Showing papers in "Annual Review of Immunology in 1984"

Antigen-Presenting Function of the Macrophage

Abstract: The functional significance of multiple cells--among lymphoid and nonlymphoid cells--capable of having Ia molecules on their membranes must be critically addressed. Ia is absolutely required before a cell can interact with helper T cells, but it is not clear whether the presence of this protein is all that is needed for antigen presentation. Indeed, at present, except for the macrophage, few cells have been studied for antigen presentation using a wide range of protein antigens, either soluble or particulate. On the basis of the studies discussed in the first section, it appears that the recruitment of most helper-T cell clones takes place by APC that can internalize and process the protein antigens, be they soluble or part of the structure of microorganisms. The fact that helper T cells are programmed to recognize antigen in the context of Ia, and therefore on an APC such as the macrophage, forces recognition of antigens that are altered or processed. Indeed, proteins in their native state may not remain membrane-bound for long periods; the T cells, therefore, have the opportunity to recognize the altered fragments. To this issue is added the requirement for the T-cell receptor to interact with Ia molecules. The available information, therefore, leads one to conclude that APC deficient in their capacity to internalize and process proteins will not be able to present them. The finding that small peptides from a previous catabolism of proteins can be presented without further handling implies that APC with limited processing capacity could be involved in presentation of such small peptides. The different Ia-positive APC of the lymphoid organs may interact to different extents with protein antigens and collaborate with each other to bring about an effective stimulation of the clones of helper T cells. The macrophage, being the most ubiquitous cell and the one capable of interacting with many proteins, is our candidate as the major APC involved in the recruitment and enlargement of clones T cells. The observations that macrophages can release proteins partially altered implies that there may be cooperativity among the various APC. Data for this have been obtained. Most likely B cells will be found to have a limited capacity to present all antigens because of their inherent difficulties in internalizing large particulate materials. In such instances, B cells may interact with the solubilized proteins released by the macrophages. The same may apply to the Langerhans/dendritic cells.(ABSTRACT TRUNCATED AT 400 WORDS)

The antigenic structure of proteins: a reappraisal

Abstract: Proteins are one of the most abundant and diverse classes of antigens to which the immune system can respond. These include trarisplantation antigens, anti­ gens of infectious and parasitic organisms, and allergens. An understanding of host defense mechanisms and of the ability to distinguish self from nonself requires a knowledge of the structural basis for protein antigenicity. The advent of hybridoma technology ( 1 ) to produce monoclonal antibodies, each of which

The Role of Arachidonic Acid Oxygenation Products in Pain and Inflammation

Abstract: Arachidonic acid oxygenation products were for many years held to be syn­ onymous with prostaglandins, but more recently they have been shown to include thromboxane A2 and a multitude of lipoxygenase pathway products, most notably the leukotrienes In their review of inflammatory mediators in the first volume of this series, Larsen & Henson (1) provided a broad per­ spective on how prostaglandins and leukotrienes play a central, often syner­ gistic role with other mediators, both in the expression of the efferent limb of immune-based inflammatory responses and in acute inflammatory responses where specific immunity does not have a primary role Prostaglandins and leukotrienes are produced by most, if not all cells, par­ ticipating in the afferent and efferent limbs of the immune system during host defense and inflammatory responses Their formation depends on the deacy­ lation of arachidonic acid from cellular phospholipids catalyzed by the activity

Heterogeneity of natural killer cells

Abstract: Natural killer cells were discovered about ten years ago (1-5) during studies of cell-mediated cytotoxicity. Although investigators expected to find specific cytotoxic activity of tumor-bearing individuals against autologous tumor cells or against allogeneic tumors of similar or the same histologic type, appreciable cytotoxic activity was observed with lymphocytes from normal individuals. Since this time, the studies of natural killer cells have expanded into a broad and multifaceted research area, stimulated by the increasing indications that these cells may play important roles in natural host resistance against cancer and infectious diseases (6-24). With the wide array of recent studies related to natural cell-mediated cytotoxicity, there has been considerable diversity in the terminology related to the effector cells and consequently some confusion in the literature. However, at a recent workshop devoted to the study of natural killer cells, a consensus definition for these effector cells was developed (25). Natural killer (NK) cells were defined as effector cells with spontaneous cyto­ toxicity against various target cells; these effector �ells lack the properties of classical macrophages, granulocytes, or cytotoxic T lymphocytes (CTL); and the observed cytotoxicity does not show restriction related to the major his­ tocompatibility complex (MHC). This definition is sufficiently broad to include not only "classical" NK cells but also other natural effector cells such as natural cytotoxic (NC) cells. The workshop participants agreed that the obser­ vations relating to the development of cytotoxic cells in culture [e.g. lectin­ activated killers (LAK), anomalous killers (AK)] remain difficult to interpret and that, for the moment, it is best to categorize separately cultured or activated cells with cytotoxic reactivity that cannot be classified as CTL. Such culture-

Suppressor cells and immunoregulation

Abstract: We have described a model system of immunoregulation in which gene products associated with both the major histocompatibility complex and the heavy-chain immunoglobulin gene complex guide a series of cellular interactions. The Igh genetic restrictions may represent the use of internal images of antigen and idiotype as suppressor-T cell receptors. The data indicate that the T-cell and B-cell Igh products are distinct. The T cell-derived idiotype-like determinants are used for suppressor-T cell communications. The MHC restrictions generally involve the I-J subregion. These restrictions are imposed by the presentation of antigen or suppressor factor by specialized populations of I-J bearing accessory cells. The role of MHC products in the induction of suppressor cells has several homologies with the mechanisms responsible for the induction of H-2-restricted helper cells. First, I-region products on specialized presenting cells determine the specificity and genetic restrictions of the T cells. Thus, recognition of antigen in the context of I-A and I-E products is required for helper-T cell induction, and similarly the various suppressor-T cell subsets recognize antigen or suppressor factor presented in the context of I-J subregion-encoded antigens. Furthermore, the data suggest that the suppressor cells bear receptors for self I-J products. As an additional analogy between suppressor and helper cells, we have shown that in H-2-heterozygous F1 animals at least two populations of suppressor cells can be induced, one specific for each parental H-2 haplotype. The NP and ABA suppressor-cell pathways consist of multiple cellular elements, including at least three and possibly four distinct T-cell populations and two or more distinctive accessory cell populations. These are summarized in Figure 1. The specific soluble suppressor factors produced by each suppressor-T cell subset are involved in cellular communication processes. The terminal phases of the suppressor-cell cascade are antigen dependent but involve nonspecific bystander effects. In this review we have indicated the numerous homologies between the data in the hapten systems studied in our laboratories and the various other suppressor-cell models previously described in the literature.

Regulation of IgE synthesis

Abstract: The IgE antibody response to protein antigens shares mechanisms with the IgM and IgC antibody responses to T-dependent antigens. However, the IgE response in experimental animals has several characteristics not easily dem­ onstrated in the IgG response. The IgE antibody response is obtained under restricted conditions and is highly dependent on the adjuvant employed. Bor­ detella pertussis vaccine (BP) and aluminum hydroxide gel (alum) are effec­ tive adjuvants for the IgE antibody response, while complete Freund's adjuvant (CFA) is less effective. Even when a high-responder mouse strain is immu­ nized with a potent immunogen together with an appropriate adjuvant, an increase in the dose of immunogen makes the IgE antibody response transient and causes a dissociation between the IgG and IgE antibody responses ( 1 ). Thus, a persistent IgE antibody response is obtained only when a high-responder strain is immunized with a minute dose of a potent immunogen together with an appropriate adjuvant. The IgE response is controlled not only by Ir-genes but also by another gene. Some strains, such as SJL, cannot form IgE antibodies to conventional antigens, in spite of a substantial IgG antibody response (2). Breeding exper­ iments showed that this genetic control is not linked to H-2 complex. Another unique aspect of the IgE antibody response is that the antibody response is selectively enhanced by low-dose X irradiation of rodents or by treatment of the animals with cyclophosphamide (3, 4). Even low-responder mouse strains, such as SlL, produce IgE antibodies if they are irradiated prior to immunization. In both humans and experimental animals, infection with some nematodes enhances the IgE synthesis (5, 6). Infection of antigen-primed

Natural Suppressor (NS) Cells, Neonatal Tolerance, and Total Lymphoid Irradiation: Exploring Obscure Relationships

Abstract: Although several laboratories have shown that the appearance of naturally occurring suppressor cells in the spleens of neonatal or irradiated mice is temporarily related to the ease of induction of tolerance, the characteristics of these cells and their regulatory functions have been poorly understood until recently. The experimental data reviewed herein suggests that these cells are related to NK cells with regard to surface phenotype but differ with regard to function. The natural suppressor (NS) cells appear only briefly during the early maturation of the lymphoid tissues but can be induced in adults by manipulation of the lymphoid tissues with certain treatment regimens such as total lymphoid irradiation (TLI). In addition, the NS cells can be propagated and cloned in long-term tissue culture, thereby allowing a more detailed investigation of their properties. The cells have the unique feature of inhibiting the antigen-specific cytolytic arm of alloreactive immune responses but leaving intact the antigen-specific suppressive arm. In this way, alloreactions in the regulatory milieu of NS cells generate large numbers of antigen-specific suppressor cells that can maintain tolerance in vivo. Thus the NS cells may play an important role in the development of host-vs-graft and graft-vs-host tolerance in allogeneic bone marrow chimeras during the "window" of tolerance in which neonate and TLI-treated mice accept the infused allogeneic cells.

Chemoattractant Receptors on Phagocytic Cells

Abstract: Chemoattractant receptors on leukocytes can trigger a number of cellular responses, including the cytoskeletal reorganization, changes in cell shape, directed motility, lysosomal enzyme secretion, and activation of the respiratory burst. The dose of chemoattractants required to induce motility-related functions is generally at least ten-fold smaller than the dose required to initiate secretory and respiratory burst activities. This finding and other pharmacological evidence clearly indicate that the two types of functions (i.e. motility and secretion) are regulated differently and can be divergently modified by drugs. The affinity of the oligopeptide chemoattractant receptor on polymorphonuclear leukocytes and macrophages is heterogeneous and dynamically regulated by guanine nucleotides and prior agonist exposure. High- and low-affinity forms of the oligopeptide receptor have been identified by direct binding studies. Our data suggest that low doses of agonists can initiate interconversion of low- and high-affinity states of that portion of chemoattractant receptors regulated by guanine nucleotides. On the other hand, high doses of agonists sufficient to induce chemotactic desensitization, lysosomal enzyme secretion, and the respiratory burst lead to the formation of a new population of high-affinity receptors. These binding sites are insensitive to the effects of guanine nucleotides and appear to be rapidly internalized. Transmethylation reactions mediated by S-adenosyl methionine are required for the activation of a phospholipase and release of arachidonate from leukocytes by chemotactic factors. We suggest that release of arachidonate from membrane phospholipid activates and translocates a cytosolic but loosely membrane-associated protein kinase C into the membrane and that this kinase participates in stimulus-response coupling of chemoattractant receptors.

Complement and Bacteria: Chemistry and Biology in Host Defense

Abstract: an enormous expansion in our understanding of the details of complement biochemistry and in our appreciation of the role of complement proteins in biologic phenomena. In this review we explore one important aspect of complement function-the role of complement in host defense against bacterial infection. We examine the mechanisms that govern the interaction of complement with bacteria, the role of complement as one of the principal heat-labile opsonin systems in serum, and the events that govern the ability of complement proteins to attack the bacterial cell wall and to lyse the microorganism. We attempt to acquaint the reader with the major recent developments in complement action and biology, assuming a fairly detailed knowledge of complement biochemistry and protein structure.

The human T-cell receptor.

Abstract: Recent studies using cloned antigen-specific T lymphocytes and monoclonal antibodies directed at their various surface glycoprotein components have led to the identification of the human T-cell antigen receptor as a surface complex comprised of a clonotypic 90-kD Ti heterodimer and the invariant 20- and 25-kD T3 molecules. Approximately 30,000-40,000 Ti and T3 molecules exist on the surface of human T lymphocytes. These glycoproteins are acquired and expressed during late thymic ontogeny, thus providing the structural basis for immunologic competence. The alpha and beta subunits of Ti bear no precursor-product relationship to one another and are encoded by separate genes. Moreover, the presence of unique peptides following proteolysis of different Ti molecules isolated by non-cross-reactive anticlonotypic monoclonal antibodies supports the notion that variable regions exist within both the alpha and the beta subunits. N-Terminal amino acid sequencing and molecular cloning of the Ti beta subunit further show that it bears an homology to the first V-region framework of immunoglobulin light chains and represents the product of a gene that rearranges specifically in T lymphocytes. Triggering of the T3-Ti receptor complex gives rise to specific antigen-induced proliferation through an autocrine pathway involving endogenous IL-2 production, release, and subsequent binding to IL-2 receptors. The implications of these findings for understanding human T-cell growth and its regulation in disease states are discussed.

Collagen Autoimmune Arthritis

Abstract: The evidence is now fairly conclusive that collagen-induced arthritis in rodents is mediated by antitype II collagen autoimmunity. Arthritis is probably initiated by binding of antibodies to the surface of intact articular cartilage. Many of the major manifestations of arthritis, including synovial proliferation, pannus formation, marginal erosion of bone, and destruction of cartilage, can be duplicated by injection of isolated antitype II collagen antibodies. It is not known whether delayed hypersensitivity reactions to collagen can provoke similar lesions in the absence of antibody, but circumstantial evidence suggests they do not. Also clear is that not all anticollagen antibodies are capable of inducing arthritis. The minimal requirements for arthritogenic potential are currently under investigation but probably include the ability to bind native autologous type II collagen. Also IgM antibodies alone are either ineffective or are required in relatively higher concentrations than IgG for induction of arthritis. Autoimmunity to collagen is found in many spontaneous and induced rheumatic diseases other than collagen-induced arthritis. There is at present, however, no direct evidence that this autoimmunity actually contributes to the arthritic process. Nevertheless, the human disease most often associated with collagen autoimmunity is rheumatoid arthritis. In many respects the immune reactions detected in humans with rheumatoid arthritis parallel those of arthritis in rodents. That is, responsiveness is under the control of genes within or linked to the major histocompatibility locus. High responders are limited to only a few haplotypes. Cell-mediated reactions are most vigorous in response to denatured collagen and probably have limited specificity for the type of collagen recognized. Antibodies may be separated into at least two groups, one with broad specificity for denatured collagen and a second highly specific for conformation-dependent determinants on native type II collagen. The latter antibodies are of most interest to researchers because they may be like those that induce arthritis in rodents. There is also ample evidence that antibodies are deposited in the joints of rheumatoid arthritis patients, although the specificity of these antibodies is unknown. Generally, collagen-induced arthritis is a model of antibody-initiated autoimmunity arthritis. Specifically, it is a model of type II collagen autoimmune arthritis. In consideration of its extraarticular manifestations, it may justifiably be referred to as type II collagen autoimmune disease.(ABSTRACT TRUNCATED AT 400 WORDS)

Transplantation of pancreatic islets

Abstract: The complications in diabetes mellitus develop over many years. They involve the eye, kidney, and cardiovascular system and may lead to blindness, renal failure, and early development of arteriosclerosis. Apparently these compli­ cations are secondary to the diabetic state and are due to the inability of our present forms of therapy to maintain the blood sugar within normal limits at all times. The insulin-producing cells (beta cells) in the islets of Langerhans of insulin-dependent diabetics have either been destroyed or altered by mech­ anisms unknown at present. Thus, a possible therapeutic approach would be to transplant normal islets into diabetic patients with the hope that the trans­ plants would maintain normoglycemia and prevent or arrest the development of diabetic complications. This approach requires that rejection of the islet transplants be prevented by procedures other than continuous immunosup­ pressive therapy. During the past few years, several procedures have been developed that prevent rejection of islet allografts and xenografts in rats and mice without requiring continuous immunosuppression of the recipient animals. In this review we describe the islet transplant model as developed with isografts, the concepts and procedures used for prevention of islet rejection, and the present status of islet transplantation as a possible therapeutic approach to human diabetes.

Transfer and expression of immunoglobulin genes.

Abstract: Over the last two decades a great deal of information has accumulated on the structure and function of the immunoglobulin molecules. Structural studies of the myeloma proteins defined the variable and constant regions. Analysis of the variable regions showed the existence of hypervariable regions (1) and began to give insight into the nature of the interaction between the antibody molecule and its specific antigen. The existence of both variable and constant regions on the same molecule gave rise to the concept \"two genes-one polypeptide chain\" (2), which challenged then-accepted genetic ideas. With the advent of modern molecular biologic techniques it became clear that the immunoglobulin (Ig) molecule, both heavy and light chain, was encoded by multiple DNA segments. In order to generate a gene encoding a functional Ig molecule, somatic rearrangements of distinct DNA segments must take place. For a complete light-chain gene a V region must be brought next to a J segment to create an active transcription unit. For a heavy-chain gene, V, D, and J segments must be assembled next to a constant-region gene; the initial constant-region gene utilized is the j.1 gene. In addition, during immune response maturation heavy-chain class switching can occur, whereupon VDJ is recom-