Stress proteins in neural cells: functional roles in health and disease

Heat shock proteins (HSPs) or stress proteins participate in protein synthesis, protein folding, transport and translocalization processes. Stress situations trigger a heat shock response leading to their induction. Similarly, they can be upregulated by impairment of the proteasomal degradation pathway. The upregulation of stress proteins is an important step in prevention of protein aggregation and misfolding after stress, and also is essential during development and differentiation. A number of HSPs are constitutively or inducibly expressed in the nervous system and connected to protection of nerve cells and glia. The cytoskeleton is affected by stress, and HSPs have been shown to interact with the cytoskeleton in normal cells and to assist proper assembly, spatial organization and cross-linking properties. The integrity of the cytoskeleton is disturbed in many neurodegenerative disorders, and filamentous cytoplasmic inclusion bodies, containing a variety of HSPs, are observed. This review summarizes the recent literature on the presence and induction of HSPs in neural cells, and their possible functional roles in health and disease are discussed.     

The role of M cells in mucosal immunity

Mucosa-associated lymphoid tissue in the respiratory and digestive tracts are covered by a specialized epithelium, the follicle-associated epithelium, which includes M cells, which are specialized for the uptake and transcytosis of macromolecules and microorganisms. Following transcytosis, antigens are released to cells of the immune system in lymphoid aggregates beneath the epithelium where antigen processing and presentation and stimulation of specific B and T lymphocytes are achieved. Circulation of the lymphoid cells enables their homing to their original, and other, mucosal sites where they exert the effector function. Such a response may be dominated by secretory immunoglobulin A release and may include cytotoxic T lymphocyte action. Binding of particles to the apical M cell membrane may be nonspecific or due to specific interaction between molecules such as integrins and lectins. Exploiting the specific binding to M cells is an aim for mucosal vaccination, for example to increase the efficiency of uptake of an oral vaccine by its conjugation to an M-cell-specific molecule. Alternatively, an M-cell-specific live vector, such as attenuated Salmonella bacteria, may be used to deliver epitopes of other organisms. Mucosal vaccination efficiency may also be enhanced by a temporary increase in the number of M cells. Therefore, investigation of the properties and ontogeny of M cells must be pursued to allow the development of better mucosal vaccines for the future.     

The balance between immunity and tolerance: The role of Langerhans cells

Langerhans cells are immature skin-homing dendritic cells that furnish the epidermis with an immune surveillance system, and translate information between the internal and external milieu. Dendritic cells, in particular Langerhans cells, are gaining prominence as one of the potential principal players orchestrating the decision between immunity and tolerance. Langerhans cells capture aberrant self-antigen and pathogen-derived antigen for display to the efferent immune response. Recent evidence suggests redundancy in the antigen-presenting function of Langerhans cells, with dermal dendritic subsets capable of fulfilling an analogous role. There is mounting evidence that Langerhans cells can cross-prime T cells to recognize antigens. Langerhans cells are proposed to stimulate T regulatory cells, and are implicated in the pathogenesis of cutaneous T cell lymphoma.The phenotype of Langerhans cells, which may be tolerogenic or immunogenic, appears to depend on their state of maturity, inciting immunogen and cytokine environment, offering the potential for manipulation in immunotherapy. Received 6 August 2008; received after revision 18 September 2008; accepted 13 October 2008     

The role of sialic acid in determining the life-span of circulating cells and glycoproteins

Summary The role of sialic acid in determining the life of circulating cells and glycoproteins is reviewed and an attempt is made to assess its real importance and to interpret the desialylation pathway. An overall view of factors, including desialylated glycoprotein fragments, that may regulate hepatic synthesis of glycoproteins is presented.Acknowledgments. The author wishes to thank Drs.A. Viti andG. P. Pessina for helpful discussion and comments.     

The role of HLA-G in immunity and hematopoiesis

The non-classical HLA class I molecule HLA-G was initially shown to play a major role in feto–maternal tolerance. Since this discovery, it has been established that HLA-G is a tolerogenic molecule which participates to the control of the immune response. In this review, we summarize the recent advances on (1) the multiple structures of HLA-G, which are closely associated with their role in the inhibition of NK cell cytotoxicity, (2) the factors that regulate the expression of HLA-G and its receptors, (3) the mechanism of action of HLA-G at the immunological synapse and through trogocytosis, and (4) the generation of suppressive cells through HLA-G. Moreover, we also review recent findings on the non-immunological functions of HLA-G in erythropoiesis and angiogenesis.     

Janus head: the dual role of HLA-G in CNS immunity

The central nervous system (CNS) is considered an immune-privileged organ that maintains an adaptable immune surveillance system. Dysregulated immune function within the CNS contributes to the development of brain tumor growth, and robust immune activation results in excessive inflammation. Human lymphocyte antigen-G (HLA-G) proteins with tolerogenic immunoreactivity have been implicated in various pathophysiological processes including immune surveillance, governing homeostasis and immune regulation. In this review, we describe the wealth of evidence for the involvement of HLA-G in the CNS under physiological and pathological conditions. Further, we review regulatory functions that may be applicable as beneficial strategies in the therapeutic manipulation of immune-mediated CNS immune responses. Additionally, we try to understand how this molecule cooperates with other CNS-resident cells to maintain normal immune homeostasis, while still facilitating the development of the appropriate immune responses.     

The role of repair in radiobiology

Apart from cancer and mutation induction, radiobiological effects on mammals are mostly attributable to cell 'death', defined as loss of proliferative capacity. Survival curves relate retention of that capacity to radiation dose, and often manifest a quasi-threshold ('shoulder'). The shoulder is attributable to an initial mechanism of repair ('Q-repair') which is gradually depleted as dose increases. Another form of repair, which is not depleted ('P-repair'), increases the dose required to deliver an average of one lethal event per cell (dose 'D0'). Neither form of repair can unambiguously be linked with repair of defects in isolated DNA. An important initial lesion may well be disruption of the complex structural relationship between the DNA, nuclear membrane and associated proteins. One form of P-repair may be restoration of that structural relationship.     

Mononuclear phagocyte-mediated antifungal immunity: the role of chemotactic receptors and ligands

Over the past two decades, fungal infections have emerged as significant causes of morbidity and mortality in patients with hematological malignancies, hematopoietic stem cell or solid organ transplantation and acquired immunodeficiency syndrome. Besides neutrophils and CD4⁺ T lymphocytes, which have long been known to play an indispensable role in promoting protective antifungal immunity, mononuclear phagocytes are now being increasingly recognized as critical mediators of host defense against fungi. Thus, a recent surge of research studies has focused on understanding the mechanisms by which resident and recruited monocytes, macrophages and dendritic cells accumulate and become activated at the sites of fungal infection. Herein, we critically review how a variety of G-protein coupled chemoattractant receptors and their ligands mediate mononuclear phagocyte recruitment and effector function during infection by the most common human fungal pathogens.     

Staphylococcus epidermidis in the circulating blood of normal and thrombocytopenic human subjects: Immunological data

Summary Immunological studies, performed with human sera and rabbit antisera upon some strains ofStaph. epidermidis carried in the circulating blood of normal and thrombocytopenic subjects, indicate that the reactivity is very low and almost completely related to antigenic properties common toStaph. aureus.     

Neurosecretory cells in the ventral nerve cord of leech (Hirudinaria granulosa)

Zusammenfassung Nachweis von 3 Typen neurosekretorischer Zellen im Bauchmark der indischen BlutegelHirudinaria granulosa undTheromyzon rude.     

Dynamic EpCAM expression on circulating and disseminating tumor cells: causes and consequences

Formation of metastasis is the most important and lethal step in cancer progression. Circulating and disseminated cancer cells (CTCs/DTCs) in blood and bone marrow are considered as potential metastases-inducing cells. Their detection and characterization has, therefore, become a field of major interest in translational and clinical research in oncology. The main strategy to detect these cells relies thus far on the epithelial characteristics of carcinoma cells and epithelial cell adhesion molecule (EpCAM) represents the most commonly used epithelial marker to capture CTCs/DTCs. Recent data, however, demonstrated a dynamic expression of EpCAM associated with a loss during epithelial-to-mesenchymal transition. The present review summarizes the potential mechanisms and reasons for a dynamic expression of EpCAM.     

The role of Sonic hedgehog in neural tube patterning

In the developing neural tube of vertebrate embryos, many types of neural and nonneuronal cells differentiate in response to the secreted signalling molecule, Shh. Shh shows a spatially restricted pattern of expression in cells located at the ventral midline, yet governs the differentiation of diverse cell types throughout the ventral half of the neural tube. Here, we describe how the distinct fate assumed by cells in response to Shh is dependent upon their position with respect to both the dorso-ventral and anterior-posterior axes of the neural tube and describe the ways in which a single factor, Shh, is able to pattern the developing nervous system. We first discuss the evidence that Shh does impose ventral identity on cells in the neural tube, then focus on the role of a graded Shh signal in patterning the neural tube and finally discuss the interaction of Shh with other factors that affect its signalling outcome.     

L- and conventional forms of micrococci in the circulating blood of thrombocytopenic patients.

The multiplication of Gram-positive Cocci originating from L-forms carried by platelets of autoimmune thrombocytopenic patients, may be attributed to the primary platelet damage enhanced following interaction with bacteria.     

The role of sialic acid in determining the survival of circulating interferon

Summary Rabbit interferon has been extensively desialylated and its metabolic behaviour has been evaluated in the rabbit. The half-life of asialointerferon is significantly shorter than the native interferon and its urinary excretion becomes negligible. Moreover the rapid uptake of asialointerferon by the isolated and perfused rabbit liver, suggests a hitherto unsuspected catabolic pathway for this glycoprotein.This work was supported by a grant from the Consiglio Nazionale delle Ricerche, Roma (subproject on antiviral therapy), contract No. 76.00646.84).     

Endothelial cells as antigen-presenting cells: role in human transplant rejection

The immunological properties of human endothelial cells suggest they perform a pivotal role in acute and chronic rejection following solid organ transplantation. In this review the basic features of acute and chronic rejection are described as are the cellular and molecular requirements for antigen presentation. Traditionally, antigen-presenting cells are considered to be bone marrow-derived cells. However, these conclusions have been derived from rodent models of allograft rejection where bone marrow-derived passenger leukocytes are the only source of donor major histocompatibility complex (MHC) class II in the grafted organ. In contrast, in humans, virtually all the microvascular and small vessel endothelial cells are ‘constitutively’ positive for MHC class II antigens. The phenotypic properties of human endothelial cells, their response to cytokines and their ability to stimulate resting T cells are described. Unlike bone marrow-derived antigen presenting cells (APCs), which utilise B7/CD28 interactions, human endothelial cells utilise lymphocyte function antigen 3 (LFA3)/CD2 pathways to stimulate T cells. They activate a CD45RO + B7-independent subpopulation of T cells. Their effect on allogeneic T cells is compared with other non-bone marrow-derived cells such as fibroblasts, epithelial cells and smooth muscle cells, which are unable to stimulate resting T cells. Evidence is presented suggesting that release of MHC and non-human leukocyte antigens (HLA) from endothelial cells stimulates an alloantibody and autoimmune response leading to chronic rejection. Received 30 March 1998; received after revision 4 May 1998; accepted 4 May 1998     

A method for the determination of thrombocyte aggregation in circulating rat blood

Zusammenfassung Das Ausmass einer experimentell induzierten Thrombozytenaggregation im strömenden Blut wird kontinuierlich bestimmt durch Messung des Blutdrucks vor und hinter einem extrakorporal in den arteriellen Kreislauf der Ratte aufgenommenen Filter. Die Aggregation wird durch Infusion von Adenosindiphosphorsäure (ADP) vor dem Filter induziert. Die Aggregate schliessen das Filter teilweise ab, was zu Änderungen im Blutdruck vor und hinter dem Filter führt. Aus diesen Änderungen lässt sich das Mass der Aggregation ermitteln. Es wurde gefunden, dass dieses durch die ADP-Gabe bedingt wird.