Lysosomal-Associated Transmembrane Protein 5 (LAPTM5) Is a Molecular Partner of CD1e

The CD1e protein participates in the presentation of lipid antigens in dendritic cells. Its transmembrane precursor is transported to lysosomes where it is cleaved into an active soluble form. In the presence of bafilomycin, which inhibits vacuolar ATPase and consequently the acidification of endosomal compartments, CD1e associates with a 27 kD protein. In this work, we identified this molecular partner as LAPTM5. The latter protein and CD1e colocalize in trans-Golgi and late endosomal compartments. The quantity of LAPTM5/CD1e complexes increases when the cells are treated with bafilomycin, probably due to the protection of LAPTM5 from lysosomal proteases. Moreover, we could demonstrate that LAPTM5/CD1e association occurs under physiological conditions. Although LAPTM5 was previously shown to act as a platform recruiting ubiquitin ligases and facilitating the transport of receptors to lysosomes, we found no evidence that LATPM5 controls either CD1e ubiquitination or the generation of soluble lysosomal CD1e proteins. Notwithstanding these last observations, the interaction of LAPTM5 with CD1e and their colocalization in antigen processing compartments both suggest that LAPTM5 might influence the role of CD1e in the presentation of lipid antigens.     

Sex Bias in Susceptibility to MCMV Infection: Implication of TLR9

Toll-like receptor (TLR)-dependent pathways control the activation of various immune cells and the production of cytokines and chemokines that are important in innate immune control of viruses, including mouse cytomegalovirus (MCMV). Here we report that upon MCMV infection wild-type and TLR7^−/− male mice were more resistant than their female counterparts, while TLR9^−/− male and female mice showed similar susceptibility. Interestingly, 36 h upon MCMV infection TLR9 mRNA expression was higher in male than in female mouse spleens. MCMV infection led to stronger reduction of marginal zone (MZ) B cells, and higher infiltration of plasmacytoid dendritic cells and neutrophils in wild-type male than female mice, while no such sex differences were observed in TLR9^−/− mice. In accordance, the serum levels of KC and MIP-2, major neutrophil chemoattractants, were higher in wild-type, but not in TLR9^−/−, male versus female mice. Wild-type MCMV-infected female mice showed more severe liver inflammation, necrosis and steatosis compared to infected male mice. Our data demonstrate sex differences in susceptibility to MCMV infection, accompanied by a lower activation of the innate immune system in female mice, and can be attributed, at least in a certain degree, to the lower expression of TLR9 in female than male mice.     

Local increase of arginase activity in lesions of patients with cutaneous leishmaniasis in Ethiopia

Background

Cutaneous leishmaniasis is a vector-borne disease that is in Ethiopia mainly caused by the parasite Leishmania aethiopica. This neglected tropical disease is common in rural areas and causes serious morbidity. Persistent nonhealing cutaneous leishmaniasis has been associated with poor T cell mediated responses; however, the underlying mechanisms are not well understood.

Methodology/Principal Findings

We have recently shown in an experimental model of cutaneous leishmaniasis that arginase-induced L-arginine metabolism suppresses antigen-specific T cell responses at the site of pathology, but not in the periphery. To test whether these results translate to human disease, we recruited patients presenting with localized lesions of cutaneous leishmaniasis and assessed the levels of arginase activity in cells isolated from peripheral blood and from skin biopsies. Arginase activity was similar in peripheral blood mononuclear cells (PBMCs) from patients and healthy controls. In sharp contrast, arginase activity was significantly increased in lesion biopsies of patients with localized cutaneous leishmaniasis as compared with controls. Furthermore, we found that the expression levels of CD3ζ, CD4 and CD8 molecules were considerably lower at the site of pathology as compared to those observed in paired PBMCs.

Conclusion

Our results suggest that increased arginase in lesions of patients with cutaneous leishmaniasis might play a role in the pathogenesis of the disease by impairing T cell effector functions.     

The CDC25B phosphatase shortens the G2 phase of neural progenitors and promotes efficient neuron production

During embryonic development, changes in cell cycle kinetics have been associated with neurogenesis. This observation suggests that specific cell cycle regulators may be recruited to modify cell cycle dynamics and influence the decision between proliferation and differentiation. In the present study, we investigate the role of core positive cell cycle regulators, the CDC25 phosphatases, in this process. We report that, in the developing chicken spinal cord, only CDC25A is expressed in domains where neural progenitors undergo proliferative self-renewing divisions, whereas the combinatorial expression of CDC25A and CDC25B correlates remarkably well with areas where neurogenesis occurs. We also establish that neural progenitors expressing both CDC25A and CDC25B have a shorter G2 phase than those expressing CDC25A alone. We examine the functional relevance of these correlations using an RNAi-based method that allows us to knock down CDC25B efficiently and specifically. Reducing CDC25B expression results in a specific lengthening of the G2 phase, whereas the S-phase length and the total cell cycle time are not significantly modified. This modification of cell cycle kinetics is associated with a reduction in neuron production that is due to the altered conversion of proliferating neural progenitor cells to post-mitotic neurons. Thus, expression of CDC25B in neural progenitors has two functions: to change cell cycle kinetics and in particular G2-phase length and also to promote neuron production, identifying new roles for this phosphatase during neurogenesis.     

BAFF and innate immunity: new therapeutic targets for systemic lupus erythematosus

Recently, the B cell has emerged as a cornerstone of systemic lupus erythematosus (SLE) pathogenesis. This has been highlighted by studies of the cytokine B-cell-activating factor of the tumour necrosis factor (TNF) family (BAFF), a crucial factor regulating B-cell maturation, survival and function. Overexpression of BAFF in mice leads to the development of an SLE-like disease, independent of T cells but instead relying on innate immunity mechanisms. Moreover, BAFF has been shown to be elevated in the serum of patients suffering from autoimmune conditions, especially SLE, and may correlate with disease activity. These findings challenge the previous notion that T:B-cell collaboration is the sole driver of SLE. In recent years, controlled trials have for the first time tested targeted therapeutics for SLE. However, agents designed to target B cells failed to meet primary endpoints in clinical trials in SLE, suggesting that a more complex role for B cells in SLE awaited elucidation. By contrast, on 9 March 2011, the US Food and Drug Administration approved belimumab, a fully human anti-BAFF monoclonal antibody, as a new B-cell-specific treatment for SLE. This article will review over 10 years of research on the BAFF system, key findings that led to this recent positive clinical outcome and propose a model potentially explaining why this B-cell-specific therapy has yielded positive results in clinical trials. We will also review promising therapies presently in clinical trials targeting innate immunity, which are likely to revolutionize SLE management towards a personalized and targeted therapy approach.     

Assessment of cellular immune parameters in paediatric toxic shock syndrome: a report of five cases

Toxic shock syndrome (TSS) and septic shock (SS) share many clinical signs of an exacerbated inflammatory response. In this report, we investigated whether TSS presents similar features of delayed immunosuppression as described in SS. Five children with TSS from paediatric intensive care units in a university hospital were monitored. TSS cases were defined by the association of standardized clinical signs of TSS and confirmed by measurement of specific Vbeta expansions corresponding to toxin gene profile of the isolated strains. As in SS, an increased percentage of circulating regulatory T cells (Treg) was observed in patients with TSS. However, in contrast to SS, neither lymphopenia nor decreased HLA-DR expression on monocytes was measured. In conclusion, whereas SS and TSS exhibited similar clinical presentation, the present observation suggests that respective pathophysiological mechanisms induce different immune alterations. Future studies must isolate and better characterize the phenotypic and functional properties of Treg subsets during TSS to understand the mechanisms sustaining their increase, especially the putative role of superantigens.     

Assessing the effectiveness of environmental enrichment in bottlenose dolphins (Tursiops truncatus)

Environmental enrichment is often used to improve well-being and reduce stereotyped behaviors in animals under human care. However, the use of objects to enrich animal environments should not be considered to be effective until its success has been scientifically demonstrated. This study was conducted at Asterix Park in France in April 2009. The study investigated the use of 21 familiar objects with a group of six bottlenose dolphins (Tursiops truncatus). The dolphin trainers introduced four different objects into the dolphin pool every day on a rotating basis. Using a focal-object sampling method, we collected and analyzed data from twenty-one 15 min sessions. The results revealed a positive correlation between interest behaviors and interactive behaviors. Some dolphins had "favorite toys". However, only 50% of objects elicited manipulative behaviors. These findings demonstrate that dolphins do not treat all objects provided to them as "toys". Behavioral changes in the animals subsequent to the introduction of objects do not necessarily indicate an enrichment effect of the objects; rather, the motivation for the dolphins' behaviors toward the objects must be investigated. The animals' behavior must be considered in light of the social context and of the animals' individual behavioral profiles. The relevance of a constructivist approach to evaluating the effectiveness of enrichment programs is discussed.