Polyreactive antibodies in adaptive immune responses to viruses

B cells express immunoglobulins on their surface where they serve as antigen receptors. When secreted as antibodies, the same molecules are key elements of the humoral immune response against pathogens such as viruses. Although most antibodies are restricted to binding a specific antigen, some are polyreactive and have the ability to bind to several different ligands, usually with low affinity. Highly polyreactive antibodies are removed from the repertoire during B-cell development by physiologic tolerance mechanisms including deletion and receptor editing. However, a low level of antibody polyreactivity is tolerated and can confer additional binding properties to pathogen-specific antibodies. For example, high-affinity human antibodies to HIV are frequently polyreactive. Here we review the evidence suggesting that in the case of some pathogens like HIV, polyreactivity may confer a selective advantage to pathogen-specific antibodies.     

NOD-like receptors: Ancient sentinels of the innate immune system

NOD-like receptors (NLRs) comprise a family of cytosolic proteins that have been implicated as ancient cellular sentinels mediating protective immune responses elicited by intracellular pathogens or endogenous danger signals. Genetic variants in NLR genes have been associated with complex chronic inflammatory barrier diseases (e.g. Crohn disease, bronchial asthma). In this review, we focus on the molecular pathophysiology of NLRs in the context of chronic inflammatory diseases and pinpoint recent advances in the evolutionary understanding of NLR biology. We propose that the field of NLRs may serve as a prototype for how a comprehensive understanding of an element of the immunological barrier will eventually lead to the development of targeted diagnostic, therapeutic and/or preventive strategies. Received 29 October 2007; received after revision 10 December 2007; accepted 19 December 2007     

Soluble polysialylated NCAM: a novel player of the innate immune system in the lung

Posttranslational modification of the neural cell adhesion molecule (NCAM) by polysialic acid (polySia) is well studied in the nervous system and described as a dynamic modulator of plastic processes like precursor cell migration, axon fasciculation, and synaptic plasticity. Here, we describe a novel function of polysialylated NCAM (polySia-NCAM) in innate immunity of the lung. In mature lung tissue of healthy donors, polySia was exclusively attached to the transmembrane isoform NCAM-140 and located to intracellular compartments of epithelial cells. In patients with chronic obstructive pulmonary disease, however, increased polySia levels and processing of the NCAM carrier were observed. Processing of polysialylated NCAM was reproduced in a mouse model by bleomycin administration leading to an activation of the inflammasome and secretion of interleukin (IL)-1β. As shown in a cell culture model, polySia-NCAM-140 was kept in the late trans-Golgi apparatus of lung epithelial cells and stimulation by IL-1β or lipopolysaccharide induced metalloprotease-mediated ectodomain shedding, resulting in the secretion of soluble polySia-NCAM. Interestingly, polySia chains of secreted NCAM neutralized the cytotoxic activity of extracellular histones as well as DNA/histone-network-containing “neutrophil extracellular traps”, which are formed during invasion of microorganisms. Thus, shedding of polySia-NCAM by lung epithelial cells may provide a host-protective mechanism to reduce tissue damage during inflammatory processes.     

Analysis of the immune system with transgenic mice: T cell development

Transgenic mice carrying functionally rearranged T cell receptor genes have contributed significantly to our knowledge of T cell development and thymic positive and negative selection processes. In addition, TCR-transgenic mice have been used to investigate mutations affecting thymocyte development, like scid and lpr. Gene targeting by homologous recombination will allow to analyze more specifically the molecular mechanisms underlying thymic selection and peripheral tolerance.     

Analysis of the immune system with transgenic mice: T cell development

Transgenic mice carrying functionally rearranged T cell receptor genes have contributed significantly to our knowledge of T cell development and thymic positive and negative selection processes. In addition, TCR-transgenic mice have been used to investigate mutations affecting thymocyte development, likescid andlpr. Gene targeting by homologous recombination will allow to analyze more specifically the molecular mechanisms underlying thymic selection and peripheral tolerance.     

Inflammation and immune system interactions in atherosclerosis

Cardiovascular disease (CVD) is the leading cause of mortality worldwide, accounting for 16.7 million deaths each year. The underlying cause of the majority of CVD is atherosclerosis. In the past, atherosclerosis was considered to be the result of passive lipid accumulation in the vessel wall. Today’s picture is far more complex. Atherosclerosis is considered a chronic inflammatory disease that results in the formation of plaques in large and mid-sized arteries. Both cells of the innate and the adaptive immune system play a crucial role in its pathogenesis. By transforming immune cells into pro- and anti-inflammatory chemokine- and cytokine-producing units, and by guiding the interactions between the different immune cells, the immune system decisively influences the propensity of a given plaque to rupture and cause clinical symptoms like myocardial infarction and stroke. In this review, we give an overview on the newest insights in the role of different immune cells and subtypes in atherosclerosis.     

Adaptation in the innate immune system and heterologous innate immunity

The innate immune system recognizes deviation from homeostasis caused by infectious or non-infectious assaults. The threshold for its activation seems to be established by a calibration process that includes sensing of microbial molecular patterns from commensal bacteria and of endogenous signals. It is becoming increasingly clear that adaptive features, a hallmark of the adaptive immune system, can also be identified in the innate immune system. Such adaptations can result in the manifestation of a primed state of immune and tissue cells with a decreased activation threshold. This keeps the system poised to react quickly. Moreover, the fact that the innate immune system recognizes a wide variety of danger signals via pattern recognition receptors that often activate the same signaling pathways allows for heterologous innate immune stimulation. This implies that, for example, the innate immune response to an infection can be modified by co-infections or other innate stimuli. This “design feature” of the innate immune system has many implications for our understanding of individual susceptibility to diseases or responsiveness to therapies and vaccinations. In this article, adaptive features of the innate immune system as well as heterologous innate immunity and their implications are discussed.     

Prolactin, growth hormone and the immune system in humans

Prolactin (PRL) and growth hormone (GH) qualify as lymphoid growth and differentiation factors. Yet, long-standing hyper- or hyposecretion of PRL or GH does not induce any significant alteration of the immune system. Subclinical changes in laboratory parameters (such as chemotaxis or phagocytosis by granulocytes or macrophages or natural killer cell activity) have been reported in some of these conditions. The GH-insulin-like growth factor (IGF)-I axis is dysregulated in ageing, in catabolic states and in critical illness. Immune parameters, such as infection rate, are being monitored during clinical trials with GH or IGF-I. Hyperprolactinaemia may play an aggravating role in systemic lupus erythematosus, in autoimmune thyroiditis and in other autoimmune diseases. The patient may benefit from increased alertness about interactions between the endocrine and immune systems.     

Interactions between mesenchymal stem cells and the immune system

In addition to being multi-potent, mesenchymal stem cells (MSCs) possess immunomodulatory functions that have been investigated as potential treatments in various immune disorders. MSCs can robustly interact with cells of the innate and adaptive immune systems, either through direct cell–cell contact or through their secretome. In this review, we discuss current findings regarding the interplay between MSCs and different immune cell subsets. We also draw attention to the mechanisms involved.     

Recognition of bacterial peptidoglycan by the innate immune system

The innate immune system recognizes microorganisms through a series of pattern recognition receptors that are highly conserved in evolution. Peptidoglycan (PGN) is a unique and essential component of the cell wall of virtually all bacteria and is not present in eukaryotes, and thus is an excellent target for the innate immune system. Indeed, higher eukaryotes, including mammals, have several PGN recognition molecules, including CD14, Toll-like receptor 2, a family of peptidoglycan recognition proteins, Nod1 and Nod2, and PGN-lytic enzymes (lysozyme and amidases). These molecules induce host responses to microorganisms or have direct antimicrobial effects.Received 15 January 2003; received after revision 28 February 2003; accepted 26 March 2003     

Effects of cadmium on the immune system of mice

Summary Chronic oral exposure of mice to Cd⁺⁺ inhibits cell-mediated immunity of delayed type hypersensitivity induced by sheep red blood cells (SRBC). No effect was detected on humoral immune response to SRBC. Spleen cells derived from mice exposed to Cd⁺⁺ showed in vitro enhanced response to T and B cell mitogens. These results demonstrate that Cd⁺⁺ exposure alters the immune system of mice.Dedicated to Prof. Georg Henneberg on the occasion of his 70th anniversary on 12.10.1978.Acknowledgments. Supported by a grant from the Umweltbundesamt. We thank Ms Odenwald, Ms Schulz, Klinikum Steglitz, and Ms Emeis, Robert Koch-Institut Abt. Immunologie, for the excellent technical assistance.     

Analysis of the immune system with transgenic mice: B cell development and lymphokines

Over the last decade transgenic mice expressing genes relevant for the immune system have been generated. Transgenic expression of immunoglobulin heavy and/or light chain genes of different isotypes and different specificities have helped to better understand phenomena relevant to B cell development such as allelic exclusion of immunoglobulins and B cell tolerance. Transgenic mice expressing interleukin genes have also been used to study the ways of action of these important growth and differentiation factors in the context of the mouse immune system.     

Analysis of the immune system with transgenic mice: B cell development and lymphokines

Over the last decade transgenic mice expressing genes relevant for the immune system have been generated. Transgenic expression of immunoglobulin heavy and/or light chain genes of different isotypes and different specificities have helped to better understand phenomena relevant to B cell development such as allelic exclusion of immunoglobulins and B cell tolerance. Transgenic mice expressing interleukin genes have also been used to study the ways of action of these important growth and differentiation factors in the context of the mouse immune system.     

The threshold osmotic reactivity of the hypothalamo-hypophyseal antidiuretic system and of the thirst mechanism

Résumé On a examiné la réactivité osmotique du système antidiurétique hypothalamo-hypophysaire et du mécanisme de la soif chez des chiens non narcotisés. Chez tous les animaux examinés, le système antidiurétique s'est montré plus sensible aux stimulus osmotiques que le mécanisme de la soif. On peut supposer que c'est le système antidiurétique qui est activé en premier lieu lors d'un déficit d'eau.     

A histochemical study of immune destruction of the lymphopoietic system

Zusammenfassung Eine auffallende Zunahme von -Galactosidase kommt im lymphoetischen Säuger-Gewebe im Zusammenhang mit der immunologischen Auflösung dieses Systems vor. Die hernach auftretende Proliferation retikulärer Zellen steht im Zusammenhang mit der Regeneration dieses Organs. Diese Zellen enthalten eine reichliche Anzahl lysosomatischer Enzyme (z.B. -Galactosidase).

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This investigation was supported in part by Public Health Service Research Grants Nos. Ca 02624 and CA 02903 from the National Cancer Institute and in part by an institutional grant to the Detroit Institute of Cancer Research Division of the Michigan Cancer Foundation from the United Foundation of Greater Detroit, and Detroit General Hospital Research Corporation. Newaygo County Cancer Association. We wish to express our gratitude for stenographic assistance to Mrs.Connie Malucusky and MissPatricia Warzocha.     

Effects of cadmium on the immune system of mice.

Chronic oral exposure of mice to Cd++ inhibits cell-mediated immunity of delayed type hypersensitivity induced by sheep red blood cells (SRBC). No effect was detected on humoral immune response to SRBC. Spleen cells derived from mice exposed to Cd++ showed in vitro enhanced response to T and B cell mitogens. These results demonstrate that Cd++ exposure alters the immune system of mice.     

CD1d and natural T cells: how their properties jump-start the immune system

Cellular and humoral immune mechanisms recruited to defend the host from infectious agents depend upon the early immune events triggered by antigen. The cytokine milieu within which the immune response matures is the most important of many factors that govern the nature of the immune response. Natural T cells, whose function is controlled by CD1d molecules, are an early source of cytokines that can bestow type 1 or type 2 differentiative potential upon helper T lymphocytes. This review attempts to illuminate the glycolipid antigen presentation properties of CD1d, how CD1d controls the function of natural T cells and how CD1d and natural T cells interact to jump start the immune system. CD1d is postulated to function as a sensor, sensing alterations in cellular lipid content by virtue of its affinity for such ligands. The presentation of a neo-self glycolipid, presumably by infectious assault of antigen-presenting cells, activates natural T cells, which promptly release pro-inflammatory and anti-inflammatory cytokines and jumpstart the immune system. Received 10 July 2000; received after revision 16 October 2000, accepted 16 November 2000