Immune physiology in tissue regeneration and aging, tumor growth, and regenerative medicine

The immune system plays an important role in immunity (immune surveillance), but also in the regulation of tissue homeostasis (immune physiology). Lessons from the female reproductive tract indicate that immune system related cells, such as intraepithelial T cells and monocyte-derived cells (MDC) in stratified epithelium, interact amongst themselves and degenerate whereas epithelial cells proliferate and differentiate. In adult ovaries, MDC and T cells are present during oocyte renewal from ovarian stem cells. Activated MDC are also associated with follicular development and atresia, and corpus luteum differentiation. Corpus luteum demise resembles rejection of a graft since it is attended by a massive influx of MDC and T cells resulting in parenchymal and vascular regression. Vascular pericytes play important roles in immune physiology, and their activities (including secretion of the Thy-1 differentiation protein) can be regulated by vascular autonomic innervation. In tumors, MDC regulate proliferation of neoplastic cells and angiogenesis. Tumor infiltrating T cells die among malignant cells. Alterations of immune physiology can result in pathology, such as autoimmune, metabolic, and degenerative diseases, but also in infertility and intrauterine growth retardation, fetal morbidity and mortality. Animal experiments indicate that modification of tissue differentiation (retardation or acceleration) during immune adaptation can cause malfunction (persistent immaturity or premature aging) of such tissue during adulthood. Thus successful stem cell therapy will depend on immune physiology in targeted tissues. From this point of view, regenerative medicine is more likely to be successful in acute rather than chronic tissue disorders

Elevated myc expression and c-myc amplification in spontaneously occurring B lymphoid cell lines

Recently, a minor subpopulation of murine B lymphocytes, Ly-1+ B cells, has been distinguished by its unique ontogeny, tissue distribution, and prominence in certain autoimmune and neoplastic B cell diseases. We have previously described a simple murine spleen culture system that results in the spontaneous and exclusive outgrowth of long-term Ly-1+ B cell lines (B Ly-1 cells). Here, we report that the immortal growth property of B Ly-1 cells correlates with a 10-45-fold elevation of steady-state myc RNA and 2-10-fold amplification of the c-myc locus. While c-myc amplification has been observed in malignant cell lines derived from several tissues of origin, its occurrence in lymphoid cells has not been previously reported. The consistent c-myc amplification in B Ly-1 cells may reflect a unique state of this locus in the Ly-1+ B lymphocyte lineage, and contribute to the spontaneous immortalization of this B cell population in vitro, and its apparent predilection for malignant transformation in vivo

Reversing T cell immunosenescence: why, who, and how

Immunosenescence is the term commonly used to describe the multifaceted phenomenon encompassing all changes occurring in the immune system during aging. It contributes to render older adults more prone to develop infectious disease and main age-related diseases. While age clearly imposes drastic changes in immune physiology, older adults have heterogeneous health and immune phenotypes. This confronts scientists and researcher to develop more age-specific interventions rather than simply adopting intervention regimes used in younger people and this in order to maintain immune protection in older adults. Thus, this review provides evidences of the central role played by cell-mediated immunity in the immunosenescence process and explores the means by which senescent state of the cell-mediated immune function could be identified and predicted using biomarkers. Furthermore considerations are given to recent advances made in the field of age-specific immune interventions that could contribute to maintain immune protection, to improve quality of life, and/or to promote healthy aging of the growing part of the populatio

Inositol phosphatase SHIP1 is a primary target of miR-155

MicroRNA-155 (miR-155) has emerged as a critical regulator of immune cell development, function, and disease. However, the mechanistic basis for its impact on the hematopoietic system remains largely unresolved. Because miRNAs function by repressing specific mRNAs through direct 3′UTR interactions, we have searched for targets of miR-155 implicated in the regulation of hematopoiesis. In the present study, we identify Src homology-2 domain-containing inositol 5-phosphatase 1 (SHIP1) as a direct target of miR-155, and, using gain and loss of function approaches, show that miR-155 represses SHIP1 through direct 3′UTR interactions that have been highly conserved throughout evolution. Repression of endogenous SHIP1 by miR-155 occurred following sustained over-expression of miR-155 in hematopoietic cells both in vitro and in vivo, and resulted in increased activation of the kinase Akt during the cellular response to LPS. Furthermore, SHIP1 was also repressed by physiologically regulated miR-155, which was observed in LPS-treated WT versus miR-155−/− primary macrophages. In mice, specific knockdown of SHIP1 in the hematopoietic system following retroviral delivery of a miR-155-formatted siRNA against SHIP1 resulted in a myeloproliferative disorder, with striking similarities to that observed in miR-155-expressing mice. Our study unveils a molecular link between miR-155 and SHIP1 and provides evidence that repression of SHIP1 is an important component of miR-155 biology

Optimizing rearing and welfare in Senegalese sole (Solea senegalesensis) broodstock: effect of ambient light intensity and handling time on stress response

Broodstock rearing conditions and handling procedures should be optimized in aquaculture species in order to benefit fish welfare and guarantee optimal conditions for spawning. In teleosts, basal cortisol levels display daily rhythms, oscillating along the 24 h of the day. In this sense, handling fish at different moments of the day may lead to different stress responses. The present study aimed at investigating the optimal rearing conditions for Senegalese sole broodstock, considering ambient light intensity and handling time. The optimal light intensity (50, 100 or 200 lx) was investigated by measuring fish cortisol levels and monitoring locomotor activity rhythms under each intensity tested. Results showed a significant increase in cortisol levels of fish exposed to 200 lx, when compared to values obtained under 100 lx, accompanied by changes in locomotor activity rhythms in both tanks under study. These results suggested that 200 lx may be too high as light intensity for this species, whereas 100 lx seems to be more adequate. Also, daily rhythms of stress response were investigated in breeders from different origins (Wild and first generation, G1). Basal cortisol levels and cortisol stress response after an acute stressor (air exposure) were monitored at two distinct moments of the day (Mid-Light and Mid-Dark). Basal levels were higher during the day in the wild group, while G1 fish seemed to have lost the daily fluctuations in basal cortisol plasma levels, as well as their daily rhythms of locomotor activity. Both groups showed lower stress responses during night-time, an indication that this is an adequate period of the day to handle this species. Senegalese sole breeders born in captivity presented more pronounced stress responses when compared to wild fish, reflecting their different life history in terms of stress challenges.FP7/SME/2008/1; UID/Multi/04326/2019; DL 57/2016/CP1361/CT0007; DL 57/2016/CP1361/CT0033info:eu-repo/semantics/publishedVersio

EROS is a selective chaperone regulating the phagocyte NADPH oxidase and purinergic signalling

EROS (essential for reactive oxygen species) protein is indispensable for expression of gp91phox, the catalytic core of the phagocyte NADPH oxidase. EROS deficiency in humans is a novel cause of the severe immunodeficiency, chronic granulomatous disease, but its mechanism of action was unknown until now. We elucidate the role of EROS, showing it acts at the earliest stages of gp91phox maturation. It binds the immature 58 kDa gp91phox directly, preventing gp91phox degradation and allowing glycosylation via the oligosaccharyltransferase machinery and the incorporation of the heme prosthetic groups essential for catalysis. EROS also regulates the purine receptors P2X7 and P2X1 through direct interactions, and P2X7 is almost absent in EROS-deficient mouse and human primary cells. Accordingly, lack of murine EROS results in markedly abnormal P2X7 signalling, inflammasome activation, and T cell responses. The loss of both ROS and P2X7 signalling leads to resistance to influenza infection in mice. Our work identifies EROS as a highly selective chaperone for key proteins in innate and adaptive immunity and a rheostat for immunity to infection. It has profound implications for our understanding of immune physiology, ROS dysregulation, and possibly gene therapy.</jats:p

Immunological basis of differences in disease resistance in the chicken

Genetic resistance to diseases is a multigenic trait governed mainly by the immune system and its interactions with many physiologic and environmental factors. In the adaptive immunity, T cell and B cell responses, the specific recognition of antigens and interactions between antigen presenting cells, T cells and B cells are crucial. It occurs through a network of mediator proteins such as the molecules of the major histocompatibility complex (MHC), T cell receptors, immunoglobulins and secreted proteins such as the cytokines and antibodies. The diversity of these proteins that mainly is due to an intrinsic polymorphism of the genes causes phenotypic variation in disease resistance. The well-known linkage of MHC polymorphism and Marek's disease resistance difference represents a classic model revealing immunological factors in resistance differences and diversity of mediator molecules. The molecular bases in any resistance variation to infectious pathogens are vaguely understood. This paper presents a review of the major immune mediators involved in resistance and susceptibility to infectious diseases and their functional mechanisms in the chicken. The genetic interaction of disease resistance with production traits and the environment is mentioned

The role of Surfacant Protein D in the control of human helminth infections

Lung produced surfactant protein D (SP-D) is essential for both homeostasis and as an innate immune opsonin. In the project presented here, we aimed to translate data recently published by our group, which demonstrated that SP-D contributes to protection against murine parasitic nematode infections, to human work. In the first part of this study, we determined whether individuals exposed to helminths have altered serum SP-D in comparison to unexposed individuals, through analysis (ELISA and Western Blot) of bio banked samples in 2 clinical cohorts from South Africa. Secondly, we aimed to identify if SP-D influences the magnitude of anti-nematode responses in human immune cells (type 2 innate lymphoid cells, monocytes and macrophages) through in vitro cell work and flow cytometry. Our findings indicated an association between serum SP-D and exposure to helminths that have a lung migration stage as part of their life cycle (Ascaris spp and Toxocara spp). Furthermore, in vitro analysis demonstrated that human immune cells primed with SP-D might have an altered response to helminth antigen. These findings point toward the need for further investigation into the novel role of SP-D in the control of human helminth infections in the context of immune physiology, as a biomarker and eventually treatment option

Patterns of Membrane Potential of Cells Isolated from the Midgut of \u3ci\u3eHeliothis virescens\u3c/i\u3e

The midgut is the main point of interaction between a lepidopteran larva and its environment, so understanding how the gut functions is important not just for understanding gut physiology but also the ecology and evolution of these organism. The midgut of these larvae is a fascinating system in which to study developmental, regeneration, and immune physiology. The midgut can exhibit up to a 200-fold increase in size through ontogeny, primarily through addition of new cells at molt, while damaged cells are replaced throughout intermolt periods. In the midgut of lepidopteran larvae, mature cells are produced from stem cells, localized in pockets underneath the mature cells. Several regulators of stem cell activity are known, but no integrative model has been established. In numerous animal taxa, bioelectric phenomena regulate stem cell activity, including duplication and differentiation. Here, we are using the tobacco budworm, Heliothis virescens, to characterize bioelectric patterns in the lepidopteran larval gut. We adapted a method to isolate stem and mature gut cells from physiologically staged fourth instar larvae and assay their membrane potential. As bioelectric phenomena are highly important in gut physiology, our results may be useful in regulating lepidopteran pests. Finally, our results could help further our understanding of how physiology and an organism’s environment interact