The use of immunological techniques in the study of disease

Traditionally, the basis for this 'investigative immunopathology' is serology. Detection of antibody against a specific pathogen, and of rising (or falling) titers of antibody, has long been the mainstay of the approach. The concept of autoimmunity is heavily based upon the identification of circulating antibodies directed against intrinsic antigens, and there is also reciprocal serology, based upon the use of antisera to detect a given antigen. There are now many ways to detect and amplify the...

B cell deficiency diseases

The physiological importance of B cell function is revealed by diseases that result from selective B cell deficiencies and consequent lack of antibodies (agammaglobulinemia). Bruton's agammaglobulinemia (XLA) is an X-linked defect in B cell maturation in humans, with arrest at the Pre-B I stage and a resulting deficiency in all immunoglobulin classes. A corresponding B cell maturation defect, the Xid mutation, also occurs in CBA N mice. In male children with XLA, the maturation block results...

Vaccines

In 1798, Edward Jenner published results of his experiments which showed that previous infection with cowpox - variolae vaccinae - protected humans against challenge with smallpox. Although the original observation can be traced back to country folklore, Jenner was the first to test the hypothesis scientifically. He had also to contend with the difficulty that cattle could be infected with either cowpox, an orthopoxvirus which did protect, or the clinically similar pseudocowpox, a parapoxvirus...

Phylogeny Of The Immune Response

Norman A Ratcliffe, Biomedical and Physiological Research Group, School of Biological Sciences, University of Wales, Swansea, UK In comparison with vertebrates, the immune response of invertebrates is extremely limited. Specific antibody produced by interactive lymphocyte subpopulations together with extremely finely tuned discrimination of self from nonself and a high degree of memory are confined to the vertebrates, and yet, invertebrates comprise over 95 of all known species of animals....

Thyroiditis

Patients with chronic autoimmune thyroiditis most commonly present with clinical and or biochemical evidence of thyroid failure with or without goitre. Clinically they can be divided into those with goitrous (Hashimoto's) thyroiditis and those with atrophic thyroiditis (primary myxedema). Historically, establishment of their autoimmune basis has relied on the presence of autoantibodies to thyroglo-bulin (in the minority) and to the thyroid microsome (in the majority), detected by...

Other mechanisms of action of NSAIDs

While there is very strong evidence supporting the hypothesis that NSAIDs produce their antiinflammatory, analgesic, antipyretic and antithrombotic effects through inhibition of prostanoid synthesis, there is also evidence for other mechanisms of action. These other mechanisms of action may explain the differences in activity from one NSAID to another. For example, NSAIDs such as indomethacin have been shown to inhibit other enzymes, including phospholipase A2, diacylglycerol kinase and...

Proinflammatory effects of NSAIDs

Ironically, while prostaglandins are typically described as mediators of inflammation, these substances exert a wide range of anti-inflammatory effects (Figure 3). For example, prostaglandins are potent inhibitors of the release of tumor necrosis factor a (TNFa) and IL-1 from macrophages, and potent inhibitors of TNFa and platelet-activating factor from mast cells. Prostaglandins also suppress the release of a number of proinflammatory mediators from platelets. On the other hand, NSAIDs, by...

Implications of determinant spreading for immunotherapy

Knowledge about the temporal pattern of appearance of new T cell specificities directed against determinants within the same or different antigens is crucial in designing appropriate therapeutic strategies. Therapeutic approaches based primarily on controlling T cell responses to the initial disease-inducing determinant may not succecd if spreading of response has already occurred. Tolerance induction with peptides comprising encephalitogenic determinants appearing later in the disease may...

Cytokines a bridge between the nervous system and the immune system

Cytokines are cell-derived peptides that may modify the functions of the cells that secrete them, as well as the functions of other cells that have receptors for them. Table 2 lists a number of cytokines that are produced and act in both the nervous system and the immune system. Some of our initial knowledge of cytokines that are produced by cells outside the nervous system but that have an apparent effect within the nervous system came from clinical observations. One early study demonstrated...

IL2 in the negative control of lymphocyte proliferation

Autoimmunity in IL-2-deficient animals The precise role of IL-2 in vivo is not well understood. An important tool for studying this question is provided by gene knockout mice produced after homologous recombination. In IL-2_ animals the ontogeny of the immune system is not dramatically affected, as demonstrated by the normal development of lymphoid organs and the presence of the major lymphocyte subsets. However IL-2_ animals have an overproduction of lymphocytes, which is morphologically...

Immune response of the host

Circulating antibodies in infected pigs can be detected by radioimmunoassay or ELISA 3-4 days after infection and they persist for life. Neutralizing antibodies have never been demonstrated. After recovery from infection with less virulent isolates, pigs are persistently infected for at least 6 months and are resistant to challenge with homologous virus, although the challenge virus may undergo limited replication without producing clinical disease they are usually fully susceptible to...

Mechanisms of immunopathology

Septicemic shock and the adult respiratory distress syndrome The cytokine release triggered by bacterial components has a protective and immunoregulatory role as described above, but when excessive, as during septicemia, there can be excessive systemic activation of phagocytes and of endothelial cells. The latter leads to adhesion of phagocytes to the endothelium, initiation of the clotting cascade via expression of tissue thromboplastin, and eventually to diffuse intravascular coagulation that...

The goal of selective immunosuppression

If any foreign material (antigen) makes its way into the body - virus, bacteria, fungi or parasites - a swift and complex immune response for destroying it is set into motion. The allelic products of the major histocompatibility complex (MHC) characterize the immunological identity of each individual. With the exception of identical twins, it is extremely unlikely that two individuals match exactly. Nature did not intend for organs to be transplanted from one individual to another. The speed...

Molecular basis of attenuation

A reduction in pathogenicity can occur either through the loss of external pathogenic factors (toxins), as is the case with some bacterial vaccines, or by impairing the invasiveness of a pathogen and limiting its access to target organs. In many cases attenuating mutations occur in capsid or envelope proteins of a virus, presumably reducing its affinity for the target cells. Detailed studies of attenuated polioviruses identified a number of mutations that distinguished vaccine viruses from...

Mechanisms of changes in reptilian immune system

Body temperature is a salient factor regulating the performance of reptilian immunological functions. It must be noted in this regard that reptiles, in contrast to fish and amphibians, have become restricted in the temperature range over which physiological activities, including immune responses, can occur. Photo-periods, humidity and nutrition are also critical modulators of reptilian immune processes. Endogenous rhythmic factors that are not as yet characterized appear also to control immune...

Stressorassociated regulation of immunity

Stress, as defined by Hans Selye, is the response to deviation from the normal resting condition (i.e. homeostasis). It is generally accepted that stressor administration causes complex neurologic and neurochemical changes as the host attempts to adapt to the demands of the situation. These CNS changes regulate many physiologic processes, including those involved in the generation of an immune response. Immunomodulatory 'stress' protocols have involved different periods of exposure to either...

Phenotypic expression of a single gene

In addition to the common polymorphisms not associated with any obvious phenotypic abnormalities, there are several examples of phenotypic disorders associated with genotypic changes in a single gene. These disorders are commonly referred to as single-gene or monogenic disorders. In these disorders, phenotypic variability is primarily determined at the corresponding gene locus and the effect of other loci and environmental factors, although they may be present, is not the major determinant....

Functions of LIF

LIF was identified as a factor capable of inducing the terminal differentiation of the murine myeloid leukemic cell line Ml into macrophages. Activation of the transcription factor STAT3 is essential for LIF-induced differentiation of Ml cells. A number of myeloid leukemic cell lines, which were unresponsive to treatment with LIF, expressed various defects in the JAK STAT signal cascade, suggesting modulations of this pathway to be a crucial step in leukemo-genesis. Although LIF expressed...

Characteristics of the organism and its antigens

Oligodendrocyte Nucleus Size

The virion of polyomaviruses is small (diameter 45 nm), with a noneveloped icosahedral capsid and a circular, superhelical, double-stranded DNA genome of about 5000 base pairs. The viral genome is functionally divided into an early region (2.3 kb) which codes for the regulatory T proteins, a late region (2.3 kb) which codes for capsid proteins, and a noncoding regulatory region (0.4 kb). The early and late regions are transcribed from different strands of the DNA molecule. Although...

Vitamin C And The Immune System

Reto Muggli, Department of Immunochemistry, Faculty of Pharmaceutical Sciences, Okayama University, Okayama, Japan Ascorbic acid (vitamin C) is required for the optimal functioning of all cells, tissues, and organs. It is the most important water soluble antioxidant and is a cofactor in many hydroxylating reactions. Man, primates, guinea pigs and a few other species lack the capability to synthesize ascorbic acid, for them ascorbic acid is an essential nutrient. There is abundant evidence from...

Characteristics of the acquired immune response

The first time an antigen enters the body a wide spectrum of events occurs. The antigen is usually contained at the site of entry and in nearby lymph nodes by various phagocytic cells such as macrophages and dendritic cells. These cells process the antigen and present pathogen-derived peptides to CD4+ and CD8+ T cells in association with major histocompatibility complex (MHC)-encoded molecules. Antigen binding by surface immunoglobulin and cognate help by CD4+ T cells induce B cells to...

Mtppe

Figure 3 Chemical structures of various MDP derivatives applied to clinical trials. adjuvanticity but shows no substantial activity regarding nonspecific resistance to infection. Clinical trials using B30-MDP as an adjuvant effect in an influenza virus vaccine demonstrate that it is able to induce both humoral and cellular immunity. MTP-PE has been shown to be highly effective in generating tumoricidal properties of macrophages. Lipo-some-encapsulated MTP-PE (L-MTP-PE) has been designed for in...

Antiinflammatory and immunosuppressive effects

Suppression of inflammatory and immune reactions and treatment of cancers of the lymphoid system are among the major applications of glucocorticoids. As noted above, despite early assumptions that such 'pharmacological' effects had no physiological basis, it is now clear that they are as physiological as are the effects on glucose metabolism. For example, induction of adrenal insufficiency in experimental animals (by adrenalectomy or administration of the glucocorticoid antagonist RU486)...

Lifespan of lymphocytes in humans

All of the figures discussed so far in this entry refer to the rodent immune system. There is some evidence that both T and B lymphocytes may live much longer in humans. Studies in patients who have either accidentally, or in the course of treatment, received a heavy radiation dose resulting in characteristic chromosome breakages that preclude mitosis, indicate that lymphocytes can persist for upwards of 10 years without dividing, although the damage to the DNA may itself have caused such...

Cooperation Mechanisms Of Cellular

Theodore J Yun, Department of Microbiology, University of Washington, Seattle, Washington, USA Edward A Clark, Departments of Microbiology and Immunology, University of Washington, Seattle, Washington, USA Various pathogens, ranging from viruses to helminths, can invade the host by a number of pathways, and usually the pathogen is cleared through an orchestrated immune response. Moreover, protection from a repeat infection is provided by a memory response, which, relative to the primary...

Nature of antigenantibody intermolecular forces

Also known as electrodynamic interactions, these occur universally between all atoms and molecules, when brought close enough together. Three different but related phenomena contribute to van der Waals interactions 1) randomly orienting dipole-dipole (orientation) interactions, or van der Waals-Keesom forces 2) randomly orienting dipole-induced dipole (induction) interactions, or van der Waals-Debye-forces 3) randomly fluctuating dipole-induced dipole (dispersion) interactions, or van der...

Hepatitis F viruses

Serologic testing has identified five hepatropic viruses HAV, HBV, HCV, HDV and HEV. These viruses account for almost all human viral hepatitis however, a small percentage of patients exhibiting the signs and symptoms of acute viral hepatitis do not have serologic evidence of infection with any of these viruses. Researchers continue to search for the viruses associated with non-ABCDE hepatitis. Many of these enterically and parenterally transmitted viruses have been tentatively designated...

Radiosensitivity of cellular components of the immune system

The type and magnitude of specific immune responses is determined by the interaction of antigen-presenting cells such as dendritic cells and macrophages with T and B lymphocytes. However, the effector arms of the immune system depend on interactions of numerous leukocyte subsets. In addition to lymphocytes and macrophages, natural killer (NK) cells, eosinophils and granulocytes contribute significantly to host resistance to infections. Macrophages are relatively radioresistant, as are other...

Virulence factors

A number of specific proteins encoded by chromosomal genes have been implicated as virulence factors that allow P. mirabilis to colonize its host, evade host defenses, and cause damage to the host (Figure 3). The production of one of these proteins, urease, is a hallmark of Proteus infection. This enzyme, which catalyzes the hydrolysis of urea to carbon dioxide and ammonia, elevates urine pH to a level where normally soluble ions precipitate to form struvite or apatite stones. These stones,...

The immune response to infections

The development of vaccines has been based on two requirements safety - the product should not induce undue morbidity and efficacy - immunization should prevent clinical disease on subsequent exposure to the wild-type agent. Other than measurement in relatively recent times of specific antibody levels and particularly a functional test such as neutralization of infectivity, generally no other parameters of the immunogenicity of the product were considered. Most current vaccines are to 'acute'...

Mechanisms of oral tolerance

The primary mechanisms by which oral tolerance is mediated include deletion, anergy and active cellular suppression with the determining factor being the dose of antigen fed (Figure 2). Low doses favor active suppression mediated by the induction of regulatory T cells in the gut-associated lymphoid tissue, such as Peyer's patches, which then migrate to the systemic immune system. When higher doses of antigen are fed, clonal anergy or deletion results. Active cellular suppression of immune...

Binding properties of class Ii Mhc molecules

The binding properties of class II MHC molecules can be studied using purified molecules, usually in detergent solutions, or directly in the APC. Purified class II molecules bind peptides in a homogeneous saturable process with binding affinity constants in the 10A-10 S m range. The rate of association of peptide with the MHC molecule is slow, but once the peptide is bound it can form a very stable and long-lived complex. The complex of MHC with peptide can be assembled and isolated in free...

B cell superantigens

Other microbial substances act as superantigens by binding to the B cell antigen receptors outside the antigen binding site. Staphylococcus aureus-& er'wzd protein A is the prototype for this interaction at the B cell level. Polymerized protein A induces strong B cell proliferation and Ig secretion in conjunction with cytokines such as IL-2. Superantigens are polyclonal activators but, rather than stimulating protective immunity, they could deviate the B cell response away from important...

Reptilian Immune System

Rashika El Ridi, Zoology Department, Faculty of Science, Cairo University, Cairo, Egypt Reptiles evolved from primitive amphibians nearly 300 million years ago during the Carboniferous period. They sprang from a basic stock, the long-extinct order Cotylosauria or 'stem reptiles'. A side-branch of stem reptiles led to the turtles and tortoises order Testudines Chelonia. The closest surviving descendants of the cotylosaurs are the tuatara that live on a few islands off New Zealand. Descended from...

Hepatitis G virus

Recently, a new hepatitis-associated virus, hepatitis G virus (HGV), has been cloned and sequenced. HGV, an RNA virus, is a member of the Flaviviridae family, and is distantly related to HCV. Originally this virus was one of the viruses referred to as HEV. Although HGV has been identified as a hepatitis-associated virus and is associated with acute and chronic hepatitis, research has failed to prove that HGV is hepatotropic. At this time no serologic test exists for detection of HGV-infected...

Interaction with CD2

Initially, LFA-3 was defined by the ability of a monoclonal antibody (mAb) to block human cytolytic T lymphocyte (CTL)-mediated lysis by binding to the target cell surface. However, even before this discovery, a method widely used by immunologists to purify human T cells by forming rosettes with sheep red blood cells utilized the molecular interaction between LFA-3 and its ligand. The CTL-mediated lysis of targets as well as T cell rosetting was also inhibited by mAbs which bound to CD2 on the...

Fetus As Allograft

Peter M Johnson, Department of Immunology, University of Liverpool, Liverpool, UK Copyright 1998 Elsevier Ltd. All Rights Reserved. Modern considerations of the haplo-nonidentical fetus as an allograft in outbred pregnancy have developed from initial postulates, put forward by Medawar, Brent and Billingham in 1953, that were derived from their work on transplantation tolcr-ance. In these, they proposed that I) the conceptus may not be immunogenic, 2) pregnancy may alter the immune response, 3)...

T Cell Receptor Recognition By

Arthur W Boylston, Department of Pathology, University of Leeds, Leeds, UK Unlike antibodies, T lymphocytes do not recognize antigens in solution. Instead, they recognize antigens on intact cells in the context of surface molecules encoded by the major histocompatibility complex (MHC). How cells could recognize both a foreign antigen and MHC proteins was the central problem in immunobiology for many years. The answers to this problem have come from elucidation of the structure of the T cell...

Newer approaches to vaccine development

There are a great variety of diseases - viral, bacterial and parasitic - for which no vaccines are available. The need is great five parasitic diseases alone affect about one-quarter of the world's population. Reasons such as the inability to grow sufficient of the organism either in vitro or in an animal, the complex nature of the infectious process (often including substantial suppressor effects), a lack of understanding of the basis of many chronic and persisting infections, all contribute...

Effector mechanisms

As to effector mechanisms, autoimmune diseases are no different from any other pathogenic immune response against foreign antigens involving reactions of types II (cytotoxic antibodies), III (immune complexes), IV (cellular-mediated immunity) and V (stimulating antibodies) according to the Gell Coombs nomenclature. Furthermore, antigen nonspecific mechanisms secondarily activated by auto-antigen-activated lymphocytes play an important pathogenetic role. The detection of circulating and or...

Insulindependent Diabetes Mellitus Experimental Models

Ji-Won Yoon and Hee-Sook Jun, Department of Microbiology and Infectious Diseases, Julia McFarlane Diabetes Research Centre, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada Institute for Medical Science, Ajou University School of Medicine, Suwon, Korea Copyright 1998 Elsevier Ltd. All Rights Reserved. Type I diabetes, also known as insulin-dependent diabetes mellitus (IDDM), results from the destruction of insulin-producing pancreatic (3 cells, culminating in hypoinsulinemia...

Immune Response Ir GENES

Jerold G Woodward, Department of Microbiology and Immunology, University of Kentucky Medical Center, Kentucky, USA Immune response (Ir) genes can be defined as any gene locus at which different alleles affect the magnitude of an immune response. Thus, Ir genes were identified on the basis of a complex phenotype and, not surprisingly, comprise a heterogeneous group of structural genes. Nevertheless, genes encoded within the major histocompatibility complex (MHC) clearly have the most dramatic...

CTL target cells

Following the demonstration of the requirements for MHC compatibility for macrophage T lymphocyte interaction and for T lymphocyte B lymphocyte interaction, it was shown by Zinkernagel and Doherty for virus-infected cells, by Shearer for targets modified with the TNP (trinitrophenyl) hapten, and by Bevan for targets bearing minor histocompatibility antigens, that the killing of antigen-bearing target cells by CD8+ T cells was also restricted by MHC antigens. In the virus studies, mice were...

Classification of idiotypes

Idiotypes are generally defined by serologic reagents collectively designated as anti-idiotype antibodies. Several criteria were used to classify the idiotypes based on the type of interaction between idiotypes and anti-idiotype antibodies. The immunochemical criterion used to classify the idiotype consists of the effect of antigen on the interaction between idiotype and anti-idiotype antibodies. In the case of some idiotypes, this reaction is inhibited by the antigen, whereas in other cases it...

Structural organization of the mucosal immune system

Lymphocytes associated with mucosal sites arc located in three major compartments 1) organized tissue such as the Peyer's patches, BALT, tonsils, mesenteric lymph nodes and appendix 2) the nonorganized lymphoid cells present diffusely throughout the lamina propria and 3) the lymphocytes present within the mucosal epithelium, the intraepithelial lymphocytes (IELs). Lymphoid cells in organized structures such as the Peyer's patches are thought to be primarily less mature cells that play an...

Contraception Immunological

GP Talwar, International Centre for Genetic Engineering and Biotechnology, New Delhi, India A major technological advance in the twentieth century was the development of a number of methods to prevent an unwanted pregnancy. Amongst newer methods currently under development are those which employ immunological approaches. Vaccines inducing appropriate immune response have been made, with demonstrated ability to control fertility in experimental animals, including subhuman primates. Extensive...

Diversity of acute phase proteins

There is considerable diversity among acute phase proteins with respect to the concentrations attained, their structures, their behavior in different species and in different diseases. The concentration of a plasma protein depends on the balance between its secretion rate and its clearance rate. The availability of the protein for a particular function is the important factor in physiological and pathophysiological situations, rather than simply its serum concentration measured ex vivo....

Effect of maternal immunity on the child

In most mammals, the offspring receives maternal immunoglobulins both in utero and in the neonatal period via the mother's milk. In humans, transfer of immunoglobulin G (IgG) via the placenta has been detected as early as 38 days gestation. This transfer remains stable until week 17 and then progressively increases towards term. Only IgG antibodies pass the placenta. The transport process involves binding of an intact Fc portion to specific placental membrane receptors, typically of the FC7...

Prospects for the future

One might think from the above that from now on it should be possible to make a vaccine to any infectious agent. But there are many other factors which Table 3 Main candidates for use as live vectors Canarypox virus Escherichia coli Table 4 Factors favoring infectious agent control or eradication by vaccination 1. Only one or a small number of causative strains 2. Agent is only moderately infectious 3. Absence of subclinical cases and a carrier state 4. Infectious process is acute agent does...

B lymphocyte development and function in the neonate

Pre-B cells express cytoplasmic p chain and lack surface immunoglobulin (Ig). In humans, pre-B cells are detected in fetal liver and omentum as early as 7-8 weeks of gestation. One to two weeks later, B lymphocytes (surface IgM+) are found in fetal liver and the development of B lymphocytes expressing other surface Ig isotypes follows. In the mouse, the earliest B lineage precursor cells can be identified as CD45R (B220)+ cells in fetal liver at -12-13 days gestation. B lineage cell development...

Postulates of idiotype network theory

Idiotype network theory is based on three major postulates 1. The idiotypes of the immune receptor of lymphocytes are recognized within the immune system and they function both as links between clones and the target of regulatory processes. Self-non self discrimination is a central element of the clonal selection theory which views the immune system as a collection of clones programmed to recognize foreign antigens. While foreign antigens selectively induce the proliferation of clones bearing...

Measurement of AgAb interaction energies

There is a large variety of equilibrium methods by which the parameters on the right-hand side of eqn (4) can be determined, allowing the calculation of Ka and from this value, of K'., and of AG. Among these methods are equilibrium dialysis or ultrafiltration, precipitation methods, analytical ultracentrifugation, gel filtration or size exclusion chromatography, affinity chromatography, fluorescence, fluorescence quenching, fluorescence polarization, immunoassay methods, hapten inhibition...

Differential gene expression in trypanosomes results in antigenic variation

Trypanosomes are eukaryotic flagellates that cause sleeping sickness in humans and nagana in cattle. These protozoan parasites are transmitted by insects to the bloodstream of the host. The trypanosome has a number of developmental stages. The bloodstream-stage trypanosomes are covered with a dense coat composed of a single type of glycoprotein, the vari ant surface glycoprotein (VSG). Antigenic variation in trypanosomes occurs through the sequential expression of different VSG genes. During...

Antigenic variation in HIV

With the availability of extensive HIV nucleotide sequence data, genetic diversity among AIDS viruses can be compared. The envelope gene of HIV-1 contains five hypervariable regions which are flanked by conserved regions. Sequence diversity is a characteristic of many RNA viruses. They are genetically error-prone by virtue of their DNA-dependent R.NA polymerase, a step in their replication cycle which escapes correction by host cell enzymes ('subediting'). It has been estimated that the HIV-1...

Immunodiffusion Single Radial

George Feinberg, formerly of The Rayne Institute, The United Medical Dental School, London As the term implies, immunodiffusion refers to an immunological reaction in which the reactants diffuse into a supporting medium, i.e. a gei. The reaction involved is that of precipitation, the objective being to visualize and immobilize an in vitro reaction between a precipitating antibody and a soluble antigen. Thus, immunodiffusion is a modification of the precipitin reaction first observed in fluid...

Effects of mercury on the immune system

Little is known about the principal mechanism by which mercury affects the immune system. An effect on the selection mechanisms in the thymus has been suggested, allowing potentially autoreactive cells to escape into the periphery. A direct mitogenic action on lymphocytes seems to be well established and could result from the chemical effects of this heavy metal on some cell membrane components, such as calcium channels, or direct action on nuclear proteins. Other possible mechanisms would be...

The first paradigm specific etiology and immunization

Louis Pasteur and the 'wonderful century' The middle of the nineteenth century (the 'wonderful century') saw political and scientific ferment and the career of Louis Pasteur (1822-1895) exemplifies that ethos. Trained as a chemist, he made important contributions to structural chemistry before he turned to the question of fermentation in 18.57. Fermentation was understood loosely it referred to the 'spon taneous' changes seen in the making of wine or beer (alcoholic fermentation), the souring...

Immunodeficiency Animal Models Of

Gregory J Bancroft, Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK The effects of mutations at specific genetic loci give considerable insight into many areas of biology. This is particularly true for the genetically determined syndromes of human immunodeficiency which can cause partial to severe impairment of immune function, often with a lethal outcome. While important information has come from analyzing tissues from these patients, animal models...

Molecules as antigens

The two types of natural macromolecules most investigated as antigens are proteins and polysaccharides. These also include glycoproteins, nucleoproteins, lipoproteins, etc., as well as peptidoglycans, glycolip-ids and other conjugates. Nucleic acids are also antigenic. Lipids are poor immunogens, but antibodies against them can be obtained, and liposomes play a role here, as they do in enhancing the immunogenicity of various other antigens. Synthetic antigens, especially synthetic polypeptides,...

Practical applications of internal image idiotypes

In the early studies on idiotype regulation, Eichmann and Rajewsky showed that polyclonal xenogeneic anti-Id antibodies of a particular isotype injected into mice can stimulate the production of antibodies against a polysaccharide antigen of streptococcus group A. Similar results have been obtained with monoclonal anti-Id antibodies in a hapten system, namely the activation of clones producing anti-TNP antibodies expressing 460Id. Important information regarding the stimulatory aspect of...

Immune responses of the host to chickenpox

In order to properly understand the immune response of the host, it is first necessary to visualize the pathogenesis of primary VZV infection. A schema is shown in Figure 2. This model includes two viremic stages, with the characteristic chicken pox exanthem appearing after the second viremia. Chickenpox is acquired from small virus-laden droplets which are carried by air currents from an infected child to a nonimmune (susceptible) individual. The site of infection is probably the conjunctivae...

Anergy T Cell

Ronald H Schwartz, Laboratory of Cellular and Molecular Immunology, National Institutes of Health, Bethesda, Maryland, USA Copyright 1998 Elsevier Ltd. All Rights Reserved. Published by Elsevier Ltd. In 1908 C. Von Pirquet first used the term anergy (from the Greek meaning without work or not working) to describe the loss of response to a tuberculin skin test in patients infected with the measles virus. Since then this type of phenomenon has been described for delayed-type hypersensitivity...

Autoimmune and immunemediated eye diseases in humans

Although strong associations have been noted between many uveitic diseases and HLA type, indicating an immunogenetic component to disease etiology, the extent to which autoimmunity in the strict sense plays a role in human disease is still controversial. The reason for this is that in most cases the eliciting antigens have not yet been positively identified. One exception is phacoanaphylaxis, caused by an autoimmune response to lens proteins, usually following trauma and disruption of the lens...

Virus evasion of host immune responses

The ability of arenaviruses to persist in their long-term carriers is facilitated by antigenic variation that allows evasion of host immune responses. Neutraliz-ation-resistant variants of Junin and Tacaribe viruses escape the humoral immune response, and certain epitope variants of LCMV escape the CTL response. In addition to viral variants that can escape host immune surveillance, variants have been described that suppress the immune response and thereby persist. Docile is a variant of the...

Newm Framework Chanoes

Plate 20 Antibody complementarity determining regions (CDRS). Computer graphic model of the structure of the VH component of NEWM human antibody. The CDRs loop out from the scaffold structure of the framework regions (blue) to provide the antigen binding surface at one end of the molecule. The framework residues marked are those most commonly involved in maintaining the correct conformation of the CDR loops. (Reproduced with permission from Harris WJ and Cunningham CC (1995) Antibody...

Repertoire expression in B cell subpopulations

The secondary B cell repertoire can be divided into three broad categories. The first category contains those secondary responses whose predominant clonotype or clonotype families are the same as those found in the primary response (i.e. total overlap in V gene usage), although the secondary antibodies have accumulated somatic mutations. Examples of these responses include the T15 clonotype, the -bearing antibodies to al,3-Dex and to some extent the NPb clonotype. In the last example, the...

Carrier

Huw Davies, Division of Life Sciences, King's College, London, UK Our current understanding of antibody production by B lymphocytes, and the underlying cooperation between T and B lymphocytes, owes much to the early use of hapten-carrier conjugates in immunologic studies. It had been known from the work of Landsteiner and of Pauling in the 1940s that haptens, small antigenic determinants such as dinitro-phenol (DNP), were insufficient by themselves to elicit specific antibody, but would bind to...

Characteristics of vitiligo

Vitiligo is a syndrome characterized by acquired loss of pigmentation in a usually symmetrical but 'spotty distribution, commonly involving the central face and lips, genitalia, hands and extremities. Pigmentation in the skin is produced by melanin, a hetero-polymer synthesized in melanocytes by a complex biochemical pathway controlled by the rate-limiting enzyme tyrosinase. Melanin is packaged in melanosomes which are transferred to keratinocytes to provide broad-spectrum photoprotection to...

Structure of IL7 and the IL7 receptor

The cDNA of IL-7 (initially designated iympho-poietin 1) was first cloned from the murine stromal cell line IXN A5. Subsequently, human IL-7 cDNA was cloned from the human hepatoma cell line SK-HEP-1. Murine IL-7 consists of 154 amino acid (aa) residues including a 25 aa signal peptide, whereas human IL-7 is 19 aa longer. This difference in size is due to the absence of an exon in the mouse gene, which corresponds to the 5th exon of the human II,-7 gene. Because of this deletion, murine IL-7...

Insights gained from animal models of ocular autoimmunity

The questions outlined above are being studied in animal models of ocular autoimmunity (Table 1). The best studied is experimental autoimmune uveo-retinitis (EAU), which serves as a model for human posterior uveitic disease that is most likely to result in impairment of vision. EAU can be induced in various species of rodents and in primates by any of several defined retinal antigens injected in emulsion with complete Ereund's adjuvant (CFA). A number of uveitogenic proteins derived from the...

Immune responses of the host

As stated above, the malaria parasite is present in the vertebrate host as two distinct extracellular forms (sporozoites and merozoites) and as intracellular stages within hepatocytes and erythrocytes. Several immune mechanisms could therefore control the different parasite stages and it is probable that no single effector mechanism is responsible for protective immunity in natural infection. The highest numbers of parasites and the most severe consequences of infection are found in young...

Methods for affinity measurement

As already pointed out, affinity is measured when the equilibrium between the two molecules has been achieved in solution. Hence, measuring KA for monoclonal antibody and its antigen consists in mixing the monoclonal antibody (mAb) and the antigen at various initial concentrations, letting the equilibrium be established, measuring the concentrations of free and saturated sites at equilibrium and analyzing the binding curve. The experimental difficulty resides in distinguishing the free and...

Immunological characteristics of nude mice

Phagocytes and natural killer (NK) cells The activities of phagocytes including phagocytic uptake, FcR expression and killing of tumor cells and bacteria are greater in nude mice than in euthymic (nu +) littermates. These alterations are considered as a result of stimulation with lipopolysaccharide (LPS) derived from gut microflora. However, the fact that increased activities of phagocytes are also detected in nude fetuses suggests that the athymic mutation influences the state of professional...

Blocking factors and suppressor cells

Circulating 'blocking factors' in the form of antigen-antibody complexes and free antigens were discovered in the late 1960s by their ability to inhibit ('block') the destruction of tumor cells by immune lymphocytes. This was demonstrated by using an assay which lasted 3-7 days and, therefore, included both lymphocyte activation and tumor cell killing. The presence of 'blocking factors' correlated with tumor growth in animal models. The immune response to a growing tumor is less effective at...

Immune responses to parasites

Because of the long-lasting nature of parasitic infections it was widely believed until comparatively recently that there were very few effective immune responses against most parasites. However, it is now clear that immunity is the rule. The evidence for this comes from a number of sources. First, there is the epidemiological evidence in endemic areas rhe majority of people develop clinical immunity to parasitic infections, the prevalence of infection falls with age while immunological...

Immunity to bacteriocins

Some diffusible substances released by bacteria into the medium inhibit the growth of other sensitive, generally closely related, bacteria. These substances, which are proteinaceous in nature, act at low concentrations. They have been called bacteriocins. A common characteristic of bacteriocin-producing strains is their ability to resist their own bacteriocin through specific-immunity peptides or proteins. The best-documented bacteriocins are the colicins produced by various members of the...

History of the immune surveillance theory

At the end of the nineteenth century, tumor biologists started to study allogeneic tumor growth in animals upon transplantation. Observations in 1902 by Jensen and Ehrlich on tumor rejection tempted Ehrlich to suggest a role for the immune system in the control of tumor growth. However, attention for this idea soon faded as it became known that transplant rejection or acceptance was merely a consequence of genotypic variation between host and donor rather than of a specific antitumor response....

Longterm infections

Ocular pathogens establish long-term infections by direct infection of the eye or indirectly following dissemination of infection from elsewhere in the host. These pathogens survive or evade the host immune response, damage the eye and affect sight. Herpes simplex virus type 1 (HSV-1) is associated with a range of eye diseases known as herpes simplex virus ophthalmia (HSVO). It causes conjunctivitis and lesions in the skin surrounding the eye, and ophthalmologists commonly describe this as...

Immune response in syphilis

T. pallidum infection evokes cellular and humoral immune responses. The humoral response manifested by production of phospholipid and treponemal antibodies is the basis for serodiagnosis of syphilis. The phospholipid or cardiolipin antibodies are detected by a variety of flocculation tests using a defined mixture of cardiolipin-lecithin-cholesterol as antigen (Venereal Disease Research Laboratory, VDRL antigen or VDRL test). A second type of antibody, known as cardiolipin F (detected by...

Ataxia Telangiectasia

Richard A Gatti, Department of Pathology, UCLA School of Medicine, Los Angeles, California, USA Ataxia telangiectasia (AT) is a rare (1 40 000 live births) pleiotropic disorder whose various pheno-typic manifestations include a progressive cerebellar ataxia, ocular apraxia, and oculocutaneous telangiectasia (Figure 1). Almost all patients have an elevated serum a-fetoprotein (AFP). Translocations involving chromosomes 7 and 14 are characteristic. About half of the patients have a moderate to...

Animal models of Addisons disease

Idiopathic Addisons disease occurs spontaneously in dogs and more rarely in cats. In the few cases that have undergone autopsy, atrophy, regeneration of adrenocortical cells and chronic inflammation of the adrenal cortex have been observed. The cause of adrenal insufficiency in dogs is probably of autoimmune, not tubercular, origin. A preferential occurrence in Chow-Chow dogs suggests a genetic predisposition. Adrenal autoimmunity with lesions of the chronic inflammatory type has been...

Immune globulin and vaccines

Chickenpox can be prevented by administration of high-titer human varicella-zoster immune globulin (VZIG) by intramuscular injection. In order to be effective, the globulin must be given within 3-4 days after exposure to chickenpox. Based on the schema of pathogenesis (Figure 2), the most likely explanation is that antibody to VZV abrogates the primary viremia and thereby inhibits spread of virus throughout the host. The medical indications for VZIG include prevention of chickenpox in VZV...

Cellular and molecular basis of the humoral immune response

An antigen, e.g. a bacterium, virus or toxin, may stimulate the differentiation of B cells into plasma cells. There are two different pathways by which B cells can be activated to differentiate into plasma cells 1. T-independent response. In this case, B cells will be activated even in the absence of T cells. There are two types of T-independent antigens Tl-'l antigens activate a proportion of B cells poly-clonally, irrespective of the specificity of their antigen receptor. Tl-2 antigens are...

Bacteroides Infection And Immunity

Michael E Shapiro, Harvard Medical School, Beth Israel Hospital, Boston, Massachusetts, USA The importance of anaerobic bacteria in clinical human disease, particularly intra-abdominal infection, has been well established over the past two decades. Much of the interest has focused upon the various Bacteroides species because of their prevalence in clinical isolates and their requirements for particular antiobiotic therapy. Once classified as subspecies of Bacteroides fragilis, six distinct...

Role of CD1 in the immune system

The initial reports implicating CD1 in T cell function demonstrated that human T cell clones expressing either a (3 or y 8 T cell receptors (TCRs) recognized tumor cells expressing specific isoforms of human CD1. These CD 1-restricted T cells were pheno-typically CD4CD8 or double negative (DN) T cells. CD lb-restricted proliferative and cytotoxic responses of human DN-ct p+ and DN-y 8+ lymphocytes specific for M. tuberculosis and M. leprae were seen in cells isolated from blood of normal...

Hyper and hyporesponsiveness examples of dysfunctional immune responses

Clearly, T cells bearing TCRs capable of recognizing self antigen-MHC complexes are present in healthy-individuals, yet autoimmune disease does not normally occur. However, if a self reactive T cell population becomes activated, a vigorous inflammatory-response can be created, spreading to other previously cryptic determinants on the self antigen ('intramolecular spreading'). In the absence of regulation, such an incident may perpetuate into a chronic, autoimmune condition. Conversely, the...

HEV development

Morphologically distinct HEVs are not visible until birth in mice, rats and humans. Blood vessels expressing sialyl Lewisx are detectable in lymphoid organs during embryonic life in humans it is not clear whether these represent a precursor to HEVs which are not yet fully differentiated. Expression of the mucosal addressin is detectable at birth in mice, however its expression is widespread in both peripheral and mucosal lymph nodes. Expression of the peripheral addressin commences after birth...

Herpes simplex viruses type 1 HSV1 and type 2 HSV2

There are several features which distinguish herpes viruses from other viruses. The genome is a linear double-stranded DNA ranging from 125 000 to 250 000 base pairs. The viron is composed of the DNA-containing core an icosahedral capsid, which is about 100 nm in diameter and exhibits 162 morphological units (capsomeres) on its surface and an outer lipid-containing membrane or envelope. These viruses use both the nucleus and the cytoplasm of the host cell for their replication. The pathology...

Nature of effector cells and antibodies involved in ADCC

NK cells are a subset of lymphocytes, morphologically identified as large granular lymphocytes, which lack typical T and B cell markers and usually express CD16 (FcyRIII) and CD56. They are able to destroy a variety of cell types, in the absence of prior stimulation, through a mechanism known as natural killer cytotoxicity. This cytotoxic response is not restricted by MHC gene products and is induced without antibody participation. NK cells, which comprise about 5 of human peripheral blood...

The biological importance of NK cells

Table 3 indicates that NK cells may participate either directly or indirectly in a variety of essential biological processes, ranging from reproduction to immuno-regulation. While there is evidence for the involvement of NK cells in various physiological pathways, the mechanisms responsible for many of the NK cell-mediated effects are not entirely clear. For example, NK cells have been shown to mediate antiviral, antifungal and antibacterial activity in vitro. Their in vivo importance in...

Calprotectin

The cytoplasm of human neutrophils contains remarkably high concentrations of 'calprotectin', a member of the widespread S-100 protein family. Human neutrophil calprotectin is a heteropolymer, composed of light (MRP8) and heavy (MRP14) chains. It constitutes over half of the total cytosolic protein present in human neutrophils. Although calprotectin is not secreted from intact neutrophils, its release from dead and dying neutrophils creates high concentrations of the protein in pus or abscess...

Non Hodgkin lymphoma NHL

This complex group of tumors have been seen to arise from all the known lymphoid lineages (B, T, NK, mononuclear phagocytic, dendritic). The lineage of origin in a given case can usually be identified without difficulty by a modern laboratory. However such information is rarely prominent in the clinical notes, first because it is not particularly discriminatory - more than 80 of NHL in Western societies arises from the B lineage - and secondly because clinicians, encouraged by classifications...

Immunoreagents

Polyclonal antisera that contain a mixture of antibody populations and monoclonal antibodies are the most commonly used reagents in immunoelectron microscopy where antigen or antibody) is being localized. Immunoglobulin G (IgG) in serum frac tions is most often preferred, unless the reaction considerations specify otherwise. Purity and specificity of polyclonal antisera can be improved by affinity purification steps. The benefits of monoclonal anti body use are well known. There are also...

Info

Outflow obstruction is a major factor and may be due to bladder neck stenosis, urethral stricture or prostatic enlargement. The particular susceptibility of women is due partly to the short urethra and its proximity to the bowel. The virulence of an organism is related to its ability to adhere to epithelial cells. Less virulent organisms may be pathogenic when the kidney is not normal, e.g. with vesico-ureteric reflux. The epithelial cell receptors for the majority of uropatho-genic E. coli...

Fusobacterium Infection And Immunity

Itzhak Brook, Department of Pediatrics, Georgetown University, Washington DC, USA Fusobacterium spp. are gram-negative, nonsporulat-ing, nonmotile and, generally, moderately long filamentous organisms, sometimes slightly elongated spindle-shaped rods, that belong to the family Bac-teroidaceae. They are weak fermenters or unable to ferment sugar. The ability of Fusobacterium spp. to produce N-butyric acid without isobutyric or isovaleric acids differentiates them from the other Bacter-oidaceae....

Pathogenesis

Uropathogenic E. coli first become established at a site outside the urinary tract (the large intestine, the introital or preputial areas). Colonization at these sites is influenced by adherence through P and type 1 fimbriae and by the receptor repertoire of the host. The uropathogenic clones enter the urinary tract and establish bacteriuria via the ascending route. The bacterial properties that determine this initial establishment are still poorly understood. The bacteria resist elimination...

Alternative explanations for the phenomena assigned to the immune surveillance theory

Those being skeptical with regard to the immune surveillance theory refer to the alternative explanations for phenomena such as increased tumor incidence in immunodeficiency, spontaneous regression of tumors, and the association of tumor cells with cells from the immune system. Tumor incidence associated with immunodeficiency Alternative explanations regarding the increased tumor incidence in immunodeficiency are also entirely plausible. The increased tumor incidence in immunodeficient renal...

Basic biology of the rabbit immune system

The rabbit immune system is comparatively similar to the human system with only minor differences in tissue and cellular organization. The rabbit gut-as-sociated lymphoid tissue (GALT) is organized into a prominent appendix, obvious Peyer's patches and some diffuse lymphatic nodules. The human appendix is vestigial and has more diffuse lymphatic nodules. The GALT, as well as other peripheral tissues of the rabbit and human, are innervated with a well-developed lymphatic system of nodes and...

Biological functions of IgE

The biological function(s) of IgE in cellular immunity can be related to its partnership with the high-affinity receptor, FceRI, on mast cells and Langerhans cells. Its interactions with the same receptor on eosinophils and monocytes are undoubtedly important also, but their significance is still somewhat obscure. Langerhans cells are bound in the epithelium and are thus favorably placed for the capture and processing of antigens recognized by IgE antibodies bound to FceRI. Following antigen...

Potential clinical significance of IL11

Two clinical trials of IL-11 in cancer patients have been performed. In a phase I trial in patients with breast cancer, IL-11 was administered daily for 14 days during a 28-day prechemotherapy cycle 0. Patients subsequently received up to four 28-day cycles of cyclophosphamide and doxorubicin chemotherapy (day 1) followed by IL-11 (days 3 through 14). The results indicated that IL-11 has thrombopoietic activity at all doses studied (10, 25, 50, 75 and 100 pg kg-1 day-1), is well tolerated at...