved in some autoimmune diseases and may be the dominant mechanism of tissue injury in certain reactions, especially those that follow viral infections. Figure 6.18. Mechanisms of T-cell-mediated (type IV) hypersensitivity reactions. (A) CD4+ Th1 cells (and sometimes CD8+ T cells, not shown ) respond to tissue antigens by secreting cytokines that stimulate inflammation and activate phagocytes, leading to tissue injury. CD4+ Th17 cells contribute to inflammation by recruiting neutrophils (and, to a lesser extent, monocytes). (B) In some diseases, CD8+ cytotoxic T lymphocytes directly kill tissue cells. APC, Antigen-presenting cell.

PAMPs and DAMPs

Cells that participate in innate immunity are capable of recognizing certain components that are shared among related microbes and that are often essential for infectivity. These microbial structures are called pathogen-associated molecular patterns. Leukocytes also recognize molecules released by injured and necrotic cells, which are called damage-associated molecular patterns. Collectively, the cellular receptors that recognize these molecules are called pattern recognition receptors. Pattern recognition receptors are located in all cellular compartments where microbes may be present: plasma membrane receptors detect extracellular microbes, endosomal receptors detect ingested microbes, and cytosolic receptors detect microbes in the cytoplasm

Class I MHC molecules

Class I MHC molecules are expressed on all nucleated cells and platelets. They are heterodimers consisting of a polymorphic α, or heavy, chain (44-kD) linked noncovalently to a smaller (12-kD) nonpolymorphic protein called β 2 -microglobulin. The extracellular region of the α chain is divided into three domains: α 1 , α 2 , and α 3 . The α 1 and α 2 domains form a cleft, or groove, where peptides bind. The polymorphic amino acid residues line the sides and the base of the peptide-binding groove, explaining why different class I alleles bind different peptides. Class I MHC molecules display peptides that are derived from cytoplasmic proteins, including normal proteins and virus- and tumor-specific antigens, which are all recognized bound to class I MHC molecules by CD8+ T cells. Peptide-loaded MHC molecules associate with β 2 -microglobulin to form a stable complex, which is transported to the cell surface. The nonpolymorphic α 3 domain of class I MHC molecules has a binding site for CD8, and therefore the peptide-class I complexes are recognized by CD8+ T cells, which function as CTLs. In this interaction, the TCR recognizes the MHC-peptide complex, and the CD8 molecule, acting as a coreceptor, binds to the class I heavy chain. Since CD8+ T cells recognize peptides only if presented as a complex with class I MHC molecules, CD8+ T cells are said to be class I MHC-restricted. Because important functions of CD8+ CTLs include the elimination of viruses, which may infect any nucleated cell, and killing of tumor cells, which may arise from any nucleated cell, it makes good sense that all nucleated cells express class I MHC molecules and can be surveyed by CD8+ T cells.

Contact dermatitis

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 or poison oak, and presents as an itchy, vesicular (blistering) 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 and elicit the reaction. Chemicals may also modify MHC molecules, making them appear foreign to T cells. The same mechanism is responsible for most drug reactions, among the most common immunologic reactions of humans. These often manifest as skin rashes.

Dendritic Cells (DCs)

DCs (sometimes called interdigitating DCs) are the most important antigen-presenting cells 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 presentation. First, these cells 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. Immature DCs within the epidermis are called Langerhans cells . Second, DCs express many receptors for capturing and responding to microbes (and other antigens), including TLRs and lectins. Third, in response to microbes, DCs are recruited to the T-cell zones of lymphoid organs, where they are ideally located to present antigens to naïve T cells. Fourth, DCs express high levels of MHC and other molecules needed for antigen presentation and T-cell activation.

Dendritic cells (DCs)

Dendritic cells (DCs) are specialized cells present in epithelia, lymphoid organs, and most tissues. They capture protein antigens and display peptides for recognition by T lymphocytes. In addition to their antigen-presenting function, DCs are endowed with a rich collection of receptors that sense microbes and cell damage and stimulate the secretion of cytokines. Thus, DCs serve as sentinels that detect danger and initiate innate immune responses, but, unlike macrophages, they are not key participants in the destruction of microbes and other offending agents.

T-cell receptor

Each T cell recognizes a specific cell-bound antigen by means of an antigen-specific TCR. In approximately 95% of T cells, the TCR consists of a disulfide-linked heterodimer made up of an α and a β polypeptide chain ( Fig. 6.6 ), each having a variable (antigen-binding) region and a constant region. The αβ TCR recognizes peptide antigens that are bound to and presented by major histocompatibility complex (MHC) molecules on the surfaces of antigen-presenting cells (APCs). By limiting the specificity of T cells for peptides displayed by cell surface MHC molecules, called MHC restriction, the immune system ensures that T cells see only cell-associated antigens (e.g., those derived from microbes in cells or from proteins ingested by cells).

TCR complex

Each TCR is noncovalently linked to six polypeptide chains, which form the CD3 complex and the ζ chain dimer. The CD3 and ζ proteins are invariant (i.e., identical) in all T cells. They are involved in the transduction of signals into the T cell that are triggered by binding of antigen to the TCR. Together with the TCR, these proteins form the TCR complex.

Class II MHC molecules

Each class II molecule is a heterodimer consisting of a noncovalently associated α chain and β chain, both of which are polymorphic. The extracellular portions of the α and β chains both have two domains designated α 1 and α 2 , and β 1 and β 2 . The crystal structure of class II molecules has revealed that, similar to class I molecules, they have peptide-binding clefts facing outward. This cleft is formed by an interaction of the α 1 and β 1 domains, and it is in this portion that most class II alleles differ. Thus, as with class I molecules, polymorphism of class II molecules is associated with differential binding of antigenic peptides. Class II MHC molecules present antigens derived from extracellular microbes and proteins following their internalization into endosomes or lysosomes. Here, the internalized proteins are proteolytically digested, producing peptides that then associate with class II heterodimers in the vesicles, from which they are transported to the cell surface as stable peptide-MHC complexes. The class II β 2 domain has a binding site for CD4, and therefore, the class II-peptide complex is recognized by CD4+ T cells, which function as helper cells. Because CD4+ T cells can recognize antigens only in the context of self class II molecules, they are referred to as class II MHC-restricted. In contrast to class I molecules, class II molecules are mainly expressed on cells that present ingested antigens and respond to T-cell help (macrophages, B lymphocytes, and DCs).

Epithelia

Epithelia of the skin and gastrointestinal and respiratory tracts act as mechanical barriers to the entry of microbes from the external environment. Epithelial cells also produce antimicrobial molecules such as defensins, and lymphocytes located in the epithelia combat microbes at these sites. If microbes breach epithelial boundaries, other defense mechanisms come into play.

Costimulators

Even before the antigens of a microbe are recognized by T and B lymphocytes, the microbe elicits an immune response through pattern recognition receptors expressed on innate immune cells; this is the first line of defense that also serves to activate adaptive immunity. In the case of immunization with a protein antigen, microbial mimics, called adjuvants, are given with the antigen, and these stimulate innate immune responses. During the innate response, the microbe or adjuvant activates antigen-presenting cells to express molecules called costimulators and to secrete cytokines that stimulate the proliferation and differentiation of T lymphocytes. The principal costimulators for T cells are the B7 proteins (CD80 and CD86) that are expressed on antigen-presenting cells and are recognized by the CD28 receptor on naïve T cells. Thus, antigen ("signal 1") and costimulatory molecules produced during innate immune responses to microbes ("signal 2") function cooperatively to activate antigen-specific lymphocytes. The requirement for microbe-triggered signal 2 ensures that the adaptive immune response is induced by microbes and not by harmless substances. In immune responses to tumors and transplants, "signal 2" may be provided by substances released from necrotic cells (the "damage-associated molecular patterns" mentioned earlier).

MHC molecules roles in regulating T cell-mediated immune response

First, because different antigenic peptides bind to different MHC molecules, it follows that an individual mounts an immune response against a protein antigen only if he or she inherits an MHC variant that can bind peptides derived from the antigen and present it to T cells. The consequences of inheriting a given MHC (e.g., class II) variant depend on the nature of the antigen bound by the class II molecule. For example, if the antigen is a peptide from ragweed pollen, the individual who expresses class II molecules capable of binding the antigen would be genetically prone to allergic reactions against ragweed. In contrast, an inherited capacity to bind a bacterial peptide may provide resistance to the infection by evoking a protective antibody response. Second, by segregating cytoplasmic and internalized antigens, MHC molecules ensure that the correct immune response is mounted against different microbes—CTL-mediated killing of cells harboring cytoplasmic microbes and tumor antigens, and helper T cell-mediated antibody production and macrophage activation to combat extracellular and phagocytosed microbes.

Macrophages

Functions in the induction and effector phases of adaptive immune responses: •Macrophages that have phagocytosed microbes and protein antigens process the antigens and present peptide fragments to T cells. Thus, macrophages function as antigen-presenting cells in T-cell activation. •Macrophages are key effector cells in certain forms of cell-mediated immunity, the reaction that serves to eliminate intracellular microbes. In this type of response, T cells activate macrophages and enhance their ability to kill ingested microbes. •Macrophages also participate in the effector phase of humoral immunity. Macrophages efficiently phagocytose and destroy microbes that are opsonized (coated) by IgG or C3b.

Mast Cell Granule Content

Granule contents. Mediators contained within mast cell granules are the first to be released and can be divided into three categories: •Vasoactive amines . The most important mast cell-derived amine is histamine. Histamine causes intense smooth muscle contraction, increases vascular permeability, and stimulates mucus secretion by nasal, bronchial, and gastric glands. •Enzymes. These are contained in the granule matrix and include neutral proteases (chymase, tryptase) and several acid hydrolases. The enzymes cause tissue damage and lead to the generation of kinins and activated components of complement (e.g., C3a) by acting on their precursor proteins. •Proteoglycans. These include heparin, a well-known anticoagulant, and chondroitin sulfate. The proteoglycans serve to package and store the amines in the granules.

Granulomatous inflammation

Granulomatous inflammation is commonly associated with strong Th1-cell activation and production of cytokines such as IFN-γ. It can also be caused by indigestible foreign bodies, which activate macrophages without eliciting an adaptive immune response. In some helminthic infections, such as schistosomiasis, the worms lay eggs that elicit granulomatous reactions. These reactions are usually rich in eosinophils and are elicited by strong Th2 responses, which are typical of many helminthic infections.

Affinity maturation

Helper T cells also stimulate the production of antibodies with high affinities for the antigen. This process, called affinity maturation, improves the quality of the humoral immune response.

Two types of adaptive immunity

Humoral immunity, which protects against extracellular microbes and their toxins, and cell-mediated (or cellular) immunity, which is responsible for defense against intracellular microbes and against cancers. Humoral immunity is mediated by B (bone marrow-derived) lymphocytes and their secreted products, antibodies (also called immunoglobulins , Ig), and cellular immunity is mediated by T (thymus-derived) lymphocytes. Both classes of lymphocytes express highly specific receptors for a wide variety of substances, which are called antigens .

Classification of Hypersensitivity Reactions

Hypersensitivity reactions can be classified on the basis of the underlying immunologic mechanism. This classification is of value in distinguishing the manner in which an immune response causes tissue injury and disease, and the accompanying pathologic and clinical manifestations. However, it is now increasingly recognized that multiple mechanisms may be operative in any one disease. The main types of hypersensitivity reactions are as follows: - In immediate hypersensitivity (type I hypersensitivity) , the injury is caused by Th2 cells, IgE antibodies, and mast cells and other leukocytes. Mast cells release mediators that act on vessels and smooth muscle and proinflammatory cytokines that recruit inflammatory cells. - In antibody-mediated disorders (type II hypersensitivity) , secreted IgG and IgM antibodies injure cells by promoting their phagocytosis or lysis and injure tissues by inducing inflammation. Antibodies may also interfere with cellular functions and cause disease without tissue injury. - In immune complex-mediated disorders (type III hypersensitivity) , IgG and IgM antibodies bind antigens usually in the circulation, and the antigen-antibody complexes deposit in tissues and induce inflammation. The leukocytes that are recruited (neutrophils and monocytes) produce tissue damage by release of lysosomal enzymes and generation of toxic free radicals. - In cell-mediated immune disorders (type IV hypersensitivity) , T lymphocytes (Th1 and Th17 cells and CD8+ CTLs) are the cause of the tissue injury.

Immediate (Type I) Hypersensitivity

Immediate, or type I, hypersensitivity is a rapid immunologic reaction occurring in a previously sensitized individual that is triggered by the binding of an antigen to IgE antibody on the surface of mast cells. These reactions are often called allergy, and the antigens that elicit them are allergens. Immediate hypersensitivity may occur as a systemic disorder or as a local reaction. The systemic reaction most often follows injection of an antigen into a sensitized individual (e.g., by a bee sting), but can also follow antigen ingestion (e.g., peanut allergens). Sometimes, within minutes the patient goes into a state of shock, which may be fatal. Local reactions are diverse and vary depending on the portal of entry of the allergen. They may take the form of localized cutaneous rash or blisters (skin allergy, hives), nasal and conjunctival discharge (allergic rhinitis and conjunctivitis), hay fever, bronchial asthma, or allergic gastroenteritis (food allergy). Most immediate hypersensitivity disorders are caused by excessive Th2 responses, and these cells play a central role by stimulating IgE production and promoting inflammation. These Th2-mediated disorders show a characteristic sequence of events.

Immunologic Tolerance

Immunologic tolerance is the phenomenon of unresponsiveness to an antigen induced by exposure of lymphocytes to that antigen . Self-tolerance refers to lack of responsiveness to an individual's own antigens, and it underlies our ability to live in harmony with our cells and tissues. The mechanisms of self-tolerance can be broadly classified into two groups: central tolerance and peripheral tolerance.

CD4+ T Cell-Mediated Inflammation

In CD4+ T cell-mediated hypersensitivity reactions, cytokines produced by 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 immune individuals. In this reaction, an antigen administered into the skin of a previously immunized individual results in a detectable cutaneous reaction within 24 to 48 hours (hence the term delayed, in contrast to immediate hypersensitivity). Both Th1 and Th17 cells contribute to organ-specific diseases in which inflammation is a prominent aspect of the pathology. The inflammatory reaction associated with Th1 cells is dominated by activated macrophages, and that triggered by Th17 cells has a greater neutrophil component. The inflammatory reactions stimulated by CD4+ T cells can be divided into sequential stages: - Activation of CD4+ T Cells - Responses of Differentiated Effector T Cells

Cytokines in adaptive immunity

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

Plasma proteins

In addition to these cells, several soluble proteins play important roles in innate immunity. The complement system consists of plasma proteins that are activated by microbes. Complement activation may occur through the alternative and lectin pathways as part of innate immune responses or through the classical pathway, which involves antibody-antigen complexes, as part of adaptive immune responses. Other circulating proteins of innate immunity are mannose-binding lectin and C-reactive protein, both of which coat microbes and promote phagocytosis. Lung surfactant is also a component of innate immunity, providing protection against inhaled microbes.

Cytokines in innate immune responses

In innate immune responses, cytokines are produced rapidly after encounter with microbes and other stimuli, and they function to induce inflammation and inhibit virus replication. These cytokines include TNF, IL-1, IL-12, type I IFNs, IFN-γ, and chemokines. Their major sources are macrophages, DCs, ILCs, and NK cells, but endothelial and epithelial cells can also produce them.

Type II hypersensitivity - cellular dysfunction

In some cases, antibodies directed against cell surface receptors impair or dysregulate function without causing cell injury or inflammation. For example, in myasthenia gravis, antibodies reactive with acetylcholine receptors in the motor end plates of skeletal muscles block neuromuscular transmission and therefore cause muscle weakness. The converse (i.e., antibody-mediated stimulation of cell function) is the basis of Graves disease. In this disorder, antibodies against the thyroid-stimulating hormone receptor on thyroid epithelial cells stimulate the cells, resulting in hyperthyroidism.

Type 1 hypersensitivity - late phase reaction

In the late-phase reaction, leukocytes are recruited that amplify and sustain the inflammatory response without additional exposure to the triggering antigen. Eosinophils are often an abundant leukocyte population in these reactions (see Fig. 6.13C ). They are recruited to sites of immediate hypersensitivity by chemokines, such as eotaxin, and others that may be produced by epithelial cells, Th2 cells, and mast cells. The Th2 cytokine IL-5 is the most potent eosinophil-activating cytokine known. Upon activation, eosinophils liberate proteolytic enzymes as well as two unique proteins called major basic protein and eosinophil cationic protein, which damage tissues. Eosniophils contain crystals called Charcot-Leyden crystals composed of the protein galectin-10, which are sometimes released into the extracellular space and can be detected in the sputum of patients with asthma. These crystals promote inflammation and enhance Th2 responses, so they may contribute to allergic reactions. It is now believed that the late-phase reaction is a major cause of symptoms in some type I hypersensitivity disorders, such as allergic asthma.

Central Tolerance

In this process, immature self-reactive T and B lymphocyte clones that recognize self antigens during their maturation in the central (primary, or generative) lymphoid organs (the thymus for T cells and the bone marrow for B cells) are killed or rendered harmless. In developing lymphocytes, random somatic antigen receptor gene rearrangements generate diverse antigen receptors, many of which by chance may have high affinity for self antigens. The mechanisms of central tolerance eliminate these potentially dangerous lymphocytes.

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 graft rejection. 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 the elimination of the infection, but in some cases it is responsible for cell damage that accompanies the infection (e.g., in viral hepatitis). Tumor antigens are also presented on the surface of tumor cells, and CTLs are involved in the host response to transformed cells. The principal mechanism of T cell-mediated killing of targets involves perforins and granzymes, preformed mediators contained in the lysosome-like granules of CTLs. CTLs that recognize the target cells secrete a complex consisting of perforin, granzymes, and other proteins that enters target cells by endocytosis. In the target cell cytoplasm, perforin facilitates the release of the granzymes from the complex. Granzymes are proteases that cleave and activate caspases, which induce apoptosis of the target cells. Activated CTLs also express Fas ligand, a molecule with homology to TNF, which also can trigger apoptosis by binding and activating Fas receptor expressed on target cells. CD8+ T cells also produce cytokines, notably IFN-γ, and are involved in inflammatory reactions resembling DTH, especially following viral infections and exposure to some contact sensitizing agents.

Hypersensitivity: Immunologically Mediated Tissue Injury

Injurious immune reactions, called hypersensitivity, are responsible for the pathology associated with immunologic diseases. This term arose from the idea that individuals who have been previously exposed to an antigen manifest detectable reactions to that antigen and are therefore said to be sensitized. Hypersensitivity implies an excessive or harmful reaction to an antigen.

Innate lymphoid cells (ILCs)

Innate lymphoid cells (ILCs) are tissue-resident lymphocytes that lack T-cell antigen receptors and cannot respond to antigens, but instead are activated by cytokines and other mediators produced at sites of tissue damage. They are thought to be sources of inflammatory cytokines during early phases of immune reactions. ILCs are classified into groups based on the dominant cytokines they produce: groups 1, 2, and 3 ILCs produce many of the same cytokines as Th1, Th2, and Th17 subsets of CD4+ T cells. Natural killer (NK) cells are one type of ILC that provide early protection against many viruses and intracellular bacteria.

Killing of target cells by NK cells

Killing of target cells by NK cells is regulated by signals from activating and inhibitory receptors. There are many types of activating receptors, which recognize surface molecules that are induced by various kinds of stress, such as infection and DNA damage. Thus, these receptors enable NK cells to recognize damaged or infected cells. NK cell inhibitory receptors recognize self class I MHC molecules, which are expressed on all healthy cells. The inhibitory receptors prevent NK cells from killing normal cells. Virus infection or neoplastic transformation often enhances expression of ligands for activating receptors and at the same time reduces the expression of class I MHC molecules. As a result, when NK cells engage these abnormal cells the balance is tilted toward activation, and the infected or tumor cell is killed. Figure 6.4. Activating and inhibitory receptors of natural killer (NK) cells. (A) Healthy cells express self class I major histocompatibility complex (MHC) molecules, which are recognized by inhibitory receptors, thus ensuring that NK cells do not attack normal cells. Note that healthy cells may express ligands for activating receptors (not shown) or may not express such ligands (as shown), but they do not activate NK cells because they engage the inhibitory receptors. (B) In infected and stressed cells, class I MHC expression is reduced so that the inhibitory receptors are not engaged, and ligands for activating receptors are expressed. The result is that NK cells are activated and the infected cells are killed.

Mast Cell Lipid Mediators

Lipid mediators. The major lipid mediators are arachidonic acid-derived products. Mast cell activation is associated with activation of phospholipase A 2 , an enzyme that converts membrane phospholipids to arachidonic acid. This is the parent compound from which leukotrienes and prostaglandins are produced by the 5-lipoxygenase and the cyclooxygenase pathways, respectively. •Leukotrienes. Leukotrienes C 4 and D 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 causing bronchial smooth muscle contraction. Leukotriene B 4 is highly chemotactic for neutrophils, eosinophils, and monocytes. •Prostaglandin D 2 . This is the most abundant mediator produced in mast cells by the cyclooxygenase pathway. It causes intense bronchospasm and increases mucus secretion. •Platelet-activating factor (PAF). PAF is a lipid mediator produced by some mast cell populations that is not derived from arachidonic acid. It causes platelet aggregation, histamine release, bronchospasm, increased vascular permeability, and vasodilation. Its role in immediate hypersensitivity reactions is not well established.

Lymph nodes

Lymph nodes are nodular aggregates of lymphoid tissues located along lymphatic channels throughout the body. As lymph slowly suffuses through lymph nodes, antigen-presenting cells are positioned to recognize antigens. In addition, DCs pick up and transport antigens of microbes from epithelia and tissues via lymphatic vessels to the lymph nodes. Thus, the antigens of microbes that enter through epithelia or colonize tissues become concentrated in draining lymph nodes. Because most foreign antigens enter through epithelia or are produced in tissues, lymph nodes are the site of generation of the majority of adaptive immune responses. Figure 6.8. Morphology of a lymph node. (A) The histology of a lymph node, with an outer cortex containing follicles and an inner medulla. (B) The segregation of B cells and T cells in different regions of the lymph node, illustrated schematically. (C) The location of B cells ( stained green, using the immunofluorescence technique) and T cells (stained red) in a lymph node.

Lymphocyte Recirculation

Lymphocytes constantly recirculate between tissues and home to particular sites; naïve lymphocytes traverse the secondary lymphoid organs where immune responses are initiated, and effector lymphocytes migrate to sites of infection and inflammation. This process of lymphocyte recirculation is most important for T cells, because naïve T cells have to circulate through the secondary lymphoid organs where antigens are concentrated and effector T cells have to migrate to sites of infection to eliminate microbes. In contrast, plasma cells remain in lymphoid organs and the bone marrow and do not need to traffic to sites of infection because they secrete antibodies that are carried through the blood to distant tissues.

Clonal selection

Lymphocytes specific for a large number of antigens exist before exposure to antigen, and when an antigen appears it selectively activates the antigen-specific cells. This fundamental concept is called clonal selection . Lymphocytes of the same specificity are said to constitute a clone; all members of one clone express identical antigen receptors, which are different from the receptors in all other clones.

Peripheral Tolerance - Anergy

Lymphocytes that recognize self antigens may be rendered functionally unresponsive, a phenomenon called anergy. We discussed earlier that activation of antigen-specific T cells requires two signals: recognition of peptide antigen in association with self MHC molecules on the surface of APCs and a set of costimulatory signals ("second signals") from APCs. These second signals are provided by certain T cell-associated molecules, such as CD28, that bind to their ligands (the costimulators B7-1 and B7-2) on APCs. If the antigen is presented to T cells without adequate levels of costimulators, the cells become anergic. Because costimulatory molecules are not expressed or are weakly expressed on resting DCs in normal tissues, the encounter between autoreactive T cells and their specific self antigens displayed by these DCs may lead to anergy. Several mechanisms of T-cell anergy have been demonstrated in various experimental systems. One of these, which has clinical implications, is that T cells that recognize self antigens receive an inhibitory signal from receptors that are structurally homologous to CD28 but serve the opposite functions. Two of these inhibitory receptors, sometimes called coinhibitors (to contrast them with costimulators mentioned earlier), are CTLA-4, which (like CD28) binds to B7 molecules, and PD-1, which binds to two ligands, PD-L1 and PD-L2, that are expressed on a wide variety of cells. Anergy also affects mature B cells in peripheral tissues. It is believed that if B cells encounter self antigen in peripheral tissues, especially in the absence of specific helper T cells, the B cells become unable to respond to subsequent antigenic stimulation and may be excluded from lymphoid follicles, resulting in their death.

Mannose receptors

Mannose receptors recognize microbial sugars (which often contain terminal mannose residues, unlike mammalian glycoproteins) and induce phagocytosis of the microbes.

Cytokines: Messenger Molecules of the Immune System

Many functions of leukocytes are stimulated and regulated by secreted proteins called cytokines. Molecularly defined cytokines are called interleukins because they mediate communications between leukocytes (although many also act on cells other than leukocytes). Most cytokines have a wide spectrum of effects, and some are produced by several different cell types. The majority of these cytokines act on the cells that produce them (autocrine actions) or on neighboring cells (paracrine) and rarely at a distance (endocrine).

phases of immediate hypersensitivity reactions

Many local type I hypersensitivity reactions have two well-defined phases. The immediate reaction is characterized by vasodilation, vascular leakage, and, depending on the tissue, smooth muscle spasm or glandular secretions. These changes usually become evident within minutes after exposure to an allergen and tend to subside in a few hours. In many instances a second, late-phase reaction sets in 2 to 24 hours later without additional exposure to antigen and may last for several days. This late-phase reaction is characterized by infiltration of tissues with eosinophils, neutrophils, basophils, monocytes, and CD4+ T cells, as well as tissue destruction, typically in the form of mucosal epithelial cell damage.

Mast Cell Mediators

Mast cell activation leads to degranulation, with the discharge of preformed mediators that are stored in the granules, and de novo synthesis and release of additional mediators including lipid products and cytokines. The mediators produced by mast cells are responsible for most of the manifestations of immediate hypersensitivity reactions. Some, such as histamine and leukotrienes, are released rapidly from sensitized mast cells and trigger the intense immediate reactions characterized by edema, mucus secretion, and smooth muscle spasm; others, exemplified by cytokines, including chemokines, set the stage for the late-phase response by recruiting additional leukocytes. Not only do these inflammatory cells release additional waves of mediators (including cytokines), but they also cause epithelial cell damage. Epithelial cells themselves are not passive bystanders in this reaction; they can also produce soluble mediators, such as chemokines. Figure 6.15. Mast cell mediators. On activation, mast cells release various classes of mediators that are responsible for the immediate and late-phase reactions. PAF, Platelet-activating factor.

Mast cell characteristics

Mast cells are bone marrow-derived cells that are widely distributed in the tissues. They are abundant near small blood vessels and nerves and in subepithelial tissues, which explains why local immediate hypersensitivity reactions often occur at these sites. Mast cells have cytoplasmic membrane-bound granules that contain a variety of biologically active mediators. The granules also contain acidic proteoglycans that bind basic dyes such as toluidine blue. Mast cells (and their circulating counterpart, basophils) are activated by the cross-linking of high-affinity IgE Fc receptors; in addition, mast cells may also be triggered by several other stimuli, such as complement components C5a and C3a (called anaphylatoxins because they elicit reactions that mimic anaphylaxis), both of which act by binding to receptors on the mast cell membrane. Other mast cell secretagogues include some chemokines (e.g., IL-8), drugs such as codeine and morphine, adenosine, melittin (present in bee venom), and physical stimuli (e.g., heat, cold, sunlight). Basophils are similar to mast cells in many respects, including the presence of cell surface IgE Fc receptors as well as cytoplasmic granules. In contrast to mast cells, however, basophils are not normally present in tissues but rather circulate in the blood in small numbers. Similar to other granulocytes, basophils can be recruited to inflammatory sites.

Mast Cell Cytokines

Mast cells are sources of many cytokines, which may play an important role at several stages of immediate hypersensitivity reactions. The cytokines include: TNF, IL-1, and chemokines, which promote leukocyte recruitment (typical of the late-phase reaction); IL-4, which amplifies the Th2 response; and numerous others. The inflammatory cells that are recruited by mast cell-derived TNF and chemokines are additional sources of cytokines.

Display and Recognition of Antigens

Microbes and other foreign antigens can enter the body anywhere. Microbes and their protein antigens are captured by DCs that are resident in epithelia and tissues. These cells carry their antigenic cargo to draining lymph nodes. Here the antigens are processed and displayed complexed with MHC molecules on the cell surface, where the antigens are recognized by T cells. B lymphocytes use their antigen receptors (membrane-bound antibody molecules) to recognize antigens of many different chemical types, including proteins, polysaccharides, and lipids. Figure 6.10 Cell-mediated immunity. Dendritic cells capture microbial antigens from epithelia and tissues and transport the antigens to lymph nodes. During this process, the dendritic cells mature, and express high levels of MHC molecules and costimulators. Naïve T cells recognize MHC-associated peptide antigens displayed on dendritic cells. The T cells are activated to proliferate and to differentiate into effector and memory cells, which migrate to sites of infection and serve various functions in cell-mediated immunity. CD4+ effector T cells of the Th1 subset recognize the antigens of microbes ingested by phagocytes and activate the phagocytes to kill the microbes; other subsets of effector cells enhance leukocyte recruitment and stimulate different types of immune responses. CD8+ cytotoxic T lymphocytes (CTLs) kill infected cells harboring microbes in the cytoplasm. Some activated T cells remain in the lymphoid organs and help B cells to produce antibodies, and some T cells differentiate into long-lived memory cells (not shown). APC, Antigen-presenting cell.

Monocytes and neutrophils

Monocytes and neutrophils are phagocytes in the blood that can be rapidly recruited to any site of infection; monocytes that enter the tissues and mature are called macrophages . Some tissue-resident macrophages (Kupffer cells in the liver, microglia in the brain, and alveolar macrophages in the lungs) develop from the yolk sac or fetal liver early in life and populate various tissues. Phagocytes sense the presence of microbes and other offending agents, ingest (phagocytose) these invaders, and destroy them.

IgG half life and duration of antibody secretion

Most circulating IgG antibodies have half-lives of about 3 weeks. Some antibody-secreting plasma cells, particularly those that are generated in germinal centers, migrate to the bone marrow and take up residence for months or even years, continuously producing antibodies during this time.

NK cells cytokine secretion

NK cells secrete cytokines such as interferon-γ (IFN-γ), which activates macrophages to destroy ingested microbes, and thus NK cells provide an early defense against intracellular microbial infections. The activity of NK cells is regulated by many cytokines, including the interleukins IL-2, IL-15, and IL-12. IL-2 and IL-15 stimulate proliferation of NK cells, whereas IL-12 activates the killing of target cells and the secretion of IFN-γ.

NOD-like receptors and the inflammasome

NOD-like receptors (NLRs) are cytosolic receptors named after the founding member NOD-2. They recognize a wide variety of substances, including products released from necrotic or damaged cells (e.g., uric acid and adenosine triphosphate [ATP]), loss of intracellular K + ions, and some microbial products. Several of the NLRs signal via a cytosolic multiprotein complex called the inflammasome, which activates an enzyme (caspase-1) that cleaves a precursor form of the cytokine interleukin-1 (IL-1) to generate the biologically active form. As discussed later, IL-1 is a mediator of inflammation that recruits leukocytes and induces fever. The inflammasome pathway may also play a role in many common disorders. For example, recognition of urate crystals by a class of NLRs underlies the inflammation associated with gout. These receptors are also capable of detecting lipids and cholesterol crystals that are deposited in abnormally large amounts in tissues, and the resulting inflammation appears to contribute to obesity-associated type 2 diabetes and atherosclerosis, respectively.

Activation of CD4+ T Cells

Naïve CD4+ T cells recognize peptides displayed by DCs and secrete IL-2, which functions as an autocrine growth factor to stimulate proliferation of the antigen-responsive T cells. The subsequent differentiation of antigen-stimulated T cells to Th1 or Th17 cells is driven by the cytokines produced by APCs at the time of T-cell activation. In some situations, the APCs (DCs and macrophages) produce IL-12, which induces differentiation of CD4+ T cells to the Th1 subset. IFN-γ produced by these effector cells promotes further Th1 development, thus amplifying the reaction. If the APCs produce the inflammatory cytokines IL-1, IL-6, and a close relative of IL-12 called IL-23, the T cells are induced to differentiate to the Th17 subset. Some of the differentiated effector cells enter the circulation and join the pool of memory T cells, where they persist for long periods, sometimes years.

Naïve T lymphocytes activation

Naïve T lymphocytes are activated by antigen and costimulators in peripheral lymphoid organs, and proliferate and differentiate into effector cells that migrate to any site where microbial antigens are present. One of the earliest responses of CD4+ helper T cells is secretion of the cytokine IL-2 and expression of high-affinity receptors for IL-2. This creates an autocrine loop wherein IL-2 acts as a growth factor that stimulates T-cell proliferation, leading to an increase in the number of antigen-specific lymphocytes. The functions of helper T cells are mediated by the combined actions of CD40-ligand (CD40L) and cytokines. When CD4+ helper T cells recognize antigens being displayed by macrophages or B lymphocytes, the T cells express CD40L, which engages CD40 on the macrophages or B cells and activates these cells.

Responses of Differentiated Effector T Cells

On repeat exposure to an antigen, Th1 cells secrete cytokines, mainly IFN-γ, which are responsible for many of the manifestations of delayed-type hypersensitivity. IFN-γ-activated ("classically activated") macrophages are altered in several ways: their ability to phagocytose and kill microorganisms is markedly augmented; they express more class II MHC molecules on the surface, enhancing antigen presentation; they secrete TNF, IL-1, and chemokines, which promote inflammation; and they produce more IL-12, amplifying the Th1 response. Thus, activated macrophages serve to eliminate the offending antigen; if the activation is sustained, continued inflammation and tissue injury result. Activated Th17 cells secrete IL-17, IL-22, chemokines, and several other cytokines. Collectively, these cytokines recruit neutrophils and monocytes to the reaction, thus promoting inflammation.

Type II hypersensitivity - opsonization and phagocytosis

Phagocytosis is largely responsible for depletion of cells coated with antibodies. Cells opsonized by IgG antibodies are recognized by phagocyte Fc receptors, which are specific for the Fc portions of some IgG subclasses. In addition, when IgM or IgG antibodies are deposited on the surfaces of cells, they may activate the complement system by the classical pathway. Complement activation generates cleavage products of C3, mainly C3b and C4b, which are deposited on the surfaces of the cells and recognized by phagocytes that express receptors for these proteins. The net result is phagocytosis of the opsonized cells and their destruction inside the phagocytes. Complement activation on cells also leads to the formation of the membrane attack complex, which disrupts membrane integrity by "drilling holes" through the lipid bilayer, thereby causing osmotic lysis of the cells. This mechanism is probably effective in destroying only cells and microbes with thin cell walls. Antibody-mediated destruction of cells also may occur by another process called antibody-dependent cellular cytotoxicity (ADCC). Cells that are coated with IgG antibody are killed by effector cells, mainly NK cells and macrophages, which bind to the target by their receptors for the Fc fragment of IgG, and cell lysis proceeds without phagocytosis. The contribution of ADCC to common hypersensitivity diseases is uncertain.

Plasma membrane G protein-coupled receptors

Plasma membrane G protein-coupled receptors on neutrophils, macrophages, and most other types of leukocytes recognize short bacterial peptides containing N -formylmethionyl residues. Because all bacterial proteins and few mammalian proteins (only those synthesized within mitochondria) are initiated by N -formylmethionine, this receptor enables neutrophils to detect bacterial proteins and move toward their source (chemotaxis).

Isotype switching

Protein antigens, by virtue of CD40L- and cytokine-mediated helper T-cell actions, induce the production of antibodies of different classes, or isotypes (IgG, IgA, IgE), a process called isotype switching . Polysaccharides and lipids stimulate secretion mainly of IgM antibody.

RIG-like receptors (RLRs)

RIG-like receptors (RLRs), named after the founding member RIG-I (retinoic acid-inducible gene-I), are located in the cytosol of most cell types and detect nucleic acids of viruses that replicate in the cytoplasm of infected cells. These receptors stimulate the production of antiviral cytokines. Cytosolic receptors for microbial DNA, often derived from viruses in the cell, activate a pathway called STING (for stimulator of interferon genes), which leads to the production of the antiviral cytokine interferon-α. Excessive activation of the STING pathway causes systemic inflammatory disorders collectively called interferonopathies .

Serum sickness

Serum sickness is the prototype of a systemic immune complex disease; it was once a frequent sequela to the administration of large amounts of foreign serum (e.g., serum from immunized horses used for protection against diphtheria).

Peripheral Tolerance

Several mechanisms silence potentially autoreactive T and B cells in peripheral tissues; these are best defined for T cells. These mechanisms include the following: - Anergy - Suppression by regulatory T cells - Deletion by apoptosis

Immune-privileged sites

Some antigens are hidden (sequestered) from the immune system, because the tissues in which these antigens are located do not communicate with the blood and lymph. As a result, self antigens in these tissues fail to elicit immune responses and are essentially ignored by the immune system. This is believed to be the case for the testis, eye, and brain, all of which are called immune-privileged sites because antigens introduced into these sites tend to elicit weak or no immune responses. If the antigens of these tissues are released, for example, as a consequence of trauma or infection, the result may be an immune response that leads to prolonged tissue inflammation and injury. This is the postulated mechanism for post-traumatic orchitis and uveitis.

Cytokines in hematopoiesis

Some cytokines stimulate hematopoiesis and are called colony-stimulating factors (CSFs) because they are assayed by their ability to stimulate formation of blood cell colonies from bone marrow progenitors. Their functions are to increase leukocyte production during immune and inflammatory responses, both to increase their numbers and to replace leukocytes that die during such responses. They are produced by marrow stromal cells, T lymphocytes, macrophages, and other cells. Examples include GM-CSF and other CSFs, and IL-3.

Differentiation of CD4+ T lymphocytes

Some of the activated CD4+ T cells differentiate into effector cells that secrete distinct sets of cytokines and perform different functions. Cells of the Th1 subset secrete the cytokine IFN-γ, which is a potent macrophage activator. The combination of CD40- and IFN-γ-mediated activation results in "classical" macrophage activation, leading to the production of microbicidal substances in macrophages and the destruction of ingested microbes. Th2 cells produce IL-4, which stimulates B cells to differentiate into IgE-secreting plasma cells, and IL-5, which stimulates the production of eosinophils in the marrow and activates eosinophils at sites of immune responses. Eosinophils and mast cells bind to IgE-coated microbes such as helminthic parasites, and function to eliminate helminths. Th2 cells also induce the "alternative" pathway of macrophage activation, which is associated with tissue repair and fibrosis. Th17 cells, so called because the signature cytokine of these cells is IL-17, recruit neutrophils and monocytes, which destroy extracellular bacteria and fungi and are involved in some inflammatory diseases.

Development of Allergies

Susceptibility to immediate hypersensitivity reactions is genetically determined. A 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. Environmental factors are also important in the development of allergic diseases. Exposure to environmental pollutants, which is common in industrialized societies, is an important predisposing factor for allergy. Immediate hypersensitivity reactions can be triggered by non-antigenic stimuli such as temperature extremes and exercise, and do not involve Th2 cells or IgE; such reactions are sometimes called nonatopic allergy. It is believed that in these cases mast cells are abnormally sensitive to activation by various nonimmune stimuli.

Systemic Anaphylaxis

Systemic anaphylaxis is characterized by vascular shock, widespread edema, and difficulty in breathing. It may occur in sensitized individuals in hospital settings after administration of foreign proteins (e.g., antisera), hormones, enzymes, polysaccharides, and drugs (e.g., the antibiotic penicillin), or in the community setting following exposure to food allergens (e.g., peanuts, shellfish) or insect toxins (e.g., those in bee venom). Extremely small doses of antigen may trigger anaphylaxis, for example, the tiny amounts used in skin testing for allergies. Within minutes after exposure to allergens, itching, hives, and skin erythema appear, followed shortly thereafter by a striking contraction of pulmonary bronchioles and respiratory distress. Laryngeal edema results in hoarseness and further compromises breathing. Vomiting, abdominal cramps, diarrhea, and laryngeal obstruction follow, and the patient may go into shock and even die within the hour. The risk of anaphylaxis must be borne in mind when certain therapeutic agents are administered. Although patients at risk often have a previous history of some form of allergy, the absence of such a history does not preclude the possibility of an anaphylactic reaction.

CD4, CD8, and CD28

T cells express several other proteins that assist the TCR complex in functional responses. These include CD4, CD8, CD28, and integrins. CD4 and CD8 are expressed on two mutually exclusive subsets of αβ T cells. Most CD4+ T cells function as cytokine-secreting helper cells that assist macrophages and B lymphocytes to combat infections. Most CD8+ cells function as CTLs that destroy host cells harboring microbes. CD4 and CD8 serve as coreceptors in T-cell activation. During antigen recognition, CD4 molecules bind to class II MHC molecules that are displaying antigen; CD8 molecules bind to class I MHC molecules; and the CD4 or CD8 coreceptor initiates signals that are necessary for activation of the T cells. Because of this requirement for coreceptors, CD4+ helper T cells can recognize and respond to antigen displayed only by class II MHC molecules, whereas CD8+ cytotoxic T cells recognize cell-bound antigens only in association with class I MHC molecules. Integrins are adhesion molecules that promote the attachment of T-cells to APCs. To respond, T cells have to not only recognize antigen-MHC complexes, but also have to receive additional signals provided by antigen-presenting cells. This process, in which CD28 plays an important role.

Peripheral Tolerance - Deletion by Apoptosis

T cells that recognize self antigens may receive signals that promote their death by apoptosis. Depletion of T cells occurs not only in the thymus, but also in the periphery. Two mechanisms of deletion of mature T cells in the periphery have been proposed. It is postulated that if T cells recognize self antigens, they may express a pro-apoptotic member of the Bcl family, called Bim, without antiapoptotic members of the family like Bcl-2 and Bcl-x (whose induction requires the full set of signals for lymphocyte activation). Unopposed Bim triggers apoptosis by the mitochondrial pathway. A second mechanism involves the Fas-Fas ligand system. Upon recognition of self antigens, lymphocytes express the death receptor Fas (CD95), a member of the TNF-receptor family. Fas ligand (FasL), a membrane protein that is structurally homologous to the cytokine TNF, is expressed mainly on activated T lymphocytes. The engagement of Fas by FasL induces apoptosis by the death receptor pathway. If self antigens engage antigen receptors of self-reactive T cells, Fas and FasL are co-expressed, leading to elimination of the cells via Fas-mediated apoptosis. Self-reactive B cells may also be deleted by FasL on T cells engaging Fas on the B cells.

Arthus reaction

The Arthus reaction is a localized area of tissue necrosis resulting from acute immune complex vasculitis, usually elicited in the skin. The reaction can be produced experimentally by intracutaneous injection of antigen in a previously immunized animal that contains circulating antibodies against the antigen. As the antigen diffuses into the vascular wall, it binds the preformed antibody, and large immune complexes are formed locally. These complexes precipitate in the vessel walls and cause fibrinoid necrosis, and superimposed thrombosis worsens the ischemic injury.

Toll-like receptors

The best known of the pattern recognition receptors are the Toll-like receptors (TLRs). Mammals have 10 TLRs, each recognizing a different set of microbial molecules. The TLRs are present in the plasma membrane and endosomal vesicles. All TLRs signal by a common pathway that culminates in the activation of two sets of transcription factors: (1) NF-κB, which stimulates the synthesis and secretion of cytokines and the expression of adhesion molecules, both of which are critical for the recruitment and activation of leukocytes, and (2) interferon regulatory factors (IRFs), which stimulate the production of the antiviral cytokines, type I interferons.

Tuberculin reaction

The classic example of DTH is the tuberculin reaction, which is produced by the intracutaneous injection of purified protein derivative (PPD, also called tuberculin), a protein-containing antigen of the tubercle bacillus. In a previously sensitized individual, reddening and induration of the site appear in 8 to 12 hours, reach a peak in 24 to 72 hours, and thereafter 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". In fully developed lesions, the venules show marked endothelial hypertrophy, reflecting cytokine-mediated endothelial activation.

Cutaneous and mucosal lymphoid systems

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 patches of the intestine are two anatomically defined mucosal lymphoid tissues. At any time, a large fraction of the body's lymphocytes are in the mucosal tissues (reflecting the large size of these tissues), and many of these are memory cells.

Type 1 hypersensitivity - activation of Th2 cells and production of IgE antibody

The first step in the generation of Th2 cells is the presentation of the antigen to naïve CD4+ helper T cells, probably by DCs that capture the antigen from its site of entry. For reasons that are still not understood, only some environmental antigens elicit strong Th2 responses and thus serve as allergens. In response to antigen and other stimuli, including cytokines such as IL-4 produced at the local site, the T cells differentiate into Th2 cells. The newly minted Th2 cells produce a number of cytokines on subsequent encounter with the antigen; as mentioned earlier, the signature cytokines of this subset are IL-4, IL-5, and IL-13. IL-4 acts on B cells to stimulate class switching to IgE and promotes the development of additional Th2 cells. IL-5 is involved in the development and activation of eosinophils, which are important effectors of type I hypersensitivity. IL-13 enhances IgE production and acts on epithelial cells to stimulate mucus secretion. In addition, Th2 cells (as well as mast cells and epithelial cells) produce chemokines that attract more Th2 cells, as well as other leukocytes, to the reaction site. Patients with chronic atopic diseases such as asthma and atopic dermatitis are sometimes classified into Th2-high and Th2-low based on biomarkers that reflect the intensity of the pathologic T-cell response in individual patients. Before Th2 responses develop, type 2 ILCs in tissues may respond to cytokines produced by damaged epithelia. These ILCs secrete IL-5 and IL-13 and are thus able to induce the same tissue reactions as the classical Th2 cells. Over time, the Th2 cells become the dominant contributors to the local cytokine response.

Major Histocompatibility Complex Molecules

The function of MHC molecules is to display peptide fragments of protein antigens for recognition by antigen-specific T cells. There are thousands of distinct MHC gene alleles, and as a result each individual's differ from those inherited by most other individuals in the population.

Natural Killer Cell Function

The function of NK cells is to recognize and destroy severely stressed or abnormal cells, such as virus-infected cells and tumor cells. NK cells express CD16, a receptor for IgG Fc tails that confers on NK cells the ability to lyse IgG-coated target cells. This phenomenon is known as antibody-dependent cellular cytotoxicity (ADCC).

Humoral immune responses to combats microbes

The humoral immune response combats microbes in many ways. Antibodies bind to microbes and prevent them from infecting cells, thus neutralizing the microbes. IgG antibodies coat (opsonize) microbes and target them for phagocytosis, since phagocytes (neutrophils and macrophages) express receptors for the Fc tails of IgG. IgG and IgM activate the complement system by the classical pathway, and complement products promote phagocytosis and destruction of microbes. Some antibodies serve special roles at particular anatomic sites. IgA is secreted from mucosal epithelia and neutralizes microbes in the lumens of the respiratory and gastrointestinal tracts (and other mucosal tissues). IgG is actively transported across the placenta and protects the newborn until the immune system becomes mature. IgE and eosinophils cooperate to kill parasites, mainly by release of eosinophil granule contents that are toxic to the worms. As mentioned earlier, Th2 cytokines stimulate the production of IgE and activate eosinophils, and thus the response to helminths is orchestrated by Th2 cells.

Mechanisms of Autoimmunity: General Principles

The immune system normally exists in an equilibrium in which lymphocyte activation, which is required for defense against pathogens, is balanced by the mechanisms of tolerance, which prevent reactions against self antigens. The underlying cause of autoimmune diseases is the failure of tolerance, which allows responses to develop against self antigens. Autoimmunity arises from a combination of the inheritance of susceptibility genes, which may contribute to the breakdown of self-tolerance, and environmental triggers, such as infections and tissue damage, which promote the activation of self-reactive lymphocytes. The following abnormalities appear to contribute to development: - Defective tolerance or regulation - Abnormal display of self antigens - Inflammation or an initial innate immune response

Components of Innate Immunity

The major components of innate immunity are epithelial barriers that block entry of microbes, phagocytic cells (mainly neutrophils and macrophages), dendritic cells, natural killer cells and other innate lymphoid cells, and several plasma proteins, including the proteins of the complement system.

Decline of Immune Responses and Immunologic Memory

The majority of effector lymphocytes induced by an infectious pathogen die by apoptosis after the microbe is eliminated, thus returning the immune system to its resting state. The initial activation of lymphocytes also generates long-lived memory cells, which may survive for many years after the infection. Memory cells are an expanded pool of antigen-specific lymphocytes (more numerous than the naïve cells specific for any antigen that are present before encounter with that antigen), and they respond faster and more effectively when reexposed to the antigen than do naïve cells. Generation of memory cells underlies the effectiveness of vaccination.

Primary Lymphoid Organs

The principal primary lymphoid organs are the thymus, where T cells develop, and the bone marrow, the site of production of all other blood cells, including naïve B cells.

Secondary Lymphoid Organs

The secondary lymphoid organs—lymph nodes, spleen, and the mucosal and cutaneous lymphoid tissues—are the tissues where adaptive immune responses occur . Several features of these organs promote the generation of adaptive immunity—antigens are concentrated in these organs, naïve lymphocytes circulate through them searching for the antigens, and different lymphocyte populations (such as T and B cells) are brought together when they need to interact.

Spleen

The spleen is an abdominal organ that serves the same role in immune responses to blood-borne antigens as the lymph nodes do in responses to lymph-borne antigens. Blood entering the spleen flows through a network of sinusoids lined by macrophages and DCs. Blood-borne antigens are trapped in the spleen by these cells, which can then initiate adaptive immune responses to these antigens.

Tissues of the Immune System

The tissues of the immune system consist of the primary (also called generative , or central ) lymphoid organs, in which T and B lymphocytes mature and become competent to respond to antigens, and the secondary (or peripheral ) lymphoid organs, in which adaptive immune responses to microbes are initiated.

Three major populations of T cells

There are three major populations of T cells, which serve distinct functions. Helper T lymphocytes stimulate B lymphocytes to make antibodies and activate other leukocytes (e.g., phagocytes) to destroy microbes; cytotoxic (killer) T lymphocytes (CTLs) kill infected cells; and regulatory T lymphocytes limit immune responses and prevent reactions against self antigens.

Humoral Immunity: Activation of B Lymphocytes

Upon activation, B lymphocytes proliferate and then differentiate into plasma cells that secrete different classes of antibodies with distinct functions. Antibody responses to most protein antigens require T cell help and are said to be T-dependent. In these responses, B cells that recognize protein antigens by their Ig receptors endocytose these antigens into vesicles, degrade them, and display peptides bound to class II MHC molecules for recognition by helper T cells. The helper T cells are activated and express CD40L and secrete cytokines, which work together to stimulate the B cells. Many polysaccharide and lipid antigens cannot be recognized by T cells (because they cannot bind to MHC molecules) but have multiple identical antigenic determinants (epitopes) that are able to engage many antigen receptor molecules on each B cell and initiate the process of B-cell activation; these responses are said to be T-independent. T-independent responses are relatively simple, whereas T-dependent responses show features such as Ig isotype switching and affinity maturation, which require T cell help and lead to responses that are more varied and effective.

Sensitization and Activation of Mast Cells

When a mast cell armed with IgE antibodies previously produced in response to an antigen is exposed to the same antigen, the cell is activated, leading to the release of an arsenal of powerful mediators that are responsible for immediate hypersensitivity reactions. Mast cells and basophils express a high-affinity receptor called FcεRI that is specific for the Fc portion of IgE and avidly binds IgE antibodies. IgE-coated mast cells are said to be sensitized because they are activated by subsequent encounters with antigen. In the first step of activation, the antigen binds to the IgE antibodies on the mast cell surface. Multivalent antigens bind to and cross-link adjacent IgE antibodies, bringing the underlying Fcε receptors together. This triggers signal transduction pathways from the cytoplasmic portion of the receptors that lead to the release of preformed mediators and de novo production of mediators that are responsible for the initial, sometimes explosive, symptoms of immediate hypersensitivity, and they also set into motion the events that lead to the late-phase reaction.

Type II hypersensitivity - inflammation

When antibodies deposit in fixed tissues, such as basement membranes and extracellular matrix, the resultant injury is due to inflammation. The deposited antibodies activate complement, generating cleavage products, including chemotactic agents (mainly C5a), which direct the migration of granulocytes and monocytes, and anaphylatoxins (C3a and C5a), which increase vascular permeability. The leukocytes are activated by engagement of their C3b and Fc receptors. This results in the release of substances from the leukocytes that damage tissues, such as lysosomal enzymes, including proteases capable of digesting basement membrane, collagen, elastin, and cartilage, and by generation of reactive oxygen species.

Central Tolerance - B Cells

When developing B cells strongly recognize self antigens in the bone marrow, many of the cells reactivate the machinery of antigen receptor gene rearrangement and begin to express new antigen receptors, not specific for self antigens. This process is called receptor editing ; it is estimated that one-fourth to one-half of all B cells in the body may have undergone receptor editing during their maturation. If receptor editing does not occur, the self-reactive cells undergo apoptosis, thus purging potentially dangerous lymphocytes from the mature pool.

Central Tolerance

When immature T cells expressing TCRs specific for self antigens encounter these antigens in the thymus, signals are produced that result in killing of the cells by apoptosis. This process is called negative selection or clonal deletion . A wide variety of autologous protein antigens, including antigens thought to be restricted to peripheral tissues, are processed and presented by thymic antigen-presenting cells in association with self MHC molecules and can, therefore, be recognized by potentially self-reactive T cells. A protein called AIRE (autoimmune regulator) stimulates expression of some peripheral tissue-restricted self antigens in the thymus and is thus critical for deletion of immature T cells specific for these antigens. The importance of this mechanism is emphasized by rare patients with germline loss-of-function mutations in the AIRE gene, who develop an autoimmune disorder called autoimmune polyendocrine syndrome that leads to destruction of multiple endocrine organs. In the CD4+ T-cell lineage, some of the cells that see self antigens in the thymus do not die but develop into regulatory T cells. What determines the choice between deletion and development of regulatory T cells in the thymus is not established; it may be partly related to the affinity of the antigen receptor on immature T cells for antigens present in the thymus.

Naïve T and B lymphocytes are segregation within secondary lymphoid organs

Within the secondary lymphoid organs, naïve T and B lymphocytes are segregated into different regions. In lymph nodes, the B cells are concentrated in discrete structures, called follicles, located around the periphery, or cortex, of each node. If the B cells in a follicle have recently responded to an antigen, this follicle may contain a central region called a germinal center. The T lymphocytes are concentrated in the paracortex, adjacent to the follicles. 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 follicles akin to those found in lymph nodes (the so-called splenic white pulp).

Important general features of hypersensitivity disorders

•Hypersensitivity reactions can be elicited by exogenous environmental antigens (microbial and nonmicrobial) or endogenous self antigens. Exogenous antigens include those in dust, pollen, food, drugs, microbes, and various chemicals. The immune responses against such exogenous antigens may take several forms, ranging from annoying but trivial discomforts, such as itching of the skin, to potentially fatal diseases, such as anaphylaxis. Some of the most common reactions to environmental antigens cause the group of diseases known as allergy. Immune responses against self, or autologous, antigens, cause autoimmune diseases. •Hypersensitivity usually results from an imbalance between the effector mechanisms of immune responses and the control mechanisms that serve to limit such responses . In fact, in many hypersensitivity diseases, it is suspected that the underlying cause is a failure of normal regulation. •The development of hypersensitivity diseases (both allergic and autoimmune) is often associated with the inheritance of particular susceptibility genes. •The mechanisms of tissue injury in hypersensitivity reactions are the same as the effector mechanisms of defense against infectious pathogens. The problem in hypersensitivity is that these reactions are poorly controlled, excessive, or misdirected (e.g., against normally harmless environmental and self antigens).