Semaphorins and their receptors in immune cell interactions

Semaphorins are newcomers to the growing panoply of immunoregulatory proteins. Members of this family were originally identified as proteins that provide axonal guidance cues during neuronal development. However, accumulating evidence indicates that several semaphorins, called 'immune semaphorins', are crucial to various phases of the immune response, from initiation to terminal inflammatory processes. Extensive studies of immune semaphorins have shown not only differences but also parallels in semaphorin functions among physiologically distinct systems, providing unexpected but meaningful insights into the biological activities of this protein family. Here we review the present knowledge of the function of semaphorins and their receptors in the immune system, including the most recent advances in this field.     

Neuropilin-1: The Glue between Regulatory T Cells and Dendritic Cells?

The interaction between dendritic cells and regulatory T cells is critical for the maintenance of self-tolerance. In this issue of Immunity, Sarris et al. (2008) find that Neuropilin-1 contributes to the prolonged interaction of regulatory T cells with dendritic cells.     

Bimodal regulation of T cell-mediated immune responses by TIM-4

T cell Ig and mucin domain (TIM)-4 is preferentially expressedon antigen-presenting cells, and its counter-ligand, TIM-1,is thought to deliver co-stimulating signals to T cells. However,the physiological functions of TIM-4 remain unclear. Here, wedemonstrate that TIM-4 inhibits naive T cell activation througha ligand other than TIM-1. The inhibitory effect of TIM-4 wasspecific to naive T cells which do not express TIM-1, and theeffect disappeared in pre-activated T cells. Conversely, antibody-mediatedblockade of TIM-4 in vivo substantially suppressed T cell-mediatedinflammatory responses despite enhanced generation of antigen-specificT cells. Furthermore, treatment with anti-TIM-4 reduced theinflammatory responses developed in mice that were adoptivelytransferred with antigen-primed T cells. These results suggestthat TIM-4 exerts bimodal functions depending on the activationstatus of T cells.     

Effects of methylergometrine and oxytocin on thoracic epidural pressure during cesarean section

AIM: The effects of oxytocics on thoracic epidural pressure during cesarean section were studied in 60 parturients, (American Society of Anesthesiologist physical status, class I or II) after obtaining informed consent. METHODS: The subjects were randomized to either a ergometrine (n = 30) or oxytocin treatment group (n = 30). The subjects were anesthetized with 11-12 mg of intrathecal isobaric bupivacaine (0.5%), and an epidural catheter was placed at Th 11/12, and was connected to a pressure transducer to continuously monitor thoracic epidural pressure. We analyzed epidural pressure, blood pressure, and heart rate 5 min after administering intrathecal bupivacaine (SAB5m), immediately before skin incision (pre-incision), immediately after delivery of the placenta (placenta-del), and 5 min after delivery of the fetus (CS5m). RESULTS: In both groups, epidural pressures were found to be elevated after delivery compared with their levels before the skin incisions were made, (P < 0.0001). Epidural pressures at placenta-del (P = 0.0055) and CS5m (P < 0.0001) were higher than at SAB5m in the ergometrine group. Epidural pressures at placenta-del were also higher than at SAB5m in the oxytocin group (P < 0.0001). Epidural pressures at placenta-del were lower in the ergometrine group compared with the oxytocin group (P = 0.0122), but epidural pressures at CS5m were higher in the ergometrine group compared with the oxytocin group (P < 0.0001). CONCLUSIONS: We conclude that there is an increase in thoracic epidural pressure after fetal delivery, which appears to be associated with uterine contraction.     

Swallowing disorders and 1‐year functional decline in community‐dwelling older adults receiving home care

The purpose of this study was to clarify the effect of swallowing disorders on functional decline in community‐dwelling older adults receiving home care. This was a 1‐year follow‐up survey of 176 individuals ≥60 years living at home and receiving homecare services, without total dependence in basic daily living activities, in two mid‐sized municipalities in Fukuoka, Japan. Functional decline was measured using the Barthel index (BI), and the primary outcome was total dependence in basic daily living activities (BI ≤ 20 points). Swallowing function was assessed using cervical auscultation, and the primary predictor was swallowing disorders. Logistic regression models were used to assess univariate and multivariate associations between baseline swallowing function and functional decline during follow‐up. During follow‐up 16 (9.1%), the participants became totally dependent in basic daily living activities. The participants with swallowing disorders had 6.41 times higher odds of total dependence in basic daily living activities compared to participants with normal swallowing function. After adjusting for potential confounders, swallowing disorders were significantly associated with higher odds of total dependence in basic daily living activities (odds ratio = 5.21, 95% confidence interval = 1.33‐20.44). Regarding swallowing disorders, the corresponding population attributable fraction (%) of the incidence of total dependence in basic daily living activities was 50.4%. The current findings demonstrated that swallowing disorders were associated with greater risk of functional decline in basic daily living activities among older adults living at home and receiving home nursing care. Maintenance and improvement of swallowing function may prevent late‐life functional decline.     

Deleterious effects of lymphocytes at the early stage of neurodegeneration in an animal model of amyotrophic lateral sclerosis

Background  

Non-neuronal cells, such as microglia and lymphocytes, are thought to be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). Previous studies have demonstrated neuroprotective effects of lymphocytes at the end stage of ALS, partly through induction of alternatively activated microglia (M2 microglia), which are neuroprotective. In this study, we investigated the role of lymphocytes in the early stage of the disease using an animal model of inherited ALS.     

Lip closing pressure and spoon management in passive spoon feeding

To determine the sources of lip closing pressure (P(LC) ) generation during passive spoon feeding, we used a fine pressure transducer glued into a wooden spoon, as well as electromyography (EMG) of the upper and lower lips and the submental muscle complex, in normal adult volunteers (average age 24·5 years). An assistant fed a seated subject 0·6 mL of yogurt and then withdrew the spoon from the subject's closed mouth. The spoon was held at an angle of 0° (i.e. in the naso-auricular plane) during serving and at either 0° or 60° during withdrawal. We detected simultaneous increases in P(LC) and in EMG activity in the lips and the submental muscle complex. The maximum P(LC) was significantly higher at 60° [65 ± 11 g cm(-2) (mean ± s.e.m)] than at 0° (42 ± 8 g cm(-2)). The former was correlated with the maximum EMG amplitude, which was analysed by using the mean of the root-mean-square EMG and presented as a percentage of the maximum EMG obtained in the lower lip region and the submental muscle complex during subsequent swallowing in each subject. In conclusion, in healthy adult subjects, perioral muscles of the lower lip region and the submental muscle complex participate in P(LC) generation, particularly at a steep spoon withdrawal angle. The results suggest that a steep withdrawal angle not only increases P(LC) but also promotes these muscles' activities in passive spoon feeding.     

Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages

Increased evidence suggests that cancer-associated inflammation supports tumor growth and progression. We have previously shown that semaphorin 4D (Sema4D), a ligand produced by different cell types, is a proangiogenic molecule that acts by binding to its receptor, plexin B1, expressed on endothelial cells (Conrotto, P., D. Valdembri, S. Corso, G. Serini, L. Tamagnone, P.M. Comoglio, F. Bussolino, and S. Giordano. 2005. Blood. 105:4321-4329). The present work highlights the role of Sema4D produced by the tumor microenvironment on neoplastic angiogenesis. We show that in an environment lacking Sema4D, the ability of cancer cells to generate tumor masses and metastases is severely impaired. This condition can be explained by a defective vascularization inside the tumor. We demonstrate that tumor-associated macrophages (TAMs) are the main cells producing Sema4D within the tumor stroma and that their ability to produce Sema4D is critical for tumor angiogenesis and vessel maturation. This study helps to explain the protumoral role of inflammatory cells of the tumor stroma and leads to the identification of an angiogenic molecule that might be a novel therapeutic target.