Showing papers in "Advances in Immunology in 1989"

Biology of natural killer cells.

Abstract: Publisher Summary Studies of cytotoxicity by human lymphocytes revealed not only that both allogeneic and syngeneic tumor cells were lysed in a non-MHC-restricted fashion, but also that lymphocytes from normal donors were often cytotoxic. Lymphocytes from any healthy donor, as well as peripheral blood and spleen lymphocytes from several experimental animals, in the absence of known or deliberate sensitization, were found to be spontaneously cytotoxic in vitro for some normal fresh cells, most cultured cell lines, immature hematopoietic cells, and tumor cells. This type of nonadaptive, non-MHC-restricted cellmediated cytotoxicity was defined as “natural” cytotoxicity, and the effector cells mediating natural cytotoxicity were functionally defined as natural killer (NK) cells. The existence of NK cells has prompted a reinterpretation of both the studies of specific cytotoxicity against spontaneous human tumors and the theory of immune surveillance, at least in its most restrictive interpretation. Unlike cytotoxic T cells, NK cells cannot be demonstrated to have clonally distributed specificity, restriction for MHC products at the target cell surface, or immunological memory. NK cells cannot yet be formally assigned to a single lineage based on the definitive identification of a stem cell, a distinct anatomical location of maturation, or unique genotypic rearrangements.

Antinuclear antibodies: diagnostic markers for autoimmune diseases and probes for cell biology

Abstract: Publisher Summary Early studies pointed to the directions for subsequent investigations and there has been continuing identification of other circulating autoantibodies, characterization of their respective cellular antigens, and demonstration of the relationship between autoantibodies and clinical syndromes. The antibodies identified in these studies have been used extensively by investigators in molecular and cell biology as powerful probes for understanding the precursor messenger RNA (mRNA) splicing. Autoantibodies designated SS-A or Ro and SS-B or La were identified in patients with Sjogren's syndrome (SS) and SLE, and have been shown to target intracellular proteins that may be involved with regulation of RNA polymerase III function. Investigators in the field had long perceived that these spontaneously occurring auto-antibodies in human disease would turn out to be useful reagents in cell biology. It was also appreciated that it was necessary to characterize the molecular nature of the auto-antigens so that in addition to the immunochemical properties, their structure and function might be determined. One of the purposes of this chapter is to show that the new molecular biology of cellular antigens and auto-antibodies could now be providing insights into comprehending some features of autoimmunity. In addition, there appears to be a need for the synthesis of the wealth of information that has accumulated and an evaluation of what it might signify.

Interleukin-1 and its biologically related cytokines.

Abstract: Publisher Summary Interleukin-1 (IL-1) and tumor necrosis factor (TNF) participate in self-augmentation induction mechanisms. Recombinant human IL-1 and TNF are each capable of inducing the production of their respective molecules as well as each other. IL-1 and TNF both induce IL-6. The target cells include: monocytes, endothelial cells, smooth muscle cells, and B cells. The concentrations of IL-1 and TNF that stimulate their own production in this self amplification cycle are within the range (1-10 ng/ml) of what has been measured in the supernatant media of cultured cells stimulated with viruses, bacterial toxins, and active complement components, and of immune complex. The ability of interferon-y to suppress IL-l-induced IL-1 production takes place in the presence of cyclo-oxygenase inhibition. Similarly, the ability of corticosteroids to reduce the transcription of IL-1 messenger RNA (mRNA) also takes place in the presence of cyclooxygenase inhibition. IL-1 is the prototype of a group of biologically potent polypeptides with molecular weights between 10,000 and 30,000. Because these substances are produced by a variety of cells and act on many different cell types, there is a growing acceptance of the terminology “cytokines,” rather than “lymphokines” or “monokines.” Of the various “cytokines,” several share the ability to stimulate or augment cell proliferation, initiate the synthesis of new proteins in a variety of cells, and induce the production of inflammatory metabolites. IL-1 is biologically similar to tumor necrosis factor (TNF), lymphotoxin, IL-6, fibroblast growth factor (FGF), platelet derived growth factor (PDGF), and transforming growth factor- β (TGF-β)

Heterogeneity of cytokine secretion patterns and functions of helper T cells.

Abstract: Publisher Summary Because cytokine functions are complex and overlapping, the development of precise, monospecific bioassays, and enzyme-linked immunosorbent assays (ELISAs) was essential, before a clear picture of T cell cytokine synthesis could be obtained. In vitro , some mast cell lines synthesize IL-4 and other cytokines of the Th2 pattern in response to cross-linking of surface IgE. Although functional evidence using mixed cell populations suggested different types of Th cells, the lack of discriminatory cell-surface markers has hampered efforts to define the different subtypes. The development of in vitro T cell clones led to the description of four types of helper T cell clones, and later, two types of Th clones (Th1 and Th2) were defined on the basis of different patterns of cytokine secretion. These patterns have been confirmed in several panels of Th clones and this is currently the most clear-cut criterion for separation of mouse Th subtypes. As the two types differ in the synthesis of many cytokines, and the cytokines have a major role in the regulation of immune responses, the two types of Th cells have markedly different functions. When injected simultaneously with antigen into the footpads of naive mice, Th1 clones cause an antigen-specific and major histocompatibility complex (MHC)-restricted inflammatory reaction that peaks at about 24 hours. Th2 clones do not produce a swelling reaction under these conditions. One of the major functions of helper T cells is to provide signals for activation, proliferation, and differentiation to B cells that have encountered an antigen. Several strategies have been employed for studying the functions of mouse Th clones in micro and for analyzing the roles of specific Th products in these functions. In spite of the clear dichotomy of mouse Th1 and Th2 clones, and the accumulating evidence for their involvement in normal immune responses, human T cells do not appear to segregate into two clear subsets. Many human T cell clones secrete both Th1and Th2 cytokines.

The leukocyte integrins.

Abstract: Publisher Summary This chapter focuses on the molecular biology of the leukocyte integrins, LFA-1, Mac-1, and p150,95, and on their role in mediating inflammation. Three recent developments have underscored the importance of the leukocyte integrins as adhesion receptors of the immune system: The recognition that the leukocyte integrins are evolutionarily related to other integrins; Identification of intercellular adhesion molecule-1 (ICAM-l), a ligand for LFA-1, which is induced during inflammation, and may regulate leukocyte migration and localization; and discovery and characterization of immunodeficiency patients who are genetically deficient in their expression of the leukocyte integrins. Researchers have found a class of immune-deficient patients who suffer from recurrent, life-threatening bacterial and fungal infections, and who have neutrophils deficient in chemotaxis and phagocytosis. Infected, necrotic lesions in these patients contain few leukocytes, despite the observation that these patients have chronic leukocytosis. The leukocyte integrins are α 1 β 1 heterodimers, in which the α subunit is noncovalently associated with the β subunit. The α subunits of LFA-1, Mac-1, and p150, 95 are 1,80,000, 1,70,000, and 1,50,000 Da, respectively. The α subunits have been shown to be distinct by MAb reactivity, antigen-preclearing studies, and tryptic peptide mapping. In contrast, the β subunit, M r = 95,000, has been shown to be identical in all three proteins by the same criteria. There is also substantial evidence that other ligands for LFA-1, Mac-1, and p150, 95 exist. Rational strategies must be designed to identify these ligands and to assess their contributions in different phases of the immune response. Multiple ligands may provide quite distinct signals and positional information to leukocytes.

The immunopathogenesis of HIV infection.

Abstract: Publisher Summary This chapter reviews the state of knowledge concerning the structure and function of the HIV genome, virus cell tropism, cytotoxic and noncytotoxic effects of HIV on both the immune system and the central nervous system (CNS), latent HIV infection and virus activation, and the immune response to HIV. HIV induced immunosuppression results in the emergence of opportunistic infections and neoplasms that are pathognomonic for the acquired immunodeficiency syndrome (AIDS). Infection with HIV also results in a syndrome of neurological abnormalities, which has been termed the AIDS-dementia complex. Efforts to control AIDS require a fundamental knowledge of the etiological agent itself, the mechanisms by which HIV destroys the immune systems, and the nature of the immune response against HIV. Fortunately, long-standing basic research both on retroviruses and on the immune system laid the groundwork for rapid advances in the accrual of knowledge of HIV and the immunopathogenic mechanisms of HIV infection. In other retroviral systems persistence of unintegrated retroviral DNA has been associated with a cytopathic effect. In HIV infection, a substantial amount of HIV DNA exists in an unintegrated form, potentially contributing to the cytopathicity observed in HIV infection. The interaction of HIV with the CD4 molecule that is present on the surface of the helped inducer subset of T lymphocytes is the critical event in the pathogenesis of HIV infection. The successful control of HIV infection through either therapeutic agents or vaccines requires an extensive understanding of the agent itself and its pathogenesis. The fact that HIV is a member of the lentivirus subfamily of viruses was an immediate clue that the natural history of HIV infection would entail a lengthy latent period and disease progression, despite the generation of an immune response.

Structure and Function of the Complement Receptors, CR1 (CD35) and CR2 (CD21)

Abstract: Publisher Summary This chapter reports recent findings regarding two of these receptors, complement receptor type 1 (CR1; CD35) and complement receptor type 2 (CR2; CD21), which bind the cleavage fragments of C4 and C3 that are covalently attached to activators of the complement system. The complete primary structure of CR1 is now known through molecular cloning studies. The most common allotype of CR1, the F or A allotype, is a polypeptide of 2039 residues: A 41-amino acid signal peptide, an extracellular domain of 1930 residues, a 25-amino acid transmembrane region, and a 43-amino acid cytoplasmic domain. The extracellular portion of the receptor is composed exclusively of 30 short consensus repeats (SCRs). Each SCR contains 60 to 70 amino acids, six of which are found in all SCRs: Four cysteines, a single tryptophan between the third and fourth cysteine, and a glycine after the second cysteine. The primary protein structure of CR2 has been determined through analysis of the nucleotide sequences of clones isolated from human tonsillar and Raji lymphoblastoid cell line cDNA libraries. These clones encode a 20-amino acid signal peptide, a 954-residue extracellular domain, a 24-amino acid transmembrane region, and a 34-amino acid cytoplasmic domain. The extracellular domain is composed entirely of 15 tandem short consensus repeat sequences that are homologous to those described in CR1 and other C3/C4-binding proteins, as well as in some membrane proteins that do not share this function. The molecular cloning of CR1 enabled the construction of eukaryotic expression vectors containing cDNA inserts, representing the entire CR1 coding sequence and various deletion mutants. The expression of these recombinant forms of CR1, and the analysis of their ligand binding function has led to the identification of distinct C3b and C4b recognition sites. These functional domains have been assigned to specific structural elements of the receptor, the SCR and the LHR. The functions of CR2 have been more difficult to define fully than has its structure. The experimental evidence to date suggests that this single transmembrane glycoprotein may have several important immunoregulatory.

Molecular and cellular events of T cell development.

Abstract: Publisher Summary Although some T cell differentiation can occur outside the thymus, by far majority of the T cells develop within the thymus, and this chapter discusses the intrathymic differentiation. A major turning point in this field came with the identification of the surface receptors used by T cells to recognize and respond to foreign antigens in association with the products of major histocompatibility complex (MHC). Based on the understanding of the molecular basis, T cell development can be divded into three stages: early genetic events leading to T cell receptor (TCR) expression, cellular selection, and acquisition of mature effector function. Analysis of the T cell development in the adult thymus has been greatly facilitated by the fact that thymocyte subsets can be separated, on the basis of surface markers, into relatively homogeneous populations that represent defined developmental stages. Some of these populations correspond closely to early fetal thymocytes but are present in much smaller proportion. There is an astounding evolutionary conservation in thymocyte ontogeny and subset distribution ranging from chicken to human. Although the time line is based on murine fetal ontogeny, the temporal and lineage relationships appear to be evolutionarily conserved. As with most scientific work, the recent elucidation of lineage pathways and of selection mechanisms involved in T cell development has posed new questions and opened new frontiers. The lineage map provided in the chapter represents a summary of the events, for which there is now reasonable consensus, based on multiple experimental approaches.

The Regulators of Complement Activation (RCA) Gene Cluster

Abstract: The complement system is a potent recognition and effector pathway that plays a major role in the immune response. It mediates the destruction and disposal of immune complexes and foreign substances through interactions between complement proteolytic fragments deposited on targets and complement receptors on cell surfaces. To faciliate this process, and to prevent damage to self-tissue, a remarkable family of control proteins (the regulators of complement activation or RCA proteins) has evolved (see recent reviews of Hourcade et al., 1989; Campbell et al., 1988 and Reid and Day, 1989). Each member interacts with a derivative of C4 and/or C3, shares a repeating polypeptide motif, and is encoded at a single genetic region, the RCA cluster.

Molecular Biology and Function of CD4 and CD8

Abstract: Publisher Summary Progress on the understanding of CD4 and CD8 function has proceeded at an accelerating rate in the recent years. There are still many open questions regarding how these molecules work. Also, very little is also known about the mechanisms of regulation of expression of CD4 and CD8 during T cell development and the means by which T cells that are restricted by class I or class I1 MHC proteins become CD8 or CD4 single-positives, respectively. The latter most likely involves a selection process related to the ability of CD4 or CD8 on double-positive thymocytes to bind to the same MHC molecule as the expressed TCR, but how this happens mechanistically and developmentally remains obscure. It has been suggested that CD4 might deliver a negative signal if it is cross-linked in the absence of cross-linking of the TCR/CD3 complex, and that this results in cell separation if the TCR is not bound to the appropriate antigen. There is currently no experimental evidence showing this to be the case, but several points are worthy of consideration. This hypothesis contains two separable parts: transmission of a negative signal (to turn off the T cell) and induction of cell separation. These two processes could be induced by entirely different mechanisms. The initial evidence that CD4 and CD8 play a role in T cell function came from studies using antisera, and subsequently monoclonal antibodies (Mabs) specific for these proteins. These antibodies were found to block all the antigen-driven functions, for example, cytotoxicity, proliferation, and lymphokine release, by T cells that express the corresponding molecule and are specific for the appropriate class of MHC protein.

The cellular and subcellular bases of immunosenescence.

Abstract: Publisher Summary This chapter focuses on the cellular and intracellular basis for impaired immunologic activity. The activation of B and T cells, transit through the cell cycle, and differentiation present many points that might be age sensitive. Three possible mechanisms leading to, or contributing to, the decline in immune function will be considered: A shift in lymphocyte subset distribution with age, alterations in suppressor mechanisms, and changes in the maturation of B and T lymphocytes. The entry and transit of the cell cycle in T cells is thought to require delivery to the cell surface of several signals, triggering the sequential expression of several new proteins. This scheme involves the perturbation of the T cell receptor (TcR), activation of protein kinases, phosphorylation of target proteins, new mRNA synthesis, and protein synthesis, leading to the acquisition of receptors for interleukin 2 (IL-2) and increased expression of the receptor for transferring. It is not possible to identify a single age sensitive step in this sequence, but rather a series of deficiencies contribute to the decline in the competency of the aged lymphocytes to undergo normal activation. Thus, very early events, such as Ca2+ increases, accumulation of protooncogene transcripts, expression of activation markers, and synthesis of new proteins, are deficient in the aged. The mucosal immune system provides evidence that not all lymphoid tissues are equally adversely affected by age. Thus, while the response of lymphocytes derived from the peripheral lymphoid organs is diminished, the gut-associated lymphocytes from the same individual are often normally responsive.

The CD5 B Cell

Abstract: Publisher Summary The international nomenclature established for cell differentiation antigens will be used. Historically, the CD5 B cell in mice or humans has been referred to as the Ly-1 B cell or Leu-1 B cell, respectively. Although these terms are still in use, their assigned CD number will refer to all defined surface differentiation antigens, including CD5. The relationship between the CD5 B cell and autoimmune disease and/or autoantibodies also is controversial. This chapter reviews current ideas concerning the CD5 B cell, hoping to resolve some of the controversy. With the advent of anti-CD5 Mabs and sensitive flow-cytometric analyses, CD5 was noted to be expressed by all T lymphocytes. CD5 B cells are lymphocytes that coexpress a 67-kDa pan-T lymphocyte surface glycoprotein, designated CD5, and surface antigens restricted to the B lymphocyte lineage. Surface expression of CD5 is defined by the reactivity of cells with Mabs Ly-1 in mice, or Leu-1 or its equivalent in humans. Both murine and human CD5 B cells express roughly 20% of the level of CD5 expressed by most T lymphocytes. Detection and enumeration of CD5 B cells require sensitive immunofluorescence or immunohistochemical methods. Even with the brightest of fluorochrome-labeled anti-CD5 Mabs and the most sensitive of immunofluorescence techniques, B cells expressing CD5 cannot be delineated into a separate subpopulation distinct from B cells that lack expression of this marker. Because of this, subtraction methods must be used to enumerate these cells within a mixed cell population.

Rationale for the development of an engineered sporozoite malaria vaccine.

Abstract: Publisher Summary This chapter discusses the rationale for developing sporozoite vaccines Sporozoites are the infective stages of the parasite found in the salivary glands of female Anopheles mosquitoes Infection by Plasmodium vivax is also widespread and causes an acute or subacute disease, chronic anemia and splenomegaly but is not usually lethal or drug resistant At the other end of the spectrum, Plasmodium malariue is well adapted to the human host and produces chronic illness that can persist for many years The symptoms are similar to those of P vivax infection, but relapses are less frequent Attempts to control the spread of the infection by combating the Anopheles mosquito vectors have failed Vaccine development has become an important research priority Unfortunately, however, this task is complicated by several problems; some are associated with unique features of this parasite and others, of a more fundamental nature, are associated with the obstacles facing the design of rational, efficient, engineered subunit vaccines that contain multiple B and T cell epitopes One of the problems in developing a malaria vaccine is that this parasite has a very complex life cycle and each stage bears different protective antigens In spite of the formidable obstacles, considerable progress has been made in the past few years and a few candidate malaria vaccines have been tried in humans with partial success

Diversity of the immunoglobulin gene superfamily.

Abstract: Publisher Summary The physical nature and organization of particular genetic information establish the limits and possibilities of its variation. The multigene organization and recombinogenic nature of much of the family establishes particular diversifying potentialities on many of the members. New functional possibilities arise primarily through the duplication of the various informational units involved, for example, nucleotides, exons, genes, and entire multigene families. Duplication of a multigene family and the attendant cis-acting control mechanisms can in a single event create the genetic basis of a complex new phenotype, suggesting the possibility of rapid evolutionary change. Interestingly, the number of the identified single-gene IgGSF members that are expressed in both the brain and the immune system suggests the possibility of shared cell surface recognition functions and that the related molecules may be involved in some of the intriguing phenomena linking the mental states and immune response. It seems likely that the fruitful strategies of somatic diversification, employed by well-characterized members of the IgGSF, will also be used by other receptor families, perhaps involved in the morphogenesis or neuronal development.

Genetically engineered antibody molecules.

Abstract: Publisher Summary The availability of monoclonally derived hybridoma antibodies provided an infinite supply of homogeneous reagents so that laboratories around the world could use standardized procedures. However, some limitations persisted. One approach to producing hybridoma antibodies with more desirable biological effector functions or antigen-binding specificities has been to take advantage of the high rate of somatic mutation which occurs in cultured myeloma and hybridoma cell lines. The limitation inherent in this approach is that it is possible only to switch to isotypes that lie downstream of the expressed heavy chain gene isotype in the heavy chain gene complex. An alternative approach to producing improved monoclonal antibodies is to use recombinant deoxyribonucleic acid (DNA) techniques and eukaryotic gene expression methods, the objective being to produce antibodies with improved antigen specificities and effector functions. An advantage of this approach is that producing antibodies is not a limitation as they exist in nature. Instead, design and production of antibody molecules can be done with optimized specificities and effector functions. Antigen-binding specificities can be joined to both immunoglobulin and nonimmunoglobulin sequences to provide antibody and antibody-like molecules for use in diagnosis and immunotherapy. Standard techniques of genetic engineering and gene transfection make it feasible to produce antigen-binding molecules with widely varying structures. The challenge is to define the structure that is optimal for a desired function.

Control of the immune response at the level of antigen-presenting cells: a comparison of the function of dendritic cells and B lymphocytes.

Abstract: Publisher Summary This chapter discusses three areas where there have been recent advances of the immune response control. The first is that dendritic cells and B lymphocytes differ considerably in terms of their tissue distribution in situ and their surface properties. The relevance of these differences to APC function will be considered. The second is that each cell has distinct effects when tested for APC function in vitro and in situ . Presentation of soluble proteins, MHC and Mls antigens, viral antigens, and T cell-dependent antigens for antibody formation is each dealt with separately. The evidence that both B cells and dendritic cells regulate their APC function depending on their tissue localization and exposure to antigen and cytokines will be stressed. The third area relates to the mechanism of APC function, which includes how each APC processes antigen, acquires antigen in vivo , and forms stable contacts with responsive T cells. The dendritic cell family begins with a bone marrow precursor that likely seeds most non-lymphoid tissues. Following deposition of antigen, nonlymphoid dendritic cells may be mobilized to present antigen locally, or to migrate with that antigen via the blood and lymph to the T cell areas of lymphoid organs. Except for the bone marrow precursor, dendritic cells in all tissues from which they have been isolated are potent antigen-presenting cells (APCs) for a variety of T cell-dependent immune responses. In an analogous sense, B lymphocytes also encompass a diverse array of developmental stages, each with distinct functional properties. The immune system contains two diverse groups of cells, both of which can present antigens to T cells.

Cellular Interactions in the Humoral Immune Response

Abstract: Publisher Summary This chapter discusses the interactions between T and B cells and the role of accessory cells and cytokines in the generation of specific antibody responses The first part of the chapter is a historic perspective followed by a summary of the present-day concepts The final part of the chapter speculates on how the different components of the immune system might function in vivo A highly complex system of communication has developed among the various cell types in the immune sytem One important mechanism of communication is the requirement for interactions among cells for the activation and differentiation of resting B lymphocytes into antibody-secreting cells These cellular interactions involve both cell-cell contact and the release of mediators (cytokines) that can act in either an autocrine or paracrine fashion on cells both within and outside the immune system The chapter describes two types of functionally different Th cells and the role of lymphokines in the regulation of T and B cell function Although Th1 versus Th2 cells have different effects on B cells and other cells in vitro, their role in vivo is less well understood Nonetheless, studies in vivo have confirmed the requirement for IL-4 and IFN-У in IgE and IgG2, responses, respectively

Molecular Genetics of Murine Lupus Models

Abstract: Publisher Summary The chapter that addresses the Ig germ line gene organization in lupus-prone strains of mice suggested that the disease can develop in different Ig heavy and light chain haplotypes, and that the Ig germ line genes in lupus mice are probably normal. Analyses of the Ig gene segments expressed in monoclonal autoantibodies from autoimmune mice revealed that similar, moreover, in some instances even identical, gene segments are expressed in autoantibodies and in antibodies to exogenous antigens, and that antiself and antiforeign responses are encoded by the same, or at least an overlapping, germ line gene repertoire. Evidence has been obtained that, in an individual lupus mouse, the number of autoantibody-secreting clonotypes decreases after class switch, while that of productive mutations increases, suggesting that antiself responses might be (auto) antigen-driven responses, but this conclusion should be considered tentative. Finally, based on the investigations of I-E and Mls tolerance-related Vβ clonal deletions, the chapter proposes that the abnormally proliferating, autoimmunity-inducing/enhancing double-negative TcR α:β + lpr and gld cells are not related to immature CD4 - 8 - thymocytes, but instead are derived from CD4 + 8 + precursors through a process resulting in down-regulation of both accessory molecules.

Immune mechanisms in autoimmune thyroiditis.

Abstract: Publisher Summary This chapter mainly focuses on autoimmune thyroiditis in man and animals. Discussion made in the chapter has shared thoughts from an extensive review on Graves' disease published in 1985. Autoimmune thyroid diseases result from the persistence of forbidden B cell clones. In this hypothesis, the contact of antibody (Ab)-forming cells with their respective antigens (Ags) during fetal life leads to the destruction of the corresponding clones. In this way, self-reactive clones, so-called forbidden clones, would be deleted unless they originated later in life by somatic mutation of lymphocytes. Numerous experiments have failed to verify this hypothesis for autoreactive B cells as well as for autoreactive T cells; these cells are readily detected in high frequencies in normal animals and healthy humans. Immunization with individual synthetic peptides has revealed additional T cell determinants not seen following immunization with the native molecule. The lack of responsiveness to these determinants cannot be explained by an absence of T cells in the repertoire or a failure to bind a particular major histocompatibility complex (MHC) molecule. Understanding the pathogenesis of the naturally occurring syndromes and the experimental autoimmune thyroid diseases has been a central theme n the experimental immunology of autoimmunity. Experimental models and genetic control of thyroiditis and cellular immune responses during thyroiditis have been discussed well in the chapter. The field of immunogenetics promises answers to how a given MHC gene regulates or facilitates thyroiditis and how it cooperates with genes coding for Tg, A-Abs, cytokines, or other products. The powerful transgenic mouse model appears to be one of the most appropriate tools to answer these questions.

Virus-induced immunosuppression: infections with measles virus and human immunodeficiency virus.

Abstract: Publisher Summary The basic phenomenology of disordered lymphocyte function because of the infection by a lymphotropic virus is neither novel nor unexpected. The problem of measles virus-induced immunosuppression is contemporaneous with modern immunology and virology. This chapter explains that immunosuppression associated with HIV infection currently commands significant attention in biomedical research. Any unexplained disorder of immune response, either heightened or suppressed, might well be investigated with an infectious etiology in mind. Measles virus infects a wide range of epithelial and lymphoblastoid cell lines in vitro . The cell membrane receptor for measles virus is a nonsialated oligosaccharide present on many cells. Productive infection of cells by measles virus is not lytic and constitutive cellular protein synthesis is not altered. Active tuberculosis infection is a common sequela of measles virus infection. Researchers showed that blastogenic response of lymphocytes from the peripheral blood of tuberculosis-immune individuals to tuberculin antigen is significantly reduced during acute measles virus infection. The suppression by measles virus of the proliferative response to mitogen occurs with lymphocytes from both the nonimmune and the measles-immune donors, but serum containing measles antibody abrogates the suppression. During chronic HIV infection in vivo and in vitro , proviral DNA exists in both integrated and nonintegrated forms. Unlike the other lentiviruses and most retroviruses, a cellular receptor for HIV has been well characterized. The immunosuppression in AIDS patients has been characterized by global dysfunction of cellular immunity and polyclonal B cell activation. A significant part of this chapter discusses the immune dysfunction during HIV infection prior to the onset of AIDS and on the effects of HIV infection of lymphocytes and monocytes in vivo .

MHC-Antigen Interaction: What Does the T Cell Receptor See?

Abstract: Publisher Summary It was recognized that in most cases the antigen is processed by the antigen-presenting cells (APC), such that the fragments of antigen, rather than antigen per se, are presented by major histocompatibility complex (MHC) molecules and are recognized by the T cells (TcRs). There are numerous examples of synthetic peptides corresponding to defined portions of protein antigens that actually substitute for antigen in well-defined immunological reactions involving T cells. In several instances, it was shown directly that such peptides bind to MHC molecules. So far, however, such biochemical data are rather scarce and the binding of the processed antigen to the MHC molecules is often inferred from functional assays involving recognition by TcRs. It is well known that most MHC molecules are highly polymorphic. Polymorphism of MHC molecules may influence both the antigen presentation and recognition by the TcRs in many ways. Polymorphic residues from the peptide-binding site may influence the selection of a given set of fragments from the native antigen as well as their conformation and orientation. Other polymorphic residues may positively or negatively interfere with the recognition of the bound peptide with a given TcR. The purpose of this chapter is to survey the recent data and to critically analyze their interpretation. The chapter shows that data can fit within a consistent, though hypothetical, framework of MHC-antigen-TcR interactions.

The Obese Strain of Chickens: An Animal Model with Spontaneous Autoimmune Thyroiditis

Abstract: Publisher Summary Thyroid glands of Obese Strain (OS) chickens become severely infiltrated by mononuclear cells and the occurrence of numerous germinal centers is a characteristic histological hallmark of the disease. Autoimmune thyroid destruction leads to thyroid hormone deficiency that entails the development of hypothyroid symptoms, such as small body size; massive subcutaneous and abdominal fat deposits (hence the name); lipid serum; long, silky feathers; small combs; cold sensitivity; low fertility; and poor hatching ability. The serum of 0s chickens contains AAbs to Tg, microsomal antigens, and T3 and T4. Tg-AAb formation is not because of polyclonal activation, but requires the presence of the autoantigen. The infiltrated thyroid itself has been identified as the major Tg-AAb-producing organ and can be the site of the formation of antibodies against exogenous antigens. OS chickens also produce AAbs against a variety of other organ-specific and non-organ-specific antigens, albeit with significantly lower frequency and titers, and without concomitant histopathological or functional lesions, such as Addison-like disease or diabetes mellitus. Additionally, factors extrinsic to the immune system that also affect immunoregulation have been found to be altered in the OS. Thus, OS chickens display a significantly decreased glucocorticoid tonus because of an increased serum concentration of corticosteroid-binding globulin and therefore markedly decreased free, metabolically active glucocorticoids.

Synthetic T and B Cell Recognition Sites: Implications for Vaccine Development

Abstract: Publisher Summary The advantages and disadvantages surrounding the development of synthetic peptide vaccines have been discussed in this chapter. There are obvious practical advantages to synthetic vaccines as compared to the conventional killed, attenuated, or other subunit vaccines. Conventional antiviral vaccines require large cultures to provide sufficient protein for mass immunization and not all viruses can even be propagated in culture. Whole virus vaccines must be properly inactivated or contain only attenuated virus. Many virus preparations are unstable and require special handling that may prevent their worldwide distribution in underdeveloped areas. There are also a number of more subtle immunological benefits to the use of synthetic vaccines. Certain characteristics have been demonstrated in a number of synthetic antigen systems. The synthetic immunogen elicited high-titered antibodies to each of the three antigens. Although pathogen-related T cell recognition sites were not included in this experiment, inclusion of such T cell sites would be expected to prime Th cell memory responses to each pathogen as well as antibody production. Nucleoprotein-specific Th cells were shown to elicit antienvelope antibody production as well as antinucleoprotein antibody. This finding and the proposed importance of nucleoprotein-specific T cell responses in HBV infection prompted researchers to construct a synthetic immunogen composed of nucleoprotein T cell sites and an envelope B cell epitope.

Physical maps of the mouse and human immunoglobulin-like loci.

Abstract: Publisher Summary This chapter summarizes the methods that are currently available for generating physical maps and discuss the advantages and disadvantages of each method. The immune system is highly complex and consists of many different cell types; each carrying out their unique function. The primary task of the immune response is to distinguish between self and foreign antigens. This function is mediated by cell-surface receptors located on two major types of lymphocytes, T cells and B cells. B cells constitute the humoral pathway of the immune system, which defends primarily against acute bacterial and viral infections. The cell-surface antigen receptor of B cells is a membrane-bound immunoglobulin (Ig) of the IgM class. Immunoglobulins are composed of two chains, heavy (H) and light (L). Like immunoglobulins, the α and β or У and δ chains associate following protein synthesis to form a heterodimeric receptor molecule. The molecules encoded by the genes of the major histocompatibility complex (MHC) also play an important role in the vertebrate immune response. These proteins present foreign peptide antigens to the α/β T cell receptors, thus facilitating the ability of T cells to identify and respond to foreign antigens. The chapter groups these gene families as immunoglobulin-like loci, because they are molecular families that are constructed based on the immunoglobulin homology unit. Each immunoglobulin homology unit is approximately 110 amino acids in size, and has several conserved amino acids and a centrally placed cysteine disulfide bridge usually spanning 60–75 amino acids. The tertiary structure of the homology unit is highly conserved and composed of two sheets of three to four antiparallel, 0- pleated strands. In addition to their structural similarities, discontinuous gene segments that are organized on the chromosomes as discrete loci encode these molecules all. During the course of cellular differentiation and development, gene segments in these loci are rearranged and joined to produce the final coding sequence. Because most of the discontinuous gene segments exist as multiple-member pools, the combination of different sequences gives rise to a high degree of diversity in the final protein product.

Regulation of Immunoglobulin E Biosynthesis

Abstract: Publisher Summary A crucial role of Immunoglobulin E (IgE) antibodies in reaginic (Type I) hypersensitivity immediately raised a question as to whether the antibody response can be suppressed To achieve this goal, however, it is possible to lear cellular mechanisms involved in the IgE antibody response The purpose of this chapter is to summarize some unique features for the antibody response of the IgE isotype and to discuss possible approaches to controlling the same The IgE antibody response in inbred mouse strains provided most useful information on the mechanisms of IgE synthesis However, in vitro IgE antibody responses by murine lymphoid cells have been most difficult to reproduce When mice of a good IgE producer strain were immunized with alum-absorbed antigen for the persistent IgE antibody response, their spleen cells spontaneously released a substantial amount of IgE antibodies Dissociation between the IgE and IgG antibody responses raised the possibility that the IgE antibody response may be regulated not only by antigen-specific helper and suppressor T cells but also by a mechanism selective for this isotype Because the infection of antigen-primed rats with Nb selectively potentiated the IgE antibody response and the IgE-specific potentiation is dependent on T cells, it was anticipated that T cells of Nb-infected rats would selectively enhance the differentiation of IgE B cells to IgE-forming cells Either regulation of the IgE antibody response by means of antigen-specific mechanisms has been attempted through tolerization of B cells or manipulation of the population of T cells that regulate the differentiation of B cells to IgE-forming cells Another approach to regulating the antihapten IgE antibody response is to induce antiidiotypic antibodies If the antihapten antibodies are restricted to certain idiotypes, idiotype-specific regulation may be applied The third approach is to regulate the IgE antibody response by inducing antigen-specific suppressor T cells It has been shown that intravenous injections of a soluble antigen without adjuvant into naive mice facilitate the generation of antigen-specific suppressor T cells

Origin and significance of autoreactive T cells.

Abstract: Publisher Summary Antigen-specific, MHC-restricted peripheral T cells must, nevertheless, derive from thymic precursors that expressed a functional affinity for self-MHC, perhaps in association with other self-molecules. The basis for this transition from an autoreactive thymic precursor to an antigendependent, MHC-restricted peripheral T cell is not understood. Autoreactive T cells and T cell lines derived from normal individuals have been independently described in many laboratories. Such T cells are activated in the absence of any identifiable foreign antigen by class II MHC syngeneic stimulators, but not MHC allogeneic stimulators. In particular, autoreactive responses have been demonstrated in the absence of xenogeneic serum components. Several independent lines of evidence developed and other laboratories suggest that the autoreactive T cells derive from antigen-stimulated precursors that have undergone a physiological transition that restores their ability to respond to self. This could be a normal and reversible transition that frequently accompanies specific T cell activation. The functional capabilities of autoreactive T cells have been investigated in a number of laboratories. There may be important qualitative and quantitative differences in helper functions of different autoreactive T cell clones. Some of these differences may arise during the process of in vitro adaptation. The best characterized autoreactive responses are those of in vitro-adapted continuous T cell lines that may never revert to a fully resting state. The autoreactive responses manifested by some antigen-specific T cell lines might reflect the proportion of that population that is in an activated state.