Inhibitors of T Cell Signaling Pathways

The calcineurin inhibitors cyclosporine and FK506 (tacrolimus) inhibit transcription of certain genes in T cells, FIGURE 16-10 Mechanisms of action of immunosuppressive drugs. Each major category of drugs used to prevent or to treat allograft rejection is shown along with the molecular targets of the drugs. FIGURE 16-10 Mechanisms of action of immunosuppressive drugs. Each major category of drugs used to prevent or to treat allograft rejection is shown along with the molecular targets of the...

Diseases Related to Immune Responses in the

Given the abundance of immune cells and their constant activity in the intestinal mucosa, it is not surprising that there are many intestinal diseases related to abnormal immune responses. These diseases are generally caused by unregulated responses to commensal organisms or to antigens in the food. We will now discuss selected examples of these diseases they are more thoroughly described in medical textbooks. Inflammatory bowel disease is a heterogeneous group of disorders characterized by...

Structural and Chemical Basis of Antigen Binding

The antigen-binding sites of many antibodies are planar surfaces that can accommodate conformational epitopes of macromolecules, allowing the antibodies to bind large macromolecules (see Fig. 5-6). The six CDRs, three from the heavy chain and three from the light chain, spread out to form a broad surface. Similar broad binding surfaces are characteristic of the binding sites of T cell receptors. In contrast, MHC molecules contain antigen-binding clefts that bind small peptides. In a number of...

Innate Immunity in the Gastrointestinal Tract

Intestinal epithelial cells lining the small and large bowel are an integral part of the gastrointestinal innate immune system, involved in responses to pathogens, tolerance to commensal organisms, and antigen sampling for delivery to the adaptive immune system in the gut. There are several different types of intestinal epithelial cells, all derived from a common precursor found in the crypts of intestinal glands. Among these are the mucus-secreting goblet cells, which reside at the top of the...

Summary

* Immediate hypersensitivity is an immune reaction triggered by antigen binding to IgE pre-bound to mast cells, which leads to the release of inflammatory mediators. * The steps in the development of immediate hyper-sensitivity are exposure to an antigen (allergen) that stimulates TH2 responses and IgE production, binding of the IgE to Fce receptors on mast cells, cross-linking of the IgE and the Fce receptors by the allergen, activation of mast cells, and release of mediators. * Individuals...

Immunity to Microbes

GENERAL FEATURES OF IMMUNE RESPONSES TO MICROBES, 345 IMMUNITY TO EXTRACELLULAR BACTERIA, 346 Innate Immunity to Extracellular Bacteria, 346 Adaptive Immunity to Extracellular Bacteria, 348 Injurious Effects of Immune Responses, 349 Immune Evasion by Extracellular Bacteria, 350 IMMUNITY TO INTRACELLULAR BACTERIA, 350 Innate Immunity to Intracellular Bacteria, 350 Adaptive Immunity to Intracellular Bacteria, 350 Immune Evasion by Intracellular Bacteria, 353 Innate and Adaptive Immunity to Fungi,...

Tolllike Receptors

The Toll-like receptors (TLRs), an evolutionarily conserved family of pattern recognition receptors expressed on many cell types, recognize products of a wide variety of microbes. Toll was originally identified as a Drosophila gene involved in establishing the dorsal-ventral axis during embryogenesis of the fruit fly, but subsequently it was discovered that the Toll protein also mediated antimicrobial responses in these organisms. This discovery led to the identification of mammalian homologues...

Adaptive Immunity to Extracellular Bacteria

Cancer Immun System

Humoral immunity is a major protective immune response against extracellular bacteria, and it functions to block infection, to eliminate the microbes, and to neutralize their toxins (Fig. 15-1A). Antibody responses against extracellular bacteria are directed against cell wall antigens and secreted and cell-associated toxins, which may be polysaccharides or proteins. The polysaccharides are prototypic thymus-independent antigens, and humoral immunity is the principal mechanism of defense against...

The Inflammatory Response

The major way by which the innate immune system deals with infections and tissue injury is to stimulate acute inflammation, which is the accumulation of leukocytes, plasma proteins, and fluid derived from the blood at an extravascular tissue site of infection or injury. The leukocytes and plasma proteins normally circulate in the blood and are recruited to sites of infection and injury, where they perform various effector functions that serve to kill microbes and begin to repair tissue damage....

Immediate Hypersensitivity Reactions in the Upper Respiratory Tract Gastrointestinal Tract and Skin

Allergic rhinitis, also called hay fever, is perhaps the most common allergic disease and is a consequence of immediate hypersensitivity reactions to common allergens such as plant pollen or house dust mites localized to the upper respiratory tract by inhalation. The pathologic and clinical manifestations include mucosal edema, leukocyte infiltration with abundant eosinophils, mucus secretion, coughing, sneezing, and difficulty in breathing. Allergic conjunctivitis with itchy eyes is commonly...

Role Of Mast Cells Basophils And Eosinophils In Immediate Hypersensitivity

Mast cells, basophils, and eosinophils are the effector cells of immediate hypersensitivity reactions and allergic disease. Although each of these cell types has unique characteristics, all three contain cytoplasmic granules whose contents are the major mediators of allergic reactions, and all three cell types produce lipid mediators and cytokines that induce inflammation. TH2 cells also function as effector cells of immediate hypersensitivity their role has been discussed earlier. In this...

Innate And Adaptive Immunity

Defense against microbes is mediated by the early reactions of innate immunity and the later responses of adaptive immunity (Fig. 1-1 and Table 1-2). Innate immunity (also called natural or native immunity) provides the early line of defense against microbes. It consists of cellular and biochemical defense mechanisms that are in place even before infection and are poised to respond rapidly to infections. These mechanisms react to microbes and to the products of injured cells, and they respond...

Genetic Susceptibility To Immediate Hypersensitivity

The propensity to develop allergies is influenced by the inheritance of several genes. Abnormally high levels of IgE synthesis and associated atopy often run in families. Family studies have shown clear autosomal transmission of atopy, although the full inheritance pattern is multi-genic. Within the same family, the target organ of atopic disease is variable. Thus, hay fever, asthma, and eczema can be present to various degrees in different members of the same kindred. All these individuals,...

Purified Antigen Subunit Vaccines

Subunit vaccines are composed of antigens purified from microbes or inactivated toxins and are usually administered with an adjuvant. One effective use of purified antigens as vaccines is for the prevention of diseases caused by bacterial toxins. Toxins can be rendered harmless without loss of immunogenicity, and such toxoids induce strong antibody responses. Diphtheria and tetanus are two infections whose life-threatening consequences have been largely controlled because of immunization of...

Abnormally Expressed but Unmutated Cellular Proteins

Tumor antigens that elicit immune responses may be normal cellular proteins that are abnormally expressed in tumor cells. Many such antigens have been identified in human tumors, such as melanomas, by the molecular cloning of antigens that are recognized by T cells and antibodies from tumor-bearing patients (see Fig. 17-3). One of the surprises that emerged from these studies was that some tumor antigens are normal proteins that are produced at low levels in normal cells and overexpressed in...

General Features Of Humoral Immune Responses

The earliest studies of adaptive immunity were devoted to analyses of serum antibodies produced in response to microbes, toxins, and model antigens. Much of our current understanding of adaptive immune responses and the cellular interactions that take place during such responses has evolved from studies of antibody production. We begin with a summary of some of the key features of B cell activation and antibody production. The activation of B cells results in their proliferation, leading to...

Contraction homeostasis

Stages The Immune Response

FIGURE 1-6 Phases of adaptive immune responses. Adaptive immune responses consist of distinct phases, the first three being the recognition of antigen, the activation of lymphocytes, and the elimination of antigen (the effector phase). The response contracts (declines) as antigen-stimulated lymphocytes die by apoptosis, restoring homeostasis, and the antigen-specific cells that survive are responsible for memory. The duration of each phase may vary in different immune responses. The y-axis...

Vaccination with Tumor Antigens

Immunization of tumor-bearing individuals with tumor antigens may result in enhanced immune responses against the tumor (Table 17-2 and Fig. 17-6). The identification of peptides recognized by tumor-specific CTLs and the cloning of genes that encode tumor-specific antigens recognized by CTLs have provided many candidates for tumor vaccines we have mentioned several examples earlier in the chapter. One of the earliest vaccine approaches, immunization with purified tumor antigens plus adjuvants,...

Hiv

Representative examples of different mechanisms used by viruses to resist host immunity are listed. ER, endoplasmic reticulum HIV, human immunodeficiency virus TAP, transporter associated with antigen processing. FIGURE 15-8 Generation of new influenza virus strains by genetic recombination (antigenic shift). The genome of the influenza virus is composed of eight separate RNA strands, which allows genetic recombination by reassortment of the segments in various hosts, such as a pig, bird, or...

Lumen

FIGURE 13-2 Mechanism of regulation of innate immune responses in the intestinal mucosa. Pattern recognition receptor expression and function in intestinal epithelial cells and lamina propria DCs minimize inflammatory responses to commensal bacteria in the lumen but promote responses to microbes that traverse the barrier and enter the lamina propria. Top, Pattern recognition receptors that recognize bacterial flagellin are compartmentalized in the cytosol (NLR) or basal membrane (TLR5) of...

Defects in Innate Immunity

Innate immunity constitutes the first line of defense against infectious organisms. Two important mediators of innate immunity are phagocytes and complement, both of which also participate in the effector phases of adaptive immunity. Therefore, congenital disorders of phagocytes and the complement system result in recurrent infections. Complement deficiencies were described in Chapter 12. Deficiencies have been described in the classical and alternative complement pathways as well as in the...

Pathogenesis Of Autoimmunity

The possibility that an individual's immune system may react against autologous antigens and cause tissue injury was appreciated by immunologists from the time that the specificity of the immune system for foreign antigens was recognized. In the early 1900s, Paul Ehrlich coined the rather melodramatic phrase horror autotoxicus for harmful (toxic) immune reactions against self. Autoim-munity is an important cause of disease in humans and is estimated to affect 2 to 5 of the U.S. population. The...

Altered Glycolipid and Glycoprotein Antigens

Most human and experimental tumors express higher than normal levels or abnormal forms of surface glycoproteins and glycolipids, which may be diagnostic markers and targets for therapy. These altered molecules include gangliosides, blood group antigens, and mucins. Some aspects of the malignant phenotype of tumors, including tissue invasion and metastatic behavior, may reflect altered cell surface properties that result from abnormal glycolipid and glycoprotein synthesis. Many antibodies have...

B cell zone primary follicle

FIGURE 11-8 Migration of B cells and helper T cells and T-B interaction. Antigen-activated helper T cells and B cells move toward one another in response to chemokine signals and make contact adjacent to the edge of primary follicles. In this location, the B cell presents antigen to the T cell, and the B cell receives activating signals from the T cell. Some activated helper T cells are induced during B T interactions to differentiate into T follicular helper cells Tfh cells . Activated B cells...

Functions of TH1 Cells

The principal function of TH1 cells is to activate macrophages to ingest and destroy microbes Fig. 10-5 . Recall that phagocytosed intracellular microbes are powerful stimuli for the generation of TH1 cells see Chapter 9 . Thus, TH1 effector cells develop in response to the pathogens that these cells are designed to eradicate, an excellent example of the specialization of adaptive immunity. The same reaction of TH1-mediated macrophage activation is involved in injurious delayed-type...

Overview Of Lymphocyte Development

The maturation of B and T lymphocytes involves a series of events that occur in the generative lymphoid organs Fig. 8-1 . These events include the following The commitment of progenitor cells to the B cell or T cell lineage. Proliferation of progenitors and immature committed cells at specific early stages of development, providing a large pool of cells that can generate useful lymphocytes. The sequential and ordered rearrangement of antigen receptor genes and the expression of antigen receptor...

Extrafollicular B Cell Activation

After the initial interaction of B cells with helper T cells at the interface between the follicle and the T cell zone, subsequent activation of B cells by helper T cells can occur at two different locations, one outside the follicles and the other in the follicles, in germinal centers. The nature of the B cell response differs in these locations Table 11-1 . Extrafollicular foci of T-dependent B cell activation are generated relatively early in an immune response. Germinal centers, in which...

Differentiation of CD4 T Cells into TH1 TH2 and Th17 Effector Cells

Th1 Effecting Macrophage

Effector cells of the CD4 lineage are characterized by their ability to express surface molecules and to secrete cytokines that activate other cells B lymphocytes, macrophages, and dendritic cells . Whereas naive CD4 T cells produce mostly IL-2 on activation, effector CD4 T cells are capable of producing a large number and variety of cytokines that have diverse biologic activities. There are three distinct subsets of CD4 T cells, called Th1, Th2, and TH17, that function in host defense against...

Generation of Diversity in B and T Cells

The enormous diversity of the B and T cell repertoires is created not only by random combinations of germline gene segments being brought together but also by random addition or deletion of sequences at the junctions between segments that have been united. Several genetic mechanisms contribute to this diversity, and the relative importance of each mechanism varies among the different antigen receptor loci Table 8-1 . Not discussed here is somatic hypermutation, a mechanism that involves point...

P

Conserved AT-rich stretch of 9 nucleotides, called the nonamer. The 12- and 23-nucleotide spacers roughly correspond to one or two turns of a DNA helix, respectively, and they presumably bring two distinct heptamers into positions that are simultaneously accessible to the enzymes that catalyze the recombination process. During V D J recombination, double-stranded breaks are generated between the heptamer of the RSS and the adjacent V, D, or J coding sequence. In Ig light chain V-to-J...

Signals For T Lymphocyte Activation

The proliferation of T lymphocytes and their differentiation into effector and memory cells require antigen recognition, costimulation, and cytokines that are produced by the T cells themselves and by APCs and other cells at the site of antigen recognition. In this section, we will summarize the nature of antigens recognized by T cells and discuss specific costimulators and their receptors that contribute to T cell activation. Cytokines are discussed later in the chapter. Antigen is always the...

Development of Memory T Cells

T cell-mediated immune responses to an antigen usually result in the generation of memory T cells specific for that antigen, which may persist for years, even a lifetime. Thus, memory cells provide optimal defense against pathogens that are prevalent in the environment and may be repeatedly encountered. The success of vaccination is attributed in large part to the ability to generate memory cells on initial antigen exposure. Edward Jen-ner's classic experiment of successful vaccination of a...