Malaria Plasmodium Species Infects 600 Million People Worldwide
Malaria is one of the most devastating diseases in the world today, infecting nearly 10 of the world population and causing 1-2 million deaths every year. Malaria is caused by various species of the genus Plasmodium, of which P. falci-parum is the most virulent and prevalent. The alarming development of multiple-drug resistance in Plasmodium and the increased resistance of its vector, the Anopheles mosquito, to DDT underscore the importance of developing new strategies to hinder the spread of...
Opsonization Is Promoted by Antibody
Opsonization, the promotion of phagocytosis of antigens by macrophages and neutrophils, is an important factor in antibacterial defenses. Protein molecules called Fc receptors FcR , which can bind the constant region of Ig molecules, are present on the surfaces of macrophages and neutrophils. The binding of phagocyte Fc receptors with several antibody molecules complexed with the same target, such as a bacterial cell, produces an interaction that results in the binding of the pathogen to the...
TCell Maturation Activation and Differentiation
The attribute that distinguishes antigen recognition by most T cells from recognition by B cells is MHC restriction. In most cases, both the maturation of progenitor T cells in the thymus and the activation of mature T cells in the periphery are influenced by the involvement of MHC molecules. The potential antigenic diversity of the T-cell population is reduced during maturation by a selection process that allows only MHC-restricted and nonself-reactive T cells to mature. The final stages in...
Properties of BCell Epitopes Are Determined by the Nature of the AntigenBinding
Several generalizations have emerged from studies in which the molecular features of the epitope recognized by B cells have been established. The ability to function as a B-cell epitope is determined by the nature of the antigen-binding site on the antibody molecules displayed by B cells. Antibody binds to an epitope by weak noncovalent interactions, which operate only over short distances. For a strong bond, the antibody's binding site and the epitope must have complementary shapes that place...
The PreBCell Receptor Is Essential for BCell Development
As we saw in Chapter 10, during one stage in T-cell development, the p chain of the T-cell receptor associates with preTa to form the pre-T-cell receptor see Figure 10-1 . A parallel situation occurs during B-cell development. In the pre-B cell, the membrane chain is associated with the surrogate light chain, a complex consisting of two proteins a V-like sequence called Vpre-B and a C-like sequence called Stops VH' DhJh allelic exclusion Stops VH' DhJh allelic exclusion Schematic diagram of...
SelfReactive B Cells Are Selected Against in Bone Marrow
It is estimated that in the mouse the bone marrow produces about 5 X 107 B cells day but only 5 X 106 or about 10 are actually recruited into the recirculating B-cell pool. This means that 90 of the B cells produced each day die without ever leaving the bone marrow. Some of this loss is attributable to negative selection and subsequent elimination clonal deletion of immature B cells that express auto-antibodies against self-antigens in the bone marrow. It has long been established that the...
Passive Immunization Involves Transfer of Preformed Antibodies
Jenner and Pasteur are recognized as the pioneers of vaccination, or induction of active immunity, but similar recognition is due to Emil von Behring and Hidesaburo Kitasato for their contributions to passive immunity. These investigators were the first to show that immunity elicited in one animal can be transferred to another by injecting it with serum from the first see Clinical Focus, Chapter 4 . Passive immunization, in which preformed antibodies are transferred to a recipient, occurs...
AdhesionMolecule Interactions Play Critical Roles in Extravasation
The extravasation of lymphocytes into secondary lymphoid tissue or regions of inflammation is a multistep process involving a cascade of adhesion-molecule interactions similar to those involved in neutrophil emigration from the blood stream. Figure 15-7 depicts the typical interactions in extravasation of naive T cells across HEVs into lymph nodes. The first step is usually a selectin-carbohydrate interaction similar to that seen with neutrophil adhesion. Naive lymphocytes initially bind to...
References Qck
Brown, J. H., et al. 1993. Three-dimensional structure of the human class II histocompatibility antigen HLA-DR1. Nature 364 33. Drakesmith, H., and A. Townsend. 2000. The structure and function of HFE. BioEssays. 22 595. Fahrer, A. M., et al. 2001. A genomic view of immunology. Nature 409 836. International Human Genome Sequencing Consortium. 2001. Initial sequencing and analysis of the human genome. Nature 409 860. Madden, D. R. 1995. The three-dimensional structure of pep-tide-MHC complexes....
Systemic Lupus Erythematosus Attacks Many Tissues
One of the best examples of a systemic autoimmune disease is systemic lupus erythematosus SLE , which typically appears in women between 20 and 40 years of age the ratio of female to male patients is 10 1. SLE is characterized by fever, weakness, arthritis, skin rashes, pleurisy, and kidney dysfunction Figure 20-6 . Lupus is more frequent in African-American and Hispanic women than in Caucasians, although it is not known why this is so. Affected individuals may produce auto-antibodies to a vast...
Pathogenic Organisms Are Inactivated by Heat or Chemical Treatment
Another common approach in vaccine production is inacti-vation of the pathogen by heat or by chemical means so that it is no longer capable of replication in the host. It is critically important to maintain the structure of epitopes on surface antigens during inactivation. Heat inactivation is generally unsatisfactory because it causes extensive denaturation of proteins thus, any epitopes that depend on higher orders of protein structure are likely to be altered significantly. Chemical...
MHC Molecules and Genes
Class I and class II MHC molecules are membrane-bound glycoproteins that are closely related in both structure and function. Both class I and class II MHC molecules have been isolated and purified and the three-dimensional structures of their extracellular domains have been determined by x-ray crystallography. Both types of membrane glycoproteins function as highly specialized antigen-presenting molecules that form unusually stable complexes with antigenic peptides, displaying them on the cell...
In Vitroactivated Lak And Til Cells
Animal studies have shown that lymphocytes can be activated against tumor antigens in vitro by culturing them with x-irradiated tumor cells in the presence of IL-2 and added tumor antigens. These activated lymphocytes mediate more effective tumor destruction than untreated lymphocytes when they are reinjected into the original tumor-bearing animal. It is difficult, however, to activate in vitro enough lymphocytes with antitumor specificity to be useful in cancer therapy. While sensitizing...
T Cells Play a Key Role in Allograft Rejection
In the early 1950s, Avrion Mitchison showed in adoptive-transfer experiments that lymphocytes, but not serum antibody, could transfer allograft immunity. Later studies implicated T cells in allograft rejection. For example, nude mice, which lack a thymus and consequently lack functional T cells, were found to be incapable of allograft rejection indeed, these mice even accept xenografts. In other studies, T cells derived from an allograft-primed mouse were shown to transfer second-set allograft...
Transfusion Reactions Are Type II Reactions
A large number of proteins and glycoproteins on the membrane of red blood cells are encoded by different genes, each of which has a number of alternative alleles. An individual possessing one allelic form of a blood-group antigen can recognize other allelic forms on transfused blood as foreign and mount an antibody response. In some cases, the antibodies have already been induced by natural exposure to similar antigenic determinants on a variety of microorganisms present in the normal flora of...
Hematopoiesis Is Regulated at the Genetic Level
The development of pluripotent hematopoietic stem cells into different cell types requires the expression of different sets of lineage-determining and lineage-specific genes at appropriate times and in the correct order. The proteins specified by these genes are critical components of regulatory networks that direct the differentiation of the stem cell and its descendants. Much of what we know about the dependence of hematopoiesis on a particular gene comes from studies of mice in which a gene...
Primary and Secondary Responses Differ Significantly
The kinetics and other characteristics of the humoral response differ considerably depending on whether the humoral response results from activation of naive lymphocytes primary response or memory lymphocytes secondary response . In both cases, activation leads to production of secreted antibodies of various isotypes, which differ in their ability to mediate specific effector functions see Table 4-2 . The first contact of an exogenous antigen with an individual generates a primary humoral...
Cytokine Receptors Fall Within Five Families
Receptors for the various cytokines are quite diverse structurally, but almost all belong to one of five families of receptor proteins Figure 12-6 Immunoglobulin superfamily receptors Class I cytokine receptor family also known as the hematopoietin receptor family Class II cytokine receptor family also known as the interferon receptor family Many of the cytokine-binding receptors that function in the immune and hematopoietic systems belong to the class I cytokine receptor family. The members of...
Regulation of the Complement System
Because many elements of the complement system are capable of attacking host cells as well as foreign cells and microorganisms, elaborate regulatory mechanisms have evolved to restrict complement activity to designated targets. A general mechanism of regulation in all complement pathways is the inclusion of highly labile components that undergo spontaneous inactivation if they are not stabilized by reaction with other components. In addition, a series of regulatory proteins can inactivate...
Tumor Antigens May Be Induced by Viruses
In contrast to chemically induced tumors, virally induced tumors express tumor antigens shared by all tumors induced by the same virus. For example, when syngeneic mice are injected with killed cells from a particular polyoma-induced tumor, the recipients are protected against subsequent challenge with live cells from any polyoma-induced tumors see Table 22-2 . Likewise, when lymphocytes are transferred from mice with a virus-induced tumor into normal syngeneic recipients, the recipients reject...
NAddition Adds Considerable Diversity by Addition of Nucleotides
Variable-region coding joints in rearranged heavy-chain genes have been shown to contain short amino acid sequences that are not encoded by the germ-line V, D, or J gene segments. These amino acids are encoded by nucleotides added during the D-J and V to D-J joining process by a terminal deoxynucleotidyl transferase TdT catalyzed reaction Sources of sequence variation in complementarity-determining regions of immunoglobulin heavy- and light-chain genes Sources of sequence variation in...
Class I and Class II Molecules Exhibit Diversity Within a Species and Multiple
An enormous diversity is exhibited by the MHC molecules within a species and within individuals. This variability echoes the diversity of antibodies and T-cell receptors, but the source of diversity for MHC molecules is not the same. Antibodies and T-cell receptors are generated by several somatic processes, including gene rearrangement and somatic mutation of rearranged genes see Table 5-2 . Thus, the generation of T and B cell receptors is dynamic, changing over time within an individual. By...
Immunoglobulin M IgM
IgM accounts for 5 -10 of the total serum immunoglobulin, with an average serum concentration of 1.5 mg ml. Monomeric IgM, with a molecular weight of 180,000, is expressed as membrane-bound antibody on B cells. IgM is secreted by plasma cells as a pentamer in which five monomer units are held together by disulfide bonds that link their car-boxyl-terminal heavy chain domains C 4 C 4 and their C 3 C 3 domains see Figure 4-13e . The five monomer subunits are arranged with their Fc regions in the...
SelfMHC Restriction of T Cells
Both CD4 and CD8 T cells can recognize antigen only when it is presented by a self-MHC molecule, an attribute called self-MHC restriction. Beginning in the mid-1970s, experiments conducted by a number of researchers demonstrated self-MHC restriction in T-cell recognition. A. Rosenthal and E. Shevach, for example, showed that antigen-specific proliferation of Th cells occurred only in response to antigen presented by macrophages of the same MHC haplotype as the T cells. In their experimental...
Proposed Mechanisms for Induction of Autoimmunity
A variety of mechanisms have been proposed to account for the T-cell-mediated generation of autoimmune diseases Figure 20-8 . Evidence exists for each of these mechanisms, Inappropriate MHC expression on non-APCs Inappropriate MHC expression on non-APCs TH cell B cell Plasma cell TH cell B cell Plasma cell Proposed mechanisms for inducing autoimmune responses. Normal thymic selection appears to generate some self-reactive TH cells abnormalities in this process may generate even more...
TCell Receptor Complex TCRCD3
As explained in Chapter 4, membrane-bound immunoglobulin on B cells associates with another membrane protein, the Ig-a Ig-p heterodimer, to form the B-cell antigen receptor see Figure 4-18 . Similarly, the T-cell receptor associates with CD3, forming the TCR-CD3 membrane complex. In both cases, the accessory molecule participates in signal transduction after interaction of a B or T cell with antigen it does not influence interaction with antigen. The first evidence suggesting that the T-cell...
Localized Anaphylaxis Atopy
In localized anaphylaxis, the reaction is limited to a specific target tissue or organ, often involving epithelial surfaces at the site of allergen entry. The tendency to manifest localized anaphylactic reactions is inherited and is called atopy. Atopic allergies, which afflict at least 20 of the population in developed countries, include a wide range of IgE-mediated disorders, including allergic rhinitis hay fever , asthma, atopic dermatitis eczema , and food allergies. ALLERGIC RHINITIS The...
Gene Segments Are Joined by Recombinases
V- D -J recombination, which takes place at the junctions between RSSs and coding sequences, is catalyzed by enzymes collectively called V D J recombinase. Identification of the enzymes that catalyze recombination of V, D, and J gene segments began in the late 1980s and is still ongoing. In 1990 David Schatz, Marjorie Oettinger, and David Baltimore first reported the identification of two recombination-activating genes, designated RAG-1 and RAG-2, whose encoded proteins act synergistically and...
Antibodies Are Heterodimers
Antibody molecules have a common structure of four peptide chains Figure 4-2 . This structure consists of two identical light L chains, polypeptides of about 25,000 molecular weight, and two identical heavy H chains, larger Experimental demonstration that most antibodies are in the 7-globulin fraction of serum proteins. After rabbits were immunized with ovalbumin OVA , their antisera were pooled and elec-trophoresed, which separated the serum proteins according to their electric charge and...
RecombinantVector Vaccines
Genes that encode major antigens of especially virulent pathogens can be introduced into attenuated viruses or bacteria. The attenuated organism serves as a vector, replicating within the host and expressing the gene product of the pathogen. A number of organisms have been used for vector vaccines, including vaccinia virus, the canarypox virus, attenuated poliovirus, adenoviruses, attenuated strains of Salmonella, the BCG strain of Mycobacterium bovis, and certain strains of streptococcus that...
T Helper Cells Play a Critical Role in the Humoral Response to HaptenCarrier
As Chapter 3 described, when animals are immunized with small organic compounds haptens conjugated with large proteins carriers , the conjugate induces a humoral immune response consisting of antibodies both to hapten epitopes and to unaltered epitopes on the carrier protein. Hapten-carrier conjugates provided immunologists with an ideal system for studying cellular interactions of the humoral response, and such studies demonstrated that the generation of a humoral antibody response requires...
Cellular Distribution of MHC Molecules
In general, the classical class I MHC molecules are expressed on most nucleated cells, but the level of expression differs among different cell types. The highest levels of class I molecules are expressed by lymphocytes, where they constitute approximately 1 of the total plasma-membrane proteins, or some 5 X 105 molecules per cell. In contrast, fibroblasts, muscle cells, liver hepatocytes, and neural cells express very low levels of class I MHC molecules. The low level on liver cells may...
Fc Receptors Bond to Fc Regions of Antibodies
Many cells feature membrane glycoproteins called Fc receptors FcR that have an affinity for the Fc portion of the antibody molecule. These receptors are essential for many of the biological functions of antibodies. Fc receptors are responsible for the movement of antibodies across cell membranes and the transfer of IgG from mother to fetus across the placenta. These receptors also allow passive acquisition of antibody by many cell types, including B and T lymphocytes, neutrophils, mast cells,...
The MembraneAttack Complex Can Lyse a Broad Spectrum of Cells
The membrane-attack complex formed by complement activation can lyse gram-negative bacteria, parasites, viruses, erythrocytes, and nucleated cells. Because the alternative and lectin pathways of activation generally occur without an initial antigen-antibody interaction, these pathways serve as important innate immune defenses against infectious microorganisms. The requirement for an initial antigen-antibody reaction in the classical pathway supplements these nonspecific innate defenses with a...
Info Bek
30 40 50 60 Days after BCG infection Experimental demonstration of the role of IFN-7 in host defense against intracellular pathogens. Knockout mice were produced by introducing a targeted mutation in the gene encoding IFN-7. The mice were then infected with 107 colony-forming units of attenuated Mycobacterium bovis BCG and their survival monitored. Adapted from D. K. Dalton et al, 1993, Science 259 1739. This complex is internalized by antigen-presenting cells in the skin e.g., Langerhans cells...
chapter 23
Experimental systems of various types are used to unravel the complex cellular interactions of the immune response. In vivo systems, which involve the whole animal, provide the most natural experimental conditions. However, in vivo systems have a myriad of unknown and uncontrollable cellular interactions that add ambiguity to the interpretation of data. At the other extreme are in vitro systems, in which defined populations of lymphocytes are studied under controlled and consequently repeatable...
Hybrid Lymphoid Cell Lines
In somatic-cell hybridization, immunologists fuse normal B or T lymphocytes with tumor cells, obtaining hybrid cells, or heterokaryons, containing nuclei from both parent cells. Random loss of some chromosomes and subsequent cell proliferation yield a clone of cells that contain a single nucleus with chromosomes from each of the fused cells such a clone is called a hybridoma. Historically, cell fusion was promoted with Sendai virus, but now it is generally done with polyethylene glycol. Normal...
Class I and II Molecules Exhibit Polymorphism in the Region That Binds to
Several hundred different allelic variants of class I and II MHC molecules have been identified in humans. Any one individual, however, expresses only a small number of these molecules up to 6 different class I molecules and up to 12 different class II molecules. Yet this limited number of MHC molecules must be able to present an enormous array of different antigenic pep-tides to T cells, permitting the immune system to respond specifically to a wide variety of antigenic challenges. Thus,...
In Vitro Studies Revealed the HIV1 Replication Cycle
The AIDS virus can infect human T cells in culture, replicating itself and in many cases causing the lysis of the cell host Figure 19-9 . Much has been learned about the life cycle of HIV-1 from in vitro studies. The various proteins encoded by the viral genome have been characterized and the functions of most of them are known Figure 19-10 . The first step in HIV infection is viral attachment and entry into the target cell. HIV-1 infects T cells that carry the CD4 antigen on their surface in...
XLINKED HYPERIgM SYNDROME
A peculiar immunoglobulin deficiency first thought to result from a B-cell defect has recently been shown to result instead from a defect in a T-cell surface molecule. X-linked hyper-IgM XHM syndrome is characterized by a deficiency of IgG, IgA, and IgE, and elevated levels of IgM, sometimes as high as 10 mg ml normal IgM concentration is 1.5 mg ml . Although individuals with XHM have normal numbers of B cells expressing membrane-bound IgM or IgD, they appear to lack B cells expressing...
Lymphatic System
As blood circulates under pressure, its fluid component plasma seeps through the thin wall of the capillaries into the surrounding tissue. Much of this fluid, called interstitial fluid, returns to the blood through the capillary membranes. The remainder of the interstitial fluid, now called lymph, flows from the spaces in connective tissue into a network of tiny open lymphatic capillaries and then into a series of pro- Lymphatic vessels. Small lymphatic capillaries opening into the tissue...
B and T Lymphocytes Utilize Similar Mechanisms To Generate Diversity in Antigen
The antigenic specificity of each B cell is determined by the membrane-bound antigen-binding receptor i.e., antibody expressed by the cell. As a B cell matures in the bone marrow, its specificity is created by random rearrangements of a series Overview of the humoral and cell-mediated branches of the immune system. In the humoral response, B cells interact with antigen and then differentiate into antibody-secreting plasma cells. The secreted antibody binds to the antigen and facilitates its...
Superantigens Induce TCell Activation by Binding the TCR and MHC II
Superantigens are viral or bacterial proteins that bind simultaneously to the Vp domain of a T-cell receptor and to the a chain of a class II MHC molecule. Both exogenous and endogenous superantigens have been identified. Crosslinkage of a T-cell receptor and class II MHC molecule by either type of superantigen produces an activating signal that induces T-cell activation and proliferation Figure 10-16 . Exogenous superantigens are soluble proteins secreted by bacteria. Among them are a variety...
Thymic Selection of the TCell Repertoire
Random gene rearrangement within TCR germ-line DNA combined with junctional diversity can generate an enormous TCR repertoire, with an estimated potential diversity exceeding 1015 for the ap receptor and 1018 for the 78 receptor. Gene products encoded by the rearranged TCR genes have no inherent affinity for foreign antigen plus a self-MHC molecule they theoretically should be capable of recognizing soluble antigen either foreign or self , self-MHC molecules, or antigen plus a nonself-MHC...
Polyclonal BCell Activation Can Lead to Autoimmune Disease
A number of viruses and bacteria can induce nonspecific polyclonal B-cell activation. Gram-negative bacteria, cytomegalovirus, and Epstein-Barr virus EBV are all known to be such polyclonal activators, inducing the proliferation of numerous clones of B cells that express IgM in the absence of TH cells. If B cells reactive to self-antigens are activated by this mechanism, auto-antibodies can appear. For instance, during infectious mononucleosis, which is caused by EBV, a variety of...
Monoclonal Antibodies Can Be Constructed from IgGene Libraries
A quite different approach for generating monoclonal antibodies employs the polymerase chain reaction PCR to amplify the DNA that encodes antibody heavy-chain and light-chain Fab fragments from hybridoma cells or plasma cells. A promoter region and EcoRI restriction site see Chapter 23 are added to the amplified sequences, and the resulting constructs are inserted into bacteriophage X, yielding separate heavy- and light-chain libraries. Cleavage with EcoRI and random joining of the heavy- and...
AntibodyDependent CellMediated Cytotoxicity
A number of cells that have cytotoxic potential express membrane receptors for the Fc region of the antibody molecule. When antibody is specifically bound to a target cell, these receptor-bearing cells can bind to the antibody Fc region, and thus to the target cells, and subsequently cause lysis of the target cell. Although these cytotoxic cells are nonspecific for antigen, the specificity of the antibody directs them to specific target cells. This type of cytotoxicity is referred to as...
The Alternative Pathway Is AntibodyIndependent
The alternative pathway generates bound C5b, the same product that the classical pathway generates, but it does so without the need for antigen-antibody complexes for initiation. Because no antibody is required, the alternative pathway is a component of the innate immune system. This major pathway of complement activation involves four serum proteins C3, factor B, factor D, and properdin. The alternative pathway is initiated in most cases by cell-surface constituents that are foreign to the...
Peptides Assemble with Class I MHC Aided by Chaperone Molecules
Like other proteins, the a chain and -microglobulin components of the class I MHC molecule are synthesized on polysomes along the rough endoplasmic reticulum. Assembly of these components into a stable class I MHC molecular complex that can exit the RER requires the presence of a peptide in the binding groove of the class I molecule. The assembly process involves several steps and includes the participation of molecular chaperones, which facilitate the folding of polypeptides. The first...
Emerging Infectious Diseases
A cursory glance at the current offerings in your local bookstore or video rental store brings into focus the preoccupation of the public and the press with new infectious agents. Several times a year, it seems, we hear about a new virus or bacterium that arises in a particular location and causes severe illness or death in a population. Newly described pathogens are referred to as emerging pathogens. Some of the emerging pathogens that have been described since the early 1970s appear in Table...