Monoclonal Antibodies Are Effective in Treating Some Tumors

Humanized Anti Her2 Antibody

Monoclonal antibodies have been used in various ways as experimental immunotherapeutic agents for cancer. For example, anti-idiotype monoclonal antibodies have been used with some success in treating human B-cell lymphomas and T-cell leukemias. In one remarkable study, R. Levy and his colleagues successfully treated a 64-year-old man with terminal B-cell lymphoma. At the time of treatment, the lymphoma had metastasized to the liver, spleen, bone marrow, and peripheral blood. Because this was a...

Radioimmunoassay

One of the most sensitive techniques for detecting antigen or antibody is radioimmunoassay (RIA). The technique was first developed in 1960 by two endocrinologists, S. A. Berson and Rosalyn Yalow, to determine levels of insulin-anti-insulin complexes in diabetics. Although their technique encountered some skepticism, it soon proved its value for measuring hormones, serum proteins, drugs, and vitamins at concentrations of 0.001 micrograms per milliliter or less. In 1977, some years after...

Approximately

Coolest Chain Infection Collage

500,000 infants become infected with HIV each year. The majority of these infections result from transmission of virus from HIV-infected mothers during childbirth or by transfer of virus from milk during breast-feeding. The incidence of maternal acquired infection can be reduced as much as 67 by treatment of the infected mother with a course of Zidovudine (AZT) for several months prior to delivery, and treatment of her infant for 6 weeks after birth. This treatment regimen is widely used in the...

Tumors of the Immune System

Tumors of the immune system are classified as lymphomas or leukemias. Lymphomas proliferate as solid tumors within a lymphoid tissue such as the bone marrow, lymph nodes, or thymus they include Hodgkin's and non-Hodgkin's lymphomas. Leukemias tend to proliferate as single cells and are detected by increased cell numbers in the blood or lymph. Leukemia can develop in lymphoid or myeloid lineages. Historically, the leukemias were classified as acute or chronic according to the clinical...

Cancer Associated Genes Have Many Functions

Homeostasis in normal tissue is maintained by a highly regulated process of cellular proliferation balanced by cell death. If there is an imbalance, either at the stage of cellular proliferation or at the stage of cell death, then a cancerous state will develop. Oncogenes and tumor suppressor genes have been shown to play an important role in this process, by regulating either cellular proliferation or cell death. Cancer-associated genes can be divided into three categories that reflect these...

Monoclonal Antibodies May Be Used to Treat Autoimmunity

Monoclonal antibodies have been used successfully to treat autoimmune disease in several animal models. For example, a high percentage of (NZB X NZW) F1 mice given weekly injections of high doses of monoclonal antibody specific for the CD4 membrane molecule recovered from their autoimmune lupus-like symptoms (Figure 20-11). Similar positive results were observed in NOD mice, in which treatment with an anti-CD4 monoclonal antibody led to disappearance of the lymphocytic infiltration and diabetic...

Multiple Sclerosis Attacks the Central Nervous System

Multiple sclerosis (MS) is the most common cause of neurologic disability associated with disease in Western countries. The symptoms may be mild, such as numbness in the limbs, or severe, such as paralysis or loss of vision. Most people with MS are diagnosed between the ages of 20 and 40. Individuals with this disease produce autoreactive T cells that participate in the formation of inflammatory lesions along the myelin sheath of nerve fibers. The cerebrospinal fluid of patients with active MS...

Immune Response to Infectious Diseases

Earthworm Ureathral Pictures

If a pathogen is to establish an infection in a susceptible host, a series of coordinated events must circumvent both innate and adaptive immunity. One of the first and most important features of host innate immunity is the barrier provided by the epithelial surfaces of the skin and the lining of the gut. The difficulty of penetrating these epithelial barriers ensures that most pathogens never gain productive entry into the host. In addition to providing a physical barrier to infection, the...

A CD4CD25 Subpopulation of T cells Negatively Regulates Immune Responses

Investigators first described T cell populations that could suppress immune responses during the early 1970s. These cells were called suppressor T cells (Ts) and were believed to be CD8+ T cells. However, the cellular and molecular basis of the observed suppression remained obscure, and eventually great doubt was cast on the existence of CD8+ suppressor T cells. Recent research has shown that there are indeed T cells that suppress immune responses. Unexpectedly, these cells have turned out to...

Lymphoid Cells

Immune System Figure With Heavy Chain

Lymphocytes constitute 20 -40 of the body's white blood cells and 99 of the cells in the lymph (Table 2-4). There are approximately 1011 (range depending on body size and age 101o-1012) lymphocytes in the human body. These lymphocytes continually circulate in the blood and lymph and are capable of migrating into the tissue spaces and lymphoid organs, thereby integrating the immune system to a high degree. The lymphocytes can be broadly subdivided into three populations B cells, T cells, and...

Influenza Has Been Responsible for Some of the Worst Pandemics in History

Neuraminidase And

The influenza virus infects the upper respiratory tract and major central airways in humans, horses, birds, pigs, and even seals. In 1918-19, an influenza pandemic (worldwide epidemic) killed more than 20 million people, a toll surpassing the number of casualties in World War I. Some areas, such as Alaska and the Pacific Islands, lost more than half of their population during that pandemic. Influenza viral particles, or virions, are roughly spherical or ovoid in shape, with an average diameter...

Type I Hypersensitivities Can Be Controlled Medically

The obvious first step in controlling type I hypersensitivities is to avoid contact with known allergens. Often the removal of house pets, dust-control measures, or avoidance of offending foods can eliminate a type I response. Elimination of inhalant allergens (such as pollens) is a physical impossibility, however, and other means of intervention must be pursued. Immunotherapy with repeated injections of increasing doses of allergens (hyposensitization) has been known for some time to reduce...

Ataxia Telangiectasia

Although not classified primarily as an immunodeficiency, ataxia telangiectasia is a disease syndrome that includes deficiency of IgA and sometimes of IgE. The syndrome is characterized by difficulty in maintaining balance (ataxia) and by the appearance of broken capillaries (telangiectasia) in the eyes. The primary defect appears to be in a kinase involved in regulation of the cell cycle. The relationship between the immune deficiency and the other defects in ataxia telangiectasia remains...

Vaccine May Be the Only Way to Stop the Hivaids Epidemic

The AIDS epidemic continues to rage despite the advances in therapeutic approaches outlined above. The present expense of HAART (as much as 15,000 per year), the strict regimen TABLE 19-61 Why AIDS does not fit the paradigm for classic vaccine development Classic vaccines mimic natural immunity against reinfection generally seen in individuals recovered from infection there are no recovered AIDS patients. Most vaccines protect against disease, not against infection HIV infection may remain...

Multivalent Subunit Vaccines

Experience has shown that not every vaccine candidate that was successful in laboratory and animal studies prevents disease in humans. Some potential vaccines cause unacceptable side effects, and some may even worsen the disease they were meant to prevent. Live virus vaccines pose a special threat to those with primary or acquired immunodeficiency (see Chapter 19). Stringent testing is an absolute necessity, because vaccines will be given to large numbers of well persons. Adverse...

HIV1 Infection Leads to Opportunistic Infections

Seroconversion Images

Isolation of HIV-1 and its growth in culture has allowed purification of viral proteins and the development of tests for infection with the virus. The most commonly used test is for the presence of antibodies directed against proteins of HIV-1. These generally appear in the serum of infected individuals by three months after the infection has occurred. When the antibodies appear, the individual is said to have serocon-verted or to be seropositive for HIV-1. Although the precise course of HIV-1...

NK Cells and Macrophages Are Important in Tumor Recognition

Excise Tumor Dendritic Cells

The recognition of tumor cells by NK cells is not MHC restricted. Thus, the activity of these cells is not compromised by the decreased MHC expression exhibited by some tumor cells. In some cases, Fc receptors on NK cells can bind to antibody-coated tumor cells, leading to ADCC. The importance of NK cells in tumor immunity is suggested by the mutant mouse strain called beige and by Chediak-Higashi syndrome in humans, as described in the Clinical Focus in Chapter 14. In each case, a genetic...

Use of Synthetic Peptides as Vaccines Has Progressed Slowly

Although once considered very promising, the use of synthetic peptides as vaccines has not progressed as originally projected. Peptides are not as immunogenic as proteins, and it is difficult to elicit both humoral and cellular immunity to them. The use of conjugates and adjuvants can assist in raising protective immunity to peptides, but barriers to the widespread use of peptide vaccines remain and pose an interesting problem for immunologists. Most importantly, advances in techniques to...

Systemic Function of the Immune System

The many different cells, organs, and tissues of the immune system are dispersed throughout the body, yet the various components communicate and collaborate to produce an ef fective response to an infection. An infection that begins in one area of the body initiates processes that eventually involve cells, organs, and tissues distant from the site of pathogen invasion. Consider what happens when the skin is broken, allowing bacteria to enter the body and initiate infection. The tissue damage...

Myasthenia Gravis

Tsh Receptor

Myasthenia gravis is the prototype autoimmune disease mediated by blocking antibodies. A patient with this disease produces auto-antibodies that bind the acetylcholine receptors on the motor end-plates of muscles, blocking the normal binding of acetylcholine and also inducing complement-mediated lysis of the cells. The result is a progressive weakening of the skeletal muscles Figure 20-5 . Ultimately, the antibodies destroy the cells bearing the receptors. The early signs of this disease...

Active Immunization Elicits Long Term Protection

Whereas the aim of passive immunization is transient protection or alleviation of an existing condition, the goal of active immunization is to elicit protective immunity and immunologic memory. When active immunization is successful, a subsequent exposure to the pathogenic agent elicits a heightened immune response that successfully eliminates the pathogen or prevents disease mediated by its products. Active immunization can be achieved by natural infection with a microorganism, or it can be...

Molecular Mimicry May Contribute to Autoimmune Disease

For several reasons, the notion that microbial or viral agents might play a role in autoimmunity is very attractive. It is well accepted that migrant human populations acquire the diseases of the area to which they move and that the incidence of autoimmunity has increased dramatically as populations have become more mobile. This, coupled with the fact that a number of viruses and bacteria have been shown to possess Molecular mimicry between proteins of infectious organisms and human host...

Certain Fungal Metabolites Are Immunosuppressants

Cyclosporin A CsA , FK506 tacrolimus , and rapamycin sirolimus are fungal metabolites with immunosuppressive properties. Although chemically unrelated, CsA and FK506 have similar actions. Both drugs block activation of resting T cells by inhibiting the transcription of genes encoding IL-2 and the high-affinity IL-2 receptor IL-2R , which are essential for activation. CsA and FK506 exert this effect by binding to cytoplasmic proteins called immunophilins, forming a complex that blocks the...

Privileged Sites Accept Antigenic Mismatches

In immunologically privileged sites, an allograft can be placed without engendering a rejection reaction. These sites include the anterior chamber of the eye, the cornea, the uterus, the testes, and the brain. The cheek pouch of the Syrian hamster is a privileged site used in experimental situations. Each of these sites is characterized by an absence of lymphatic vessels and in some cases by an absence of blood vessels as well. Consequently, the alloantigens of the graft are not able to...

Hashimotos Thyroiditis

In Hashimoto's thyroiditis, which is most frequently seen in middle-aged women, an individual produces auto-antibodies and sensitized TH1 cells specific for thyroid antigens. The DTH response is characterized by an intense infiltration of the thyroid gland by lymphocytes, macrophages, and plasma cells, which form lymphocytic follicles and germinal centers Figure 20-1 . The ensuing inflammatory response causes a goiter, or visible enlargement of the thyroid gland, a physiological response to...

SCID Mice and SCIDHuman Mice Are a Valuable Animal Model for Immunodeficiency

An autosomal recessive mutation resulting in severe combined immunodeficiency disease SCID developed spontaneously in a strain of mice called CB-17. These CB-17 SCID mice fail to develop mature T and B cells and consequently are severely compromised immunologically. This defect is due to a failure in V D J recombination. SCID mice must be housed in a sterile germ-free environment, because they cannot fight off microorganisms of even low pathogenicity. The absence of functional T and B cells...

There Are Several Phases of the DTH Response

Macrophage Receptor Cryptococcus

The development of the DTH response begins with an initial sensitization phase of 1-2 weeks after primary contact with an antigen. During this period, TH cells are activated and clonally expanded by antigen presented together with the requisite class II MHC molecule on an appropriate antigen-presenting cell Figure 16-17a . A variety of antigen-presenting cells have been shown to be involved in the activation of a DTH response, including Langerhans cells and macrophages. Langerhans cells are...

Corticosteroids Are Powerful Anti Inflammatory Drugs

The corticosteroids, which are cholesterol derivatives, include prednisone, prednisolone, and methylprednisolone. These potent anti-inflammatory agents exert various effects that result in a reduction in the numbers and activity of immune-system cells. They are regularly used in anti-inflammatory therapy. Corticosteroid treatment causes a decrease in the number of circulating lymphocytes as the result either of steroid-induced lysis of lymphocytes lympholysis or of alterations in...

Chemical and Enzymatic Methods Revealed Basic Antibody Structure

Igg Molecular Weight Light Chain

Our knowledge of basic antibody structure was derived from a variety of experimental observations. When the 7-globulin fraction of serum is separated into high- and low-molecular-weight fractions, antibodies of around 150,000-MW, designated as immunoglobulin G IgG are found in the low-molecular-weight fraction. In a key experiment, brief digestion of IgG with the enzyme papain produced three fragments, two of which were identical fragments and a third that was quite different Figure 4-3 . The...

The Complement System Clears Immune Complexes from Circulation

Complement Immune

The importance of the complement system in clearing immune complexes is seen in patients with the autoimmune disease systemic lupus erythematosus SLE . These individuals produce large quantities of immune complexes and suffer tissue damage as a result of complement-mediated lysis and the induction of type II or type III hypersensitivity see Chapter 16 . Although complement plays a significant role in the development of tissue damage in SLE, the paradoxical finding is that deficiencies in C1,...

Chemically Or Physically Induced Tumor Antigens

Tsta Antigen

Methylcholanthrene and ultraviolet light are two carcinogens that have been used extensively to generate lines of tumor cells. When syngeneic animals are injected with killed cells from a carcinogen-induced tumor-cell line, the animals develop a specific immunologic response that can protect against later challenge by live cells of the same line but not other tumor-cell lines Table 22-2 . Even when the same chemical carcinogen induces two separate tumors at different sites in the same animal,...

Immune Responses to Extracellular and Intracellular Bacteria Can Differ

Infection by extracellular bacteria induces production of humoral antibodies, which are ordinarily secreted by plasma cells in regional lymph nodes and the submucosa of the respiratory and gastrointestinal tracts. The humoral immune response is the main protective response against extracellular bacteria. The antibodies act in several ways to protect the host from the invading organisms, including removal of the bacteria and inactivation of bacterial toxins Figure 17-8 . Extracellular bacteria...

Retrovirus HIV1 Is the Causative Agent of AIDS

Hiv Virions

Within a few years after recognition of AIDS as an infectious disease, the causative agent was discovered and characterized by efforts in the laboratories of Luc Montagnier in Paris and Robert Gallo in Bethesda Figure 19-8 . This immunodeficiency syndrome was novel at the time in that the type of virus causing it was a retrovirus. Retroviruses carry their genetic information in the form of RNA. When the virus enters a cell, the RNA is reverse transcribed to DNA by a virally encoded enzyme,...

Autoimmune Anemias

Hashimoto Disease Labeled

Autoimmune anemias include pernicious anemia, autoimmune hemolytic anemia, and drug-induced hemolytic anemia. Pernicious anemia is caused by auto-antibodies to intrinsic factor, a membrane-bound intestinal protein on gastric parietal cells. Intrinsic factor facilitates uptake of vitamin B12 Photomicrographs of a normal thyroid gland showing a follicle lined by cuboidal follicular epithelial cells and b gland in Hashimoto's thyroiditis showing intense lymphocyte infiltration. From Web Path,...

Evidence Implicating the CD4 T Cell MHC and TCR in Autoimmunity

The inappropriate response to self-antigens that characterizes all autoimmune diseases can involve either the humoral or cell-mediated branches of the immune system. Identifying the defects underlying human autoimmune diseases has been difficult more success has been achieved in characterizing the immune defects in the various animal models. Each of the animal models has implicated the CD4 T cell as the primary mediator of autoimmune disease. For example, the evidence is quite strong that, in...

Cytokine Therapy Can Augment Immune Responses to Tumors

The isolation and cloning of the various cytokine genes has facilitated their large-scale production. A variety of experimental and clinical approaches have been developed to use recombinant cytokines, either singly or in combination, to augment the immune response against cancer. Among the cytokines that have been evaluated in cancer immunother-apy are IFN-a, p, and 7 IL-1, IL-2, IL-4, IL-5, and IL-12 GM-CSF and TNF. Although these trials have produced occasional encouraging results, many...

Cell Adhesion Molecules

Lymphocyte Recirculation Diagram

The vascular endothelium serves as an important gatekeeper, regulating the movement of blood-borne molecules Lymphocyte recirculation routes. The percentage of the lymphocyte pool that circulates to various sites and the average transit times in the major sites are indicated. Lymphocytes migrate from the blood into lymph nodes through specialized areas in postcapillary venules called high-endothelial venules HEVs . Although most lymphocytes circulate, some sites appear to contain lymphocytes...

Secondary Lymphoid Organs

Spleen Structure

Various types of organized lymphoid tissues are located along the vessels of the lymphatic system. Some lymphoid tissue in the lung and lamina propria of the intestinal wall consists of diffuse collections of lymphocytes and macrophages. Other lymphoid tissue is organized into structures called lymphoid follicles, which consist of aggregates of lym-phoid and nonlymphoid cells surrounded by a network of draining lymphatic capillaries. Until it is activated by antigen, a lymphoid follicle called...

Cytokine Secretion by TH1 and Th2 Subsets

The immune response to a particular pathogen must induce an appropriate set of effector functions that can eliminate the disease agent or its toxic products from the host. For example, the neutralization of a soluble bacterial toxin requires antibodies, whereas the response to an intracellular virus or to a bacterial cell requires cell-mediated cytotoxicity or delayed-type hypersensitivity. A large body of evidence implicates differences in cytokine-secretion patterns among TH-cell subsets as...

Autoimmunity Can Develop Spontaneously in Animals

Hashimotos Lymph Nodes

A number of autoimmune diseases that develop spontaneously in animals exhibit important clinical and pathologic similarities to certain autoimmune diseases in humans. Certain inbred mouse strains have been particularly valuable models for illuminating the immunologic defects involved in the development of autoimmunity. New Zealand Black NZB mice and F1 hybrids of NZB and New Zealand White NZW mice spontaneously develop autoimmune diseases that closely resemble systemic lupus ery-thematosus. NZB...

Insulindependent Diabetes Mellitus

Goodpasture Renal Biopsy Fluorescence

A disease afflicting 0.2 of the population, insulin-dependent diabetes mellitus IDDM is caused by an autoimmune attack on the pancreas. The attack is directed against specialized insulin-producing cells beta cells that are located in spherical clusters, called the islets of Langerhans, scattered throughout the pancreas. The autoimmune attack destroys beta cells, resulting in decreased production of insulin and consequently increased levels of blood glucose. Several factors are important in the...

2. Fill In The Blanks In The Following Statements With The Most Appropriate Terms A. And All Function As Antigen

Kaisho. 2001. Toll-like receptors Critical proteins linking innate and acquired immunity. Nature Immunol. 2 675. Burnet, F. M. 1959. The Clonal Selection Theory of Acquired Immunity. Cambridge University Press, Cambridge. Cohen, S. G., and M. Samter. 1992. Excerpts from Classics in Allergy. Symposia Foundation, Carlsbad, California. Desour, L. 1922. Pasteur and His Work translated by A. F. and B. H. Wedd . T. Fisher Unwin Ltd., London. Fritig, B., T. Heitz, and M....

Clinical Transplantation

Clinical Transplantation

For a number of illnesses, a transplant is the only means of therapy. Figure 21-10 summarizes the major organ and cell transplants being performed at the present time. In addition, certain combinations of organs, such as heart and lung or kidney and pancreas, are being transplanted simultaneously with increasing frequency. Since the first kidney transplant was performed in the 1950s, approximately 400,000 kidneys have been transplanted worldwide. The next most frequently transplanted solid...

The Nature of the Immunogen Contributes to Immunogenicity

Cytochrome Tertiary Structure

Immunogenicity is determined, in part, by four properties of the immunogen its foreignness, molecular size, chemical composition and complexity, and ability to be processed and presented with an MHC molecule on the surface of an antigen-presenting cell or altered self-cell. In order to elicit an immune response, a molecule must be recognized as nonself by the biological system. The capacity to recognize nonself is accompanied by tolerance of self, a specific unresponsiveness to self antigens....

DNA Vaccines

Gene Gun Application

In a recently developed vaccination strategy, plasmid DNA encoding antigenic proteins is injected directly into the muscle of the recipient. Muscle cells take up the DNA and the encoded protein antigen is expressed, leading to both a humoral antibody response and a cell-mediated response. What is most surprising about this finding is that the injected DNA is taken up and expressed by the muscle cells with much greater efficiency than in tissue culture. The DNA appears either to integrate into...

Hemolytic Disease of the Newborn Is Caused by Type II Reactions

Hemolytic disease of the newborn develops when maternal IgG antibodies specific for fetal blood-group antigens cross the placenta and destroy fetal red blood cells. The consequences of such transfer can be minor, serious, or lethal. Severe hemolytic disease of the newborn, called erythroblastosis fetalis, most commonly develops when an Rh fetus expresses an Rh antigen on its blood cells that the Rh- mother does not express. During pregnancy, fetal red blood cells are separated from the mother's...

Some Central Issues in Thymic Selection Remain Unresolved

Although a great deal has been learned about the developmental processes that generate mature CD4 and CD8 T cells, some mysteries persist. Prominent among them is a seeming paradox If positive selection allows only thymocytes reactive with self-MHC molecules to survive, and negative selection eliminates the self-MHC-reactive thymocytes, then no T cells would be allowed to mature. Since this is not the outcome of T-cell development, clearly, other factors operate to prevent these two...

Tuberculosis Mycobacterium tuberculosis Is Primarily Controlled by CD4 T Cells

Granuloma Formation

Tuberculosis is the leading cause of death in the world from a single infectious agent, killing about 3 million individuals every year and accounting for 18.5 of all deaths in adults between the ages of 15 and 59. About 1.79 billion people, roughly one-third of the world's population, are infected with the causative agent M. tuberculosis and are at risk of developing the disease. Long thought to have been eliminated as a public health problem in the United States, tuberculosis re-emerged in the...

Malaria Plasmodium Species Infects 600 Million People Worldwide

Gametocytes

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...

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...

Pathogenic Organisms Are Inactivated by Heat or Chemical Treatment

Attenuated Killed Dna Vaccine

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...

In Vitroactivated Lak And Til Cells

Melanocytes Photomicrograph

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...

Primary and Secondary Responses Differ Significantly

Primary Secondary Antibody Response

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...

Tumor Antigens May Be Induced by Viruses

The Cardiac Cycle Steps

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...

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...

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...

Recombinant Vector 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...

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...

The Membrane Attack Complex Can Lyse a Broad Spectrum of Cells

Erythrocyte Membrane Blebbing

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...

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...

B and T Lymphocytes Utilize Similar Mechanisms To Generate Diversity in Antigen Receptors

And Lymphocyte Antigen Receptors

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...

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...

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...

Attenuated Viruses and Bacteria Cause Immunity Without Disease

In some cases, microorganisms can be attenuated so that they lose their ability to cause significant disease pathogenicity but retain their capacity for transient growth within an inoculated host. Attenuation often can be achieved by growing a pathogenic bacterium or virus for prolonged periods under abnormal culture conditions. This procedure selects mutants that are better suited to growth in the abnormal culture conditions and are therefore less capable of growth in the natural host. For...

Release of Sequestered Antigens Can Induce Autoimmune Disease

As discussed in Chapter 10, the induction of self-tolerance in T cells results from exposure of immature thymocytes to self-antigens and the subsequent clonal deletion of those that are self-reactive. Any tissue antigens that are sequestered from the circulation, and are therefore not seen by the developing T cells in the thymus, will not induce self-tolerance. Exposure of mature T cells to such normally sequestered antigens at a later time might result in their activation. Myelin basic protein...

C3b and C4b Binding Facilitates Opsonization

C3b Macrophage Receptor

C3b is the major opsonin of the complement system, although C4b and iC3b also have opsonizing activity. The amplification that occurs with C3 activation results in a coating of C3b on immune complexes and particulate antigens. Phagocytic cells, as well as some other cells, express complement receptors CR1, CR3, and CR4 that bind C3b, C4b, or iC3b see Table 13-4 . Antigen coated with C3b binds to cells bearing CR1. If the cell is a phagocyte e.g., a neutrophil, monocyte, or macrophage ,...

Inflammation Represents a Complex Sequence of Events That Stimulates Immune Responses

Vasoactive Hormones Blood Pressure

Tissue damage caused by a wound or by an invading pathogenic microorganism induces a complex sequence of events collectively known as the inflammatory response. As described above, a molecular component of a microbe, such as LPS, may trigger an inflammatory response via interaction with cell surface receptors. The end result of inflammation may be the marshalling of a specific immune response to the invasion or clearance of the invader by components of the innate immune system. Many of the...

The Innate and Adaptive Immune Systems Collaborate Increasing the Efficiency of Immune Responsiveness

It is important to appreciate that adaptive and innate immunity do not operate independently they function as a highly interactive and cooperative system, producing a combined response more effective than either branch could produce by itself. Certain immune components play important roles in both types of immunity. An example of cooperation is seen in the encounter between macrophages and microbes. Interactions between receptors on macrophages and microbial components generate soluble proteins...

The Adaptive Immune System Requires Cooperation Between Lymphocytes and Antigen Presenting Cells

Membrane Bound Antigen Receptor

An effective immune response involves two major groups of cells T lymphocytes and antigen-presenting cells. Lymphocytes are one of many types of white blood cells produced in the bone marrow by the process of hematopoiesis see Chapter 2 . Lymphocytes leave the bone marrow, circulate in the blood and lymphatic systems, and reside in various lymphoid organs. Because they produce and display antigen-binding cell-surface receptors, lymphocytes mediate the defining immunologic attributes of...

Immune Surveillance Theory

The immune surveillance theory was first conceptualized in the early 1900s by Paul Ehrlich. He suggested that cancer cells frequently arise in the body but are recognized as foreign and eliminated by the immune system. Some 50 years later, Lewis Thomas suggested that the cell-mediated branch of the immune system had evolved to patrol the body and eliminate cancer cells. According to these concepts, tumors arise only if cancer cells are able to escape immune surveillance, either by reducing...

HttpwwwglaacukAcad Immunologycompsysthtm

Lappin at University of Glasgow, UK, on the complement system. The site includes a listing of all complement proteins and their molecular properties. Clinical Focus Question Explain why complement disorders involving regulatory components such as PNH may be more serious than deficiencies in the active complement components. 1. Indicate whether each of the following statements is true or false. If you think a statement is false, explain why. a. A single molecule of bound IgM can...

Primary Immunodeficiencies

Bruton Agammaglobulinemia

A primary immunodeficiency may affect either adaptive or innate immune functions. Deficiencies involving components of adaptive immunity, such as T or B cells, are thus differentiated from immunodeficiencies in which the nonspecific mediators of innate immunity, such as phagocytes or complement, are impaired. Immunodeficiencies are conveniently categorized by the type or the developmental stage of the cells involved. Figure 19-1 reviews the overall cellular development in the immune system,...

Localized Inflammatory Response

Vascular Changes Acute Inflammation

The hallmarks of a localized acute inflammatory response, first described almost 2000 years ago, are swelling tumor , redness rubor , heat calor , pain dolor , and loss of function. Within minutes after tissue injury, there is an increase in vascular diameter vasodilation , resulting in an increase in the volume of blood in the area and a reduction in the flow of blood. The increased blood volume heats the tissue and causes it to redden. Vascular permeability also increases, leading to leakage...

Immune Dysfunction and Its Consequences

The above overview of innate and adaptive immunity depicts a multicomponent interactive system that protects the host from infectious diseases and from cancer. This overview would not be complete without mentioning that the immune system can function improperly. Sometimes the immune system fails to protect the host adequately or misdirects its activities to cause discomfort, debilitating disease, or even death. There are several common manifestations of immune dysfunction Graft rejection and...

Diphtheria Corynebacterium diphtheriae May Be Controlled by Immunization with Inactivated Toxoid

Diphtheria is the classic example of a bacterial disease caused by a secreted exotoxin to which immunity can be induced by immunization with an inactivated toxoid. The causative agent, a gram-positive, rodlike organism called Corynebac-terium diphtheriae, was first described by Klebs in 1883 and was shown a year later by Loeffler to cause diphtheria in guinea pigs and rabbits. Autopsies on the infected animals revealed that, while bacterial growth was limited to the site of inoculation, there...

Severe Combined Immunodeficiency Scid

Jak3 Deficiency Chain Il2

The family of disorders termed SCID stems from defects in lymphoid development that affect either T cells or both T and B cells. All forms of SCID have common features despite differences in the underlying genetic defects. Clinically, SCID is characterized by a very low number of circulating lymphocytes. There is a failure to mount immune responses mediated by T cells. The thymus does not develop, and the few circulating T cells in the SCID patient do not respond to stimulation by mitogens,...

Intracellular Events Also Regulate Mast Cell Degranulation

Effects Camp

The cytoplasmic domains of the p and 7 chains of FceRI are associated with protein tyrosine kinases PTKs . Crosslink-age of the FceRI receptors activates the associated PTKs, resulting in the phosphorylation of tyrosines within the ITAMs of the 7 subunit as well as phosphorylation of residues on the p subunit and on phospholipase C. These phos-phorylation events induce the production of a number of second messengers that mediate the process of degranulation Figure 16-6 . Within 15 s after...

Designing Vaccines for Active Immunization

Antibody Mediated Resonse Polio

Several factors must be kept in mind in developing a successful vaccine. First and foremost, the development of an immune response does not necessarily mean that a state of protective immunity has been achieved. What is often critical is which branch of the immune system is activated, and therefore vaccine designers must recognize the important differences between activation of the humoral and the cellmediated branches. A second factor is the development of immunologic memory. For example, a...

Type III Reactions Can Be Localized

Type Reaction

Injection of an antigen intradermally or subcutaneously into an animal that has high levels of circulating antibody specific for that antigen leads to formation of localized immune complexes, which mediate an acute Arthus reaction within 4-8 h Figure 16-15 . Microscopic examination of the tissue reveals neutrophils adhering to the vascular endothelium and then migrating into the tissues at the site of immune-complex deposition. As the reaction develops, localized tissue and vascular damage...

Historical Perspective

Pasteur And Joseph Meister

The discipline of immunology grew out of the observation that individuals who had recovered from certain infectious diseases were thereafter protected from the disease. The Latin term immunis, meaning exempt, is the source of the English word immunity, meaning the state of protection from infectious disease. Perhaps the earliest written reference to the phenomenon of immunity can be traced back to Thucydides, the great historian of the Peloponnesian War. In describing a plague in Athens, he...

Primary Lymphoid Organs

Thymus Cross Section

Immature lymphocytes generated in hematopoiesis mature and become committed to a particular antigenic specificity within the primary lymphoid organs. Only after a lympho- Scanning electron micrograph of follicular dendritic cells showing long, beaded dendrites. The beads are coated with antigen-antibody complexes. The dendrites emanate from the cell body. From A. K. Szakal et al, 1985, J. Immunol. 134 1353 1996 by American Association of Immunologists, reprinted with permission. Scanning...

CTLs Kill Cells in Two Ways

Mice Lymphoid Organs Scheme

The effector phase of a CTL-mediated response involves a carefully orchestrated sequence of events that begin with the embrace of the target cell by the attacking cell Figure 14-5 . Long-term cultures of CTL clones have been used to identify many of the membrane molecules and membrane events involved in this process. As described below, studies with Localizing antigen specific CD8 T-cell populations in vivo. Mice were infected with vesicular stomatitis virus VSV and during the course of the...

Effector CTLs Are Generated from CTL Precursors

Generation Effector Ctls

Naive TC cells are incapable of killing target cells and are therefore referred to as CTL precursors CTL-Ps to denote their functionally immature state. Only after a CTL-P has been activated will the cell differentiate into a functional CTL with cytotoxic activity. Generation of CTLs from CTL-Ps appears to require at least three sequential signals Figure 14-1 An antigen-specific signal 1 transmitted by the TCR complex upon recognition of a peptide-class I MHC molecule complex A co-stimulatory...

The Classical Pathway Begins with Antigen Antibody Binding

C1q Binds Bound Antigen Antibody

Complement activation by the classical pathway commonly begins with the formation of soluble antigen-antibody complexes immune complexes or with the binding of antibody to antigen on a suitable target, such as a bacterial cell. IgM and certain subclasses of IgG human IgG1, IgG2, and IgG3 can activate the classical complement pathway. The initial stage of activation involves C1, C2, C3, and C4, which are present in plasma in functionally inactive forms. Because the components were named in order...

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The American Association of Allergy, Asthma and Immunology Web site. A good site for exploring the many aspects of asthma. Clinical Focus Question Discuss why IL-4 and FceRIp are excellent candidate genes involved in the genetic susceptibility to asthma. 1. Indicate whether each of the following statements is true or false. If you think a statement is false, explain why. a. Mice infected with Nippostrongylus brasiliensis exhibit decreased production of IgE. b. IL-4 decreases IgE production by B...

Oncofetal Tumor Antigens

Oncofetal tumor antigens, as the name implies, are found not only on cancerous cells but also on normal fetal cells. These antigens appear early in embryonic development, before the immune system acquires immunocompetence if these antigens appear later on cancer cells, they are recognized as nonself and induce an immunologic response. Two well-studied onco-fetal antigens are alpha-fetoprotein AFP and carcinoem-bryonic antigen CEA . Although the serum concentration of AFP drops from milligram...

Radiolabeling Techniques Allow Sensitive Detection of Antigens or Antibodies

Cell Hybridoma

Radioactive labels on antigen or antibody are extremely sensitive markers for detection and quantification. There are a number of ways to introduce radioactive isotopes into proteins or peptides. For example, tyrosine residues may be labeled with radioiodine by chemical or enzymatic procedures. These reactions attach an iodine atom to the phenol ring of the tyrosine molecule. One of the enzymatic iodina-tion techniques, which uses lactoperoxidase, can label proteins on the plasma membrane of a...

Antigen Selection of Lymphocytes Causes Clonal Expansion

Ction Clonale Des Lymphocyte

A mature immunocompetent animal contains a large number of antigen-reactive clones of T and B lymphocytes the antigenic specificity of each of these clones is determined by the specificity of the antigen-binding receptor on the mem- Processing and presentation of exogenous and endogenous antigens. a Exogenous antigen is ingested by endocytosis or phagocytosis and then enters the endocytic processing pathway. Here, within an acidic environment, the antigen is degraded into small peptides, which...

Mature Self Reactive B Cells Can Be Negatively Selected in the Periphery

Cell Cell Contact

Because some self-antigens do not have access to the bone marrow, B cells expressing mIgM specific for such antigens cannot be eliminated by the negative-selection process in the bone marrow described earlier. To avoid autoimmune responses from such mature self-reactive B cells, some process for deleting them or rendering them inactive must occur in peripheral lymphoid tissue. A transgenic system developed by C. Goodnow and his coworkers has helped to clarify the process of negative selection...

Inappropriate Expression of Class Ii Mhc Molecules Can Sensitize Autoreactive T Cells

The pancreatic beta cells of individuals with insulin-dependent diabetes mellitus IDDM express high levels of both class I and class II MHC molecules, whereas healthy beta cells express lower levels of class I and do not express class II at all. Similarly, thyroid acinar cells from those with Graves' disease have been shown to express class II MHC molecules on their membranes. This inappropriate expression of class II MHC molecules, which are normally expressed only on antigen-presenting cells,...

Neutrophil Extravasation

Migration Extravasation Des Monocytes

As an inflammatory response develops, various cytokines and other inflammatory mediators act upon the local blood vessels, inducing increased expression of endothelial CAMs. The vascular endothelium is then said to be activated, or inflamed. Neutrophils are generally the first cell type to bind to inflamed endothelium and extravasate into the tissues. To accomplish this, neutrophils must recognize the inflamed endothelium and adhere strongly enough so that they are not swept away by the flowing...

Bacterial Polysaccharide Capsules Are Used as Vaccines

The virulence of some pathogenic bacteria depends primarily on the antiphagocytic properties of their hydrophilic polysac-charide capsule. Coating of the capsule with antibodies and or complement greatly increases the ability of macrophages and neutrophils to phagocytose such pathogens. These findings provide the rationale for vaccines consisting of purified capsular polysaccharides. The current vaccine for Streptococcus pneumoniae, which causes pneumococcal pneumonia, consists of 23...

Late Phase Reactions Induce Localized Inflammatory Reactions

Early And Late Asthmatic Reaction

As a type I hypersensitive reaction begins to subside, mediators released during the course of the reaction often induce localized inflammation called the late-phase reaction. Distinct from the late response seen in asthma, the late-phase reaction begins to develop 4-6 h after the initial type I reaction and persists for 1-2 days. The reaction is characterized by infiltration of neutrophils, eosinophils, macrophages, lymphocytes, and basophils. The localized late-phase response also may be...

General Organization and Inheritance of the MHC

Mouse Mhc Molecule

The concept that the rejection of foreign tissue is the result of an immune response to cell-surface molecules, now called histocompatibility antigens, originated from the work of Peter Gorer in the mid-1930s. Gorer was using inbred strains of mice to identify blood-group antigens. In the course of these studies, he identified four groups of genes, designated I through IV, that encoded blood-cell antigens. Work carried out in the 1940s and 1950s by Gorer and George Snell established that...

Mice Have Been Engineered with Human Immunoglobulin Loci

It is possible to functionally knock out, or disable, the heavy-and light-chain immunoglobulin loci in mouse embryonic stem ES cells. N. Lonberg and his colleagues followed this procedure and then introduced large DNA sequences as much as 80 kb containing human heavy- and light-chain gene segments. The DNA sequences contained constant-region gene segments, J segments, many V-region segments, and, in the case of the heavy chain, DH segments. The ES cells containing these miniature human Ig gene...

Immunoglobulin E IgE

Componente Secretor Iga

The potent biological activity of IgE allowed it to be identified in serum despite its extremely low average serum concentration 0.3 g ml . IgE antibodies mediate the immediate hypersensitivity reactions that are responsible for the symptoms of hay fever, asthma, hives, and anaphylactic shock. The presence of a serum component responsible for allergic reactions was first demonstrated in 1921 by K. Prausnitz and H. Kustner, who injected serum from an allergic person intra-dermally into a...

Lymphoid Cells and Organs Evolutionary Comparisons

Myeloid Stem Cell Development

Contrast to a unipotent cell, which differentiates into a single cell type, a hematopoietic stem cell is multipotent, or pluripo-tent, able to differentiate in various ways and thereby generate erythrocytes, granulocytes, monocytes, mast cells, lymphocytes, and megakaryocytes. These stem cells are few, normally fewer than one HSC per 5 X 104 cells in the bone marrow. The study of hematopoietic stem cells is difficult both because of their scarcity and because they are hard to grow in vitro. As...

Dreyer and Bennett Proposed the Two Gene Model

In an attempt to develop a genetic model consistent with the known findings about the structure of immunoglobulins, W. Dreyer and J. Bennett suggested, in their classic theoretical paper of 1965, that two separate genes encode a single immunoglobulin heavy or light chain, one gene for the V region variable region and the other for the C region constant region . They suggested that these two genes must somehow come together at the DNA level to form a continuous message that can be transcribed...

Immunoglobulin A IgA

Although IgA constitutes only 10 -15 of the total im-munoglobulin in serum, it is the predominant im-munoglobulin class in external secretions such as breast milk, saliva, tears, and mucus of the bronchial, genitourinary, and digestive tracts. In serum, IgA exists primarily as a monomer, but polymeric forms dimers, trimers, and some tetramers are sometimes seen, all containing a J-chain called the J chain, that is linked by two disulfide bonds to the Fc region in two different monomers. Serum...

What Structural Features Would Protein X Have To Have In Order To Be Classified As An Immunoglobulin

Capra. 1999. Immunoglobulins structure and function. In Fundamental Immunology, 4th ed. W. E. Paul, ed. Philadelphia, Lippincott-Raven. Kohler, G., and C. Milstein. 1975. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256 495. Kraehenbuhl, J. P., and M. R. Neutra. 1992. Transepithelial transport and mucosal defence II secretion of IgA. Trends Cell Biol. 2 134. Immunology Today, The Immune Receptor Supplement, 2nd ed. 1997....