Default in plasma and intestinal IgA responses during acute infection by Simian Immunodeficiency Virus.

International audienceABSTRACT: BACKGROUND: Conflicting results regarding changes in mucosal IgA production or in the proportions of IgA plasma cells in the small and large intestines during HIV-infection have been previously reported. Except in individuals repeatedly exposed to HIV-1 but yet remaining uninfected, HIV-specific IgA are frequently absent in mucosal secretions from HIV-infected patients. However, little is known about the organization and functionality of mucosal B-cell follicles in acute HIV/SIV infection during which a T-dependent IgA response should have been initiated. In the present study, we evaluated changes in B-cell and T-cell subsets as well as the extent of apoptosis and class-specific plasma cells in Peyer's Patches, isolated lymphoid follicles, and lamina propria. Plasma levels of IgA, BAFF and APRIL were also determined. RESULTS: Plasma IgA level was reduced by 46 percent by 28 dpi and no IgA plasma cells were found within germinal centers of Peyer's Patches and isolated lymphoid follicles. This lack of a T-dependent IgA response occurs although germinal centers remained functional with no sign of follicular damage, but a prolonged survival of follicular CD4+ T-cells and normal generation of IgG plasma cells is observed. Whereas the average plasma BAFF level was increased by 4.5-fold and total plasma cells were 1.7 to 1.9-fold more numerous in the lamina propria, the relative proportion of IgA plasma cells in this effector site was reduced by 19 percent (duodemun) to 35 percent (Ileum) at 28 dpi. CONCLUSION: Our data provide evidence that SIV is unable to initiate a T-dependent IgA response during the acute phase of infection and favors the production of IgG (ileum) or IgM (duodenum) plasma cells at the expense of IgA plasma cells. Therefore, an early and generalized default in IgA production takes place during the acute of phase of HIV/SIV infection, which might impair not only a virus-specific antibody response but also IgA responses to other pathogens and vaccines as well. Understanding the mechanisms that impair IgA production during acute HIV/SIV infection is crucial to improve virus-specific response in mucosa and control microbial translocation

High levels of gut-homing immunoglobulin A+ B lymphocytes support the pathogenic role of intestinal mucosal hyperresponsiveness in immunoglobulin A nephropathy patients

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Altérations des lymphocytes B systémiques et muqueux au cours de la primo-infection par les virus de l'immunodéficience simienne et humaine

LE KREMLIN-B.- PARIS 11-BU Méd (940432101) / SudocSudocFranceF

Antigen-Specific In Vivo Killing Assay

International audienceThe in vivo killing assay allows the quantification of the antigen-specific killing capacity of Cytotoxic CD8+ T Lymphocytes (CTLs) in mice. CTLs are indeed known for the lysis of cells expressing foreign or modified antigen peptides on their MHC class I molecules. Here we describe the detailed protocol used for the in vivo specific lysis of cells expressing the H-2 Kb immunodominant CD8+ T-cell epitope of the OVA protein: an 8 amino acid peptide corresponding to the 257-264 region of OVA (SIINFEKL)

Stress from Urban Sprawl on the Fauna and Flora of the Beirut Metropolitan Area

Le Liban fait partie du point chaud de la biodiversité méditerranéenne et est bien connu pour son grand nombre d’espèces vivantes, spécialement terrestres. Son urbanisation incontrôlée représente la principale cause de la fragmentation des habitats de ces dernières. Cette recherche propose l’utilisation des SIG et de l’analyse du paysage pour appréhender le processus de fragmentation dans la Région Métropolitaine de Beyrouth (RMB) au cours des trente dernières années. Des images satellitaires de 1985 et 2016 ont été traitées dans un SIG et des indices de fragmentation ont pu être calculés grâce à Fragstat4.2. Cinq sites ont été étudiés à une échelle fine, afin d’identifier les causes de ce morcellement qui va en augmentant. Les résultats montrent une fragmentation croissante des espaces verts, une ségrégation considérable entre ces parcelles et une coupure de leur connectivité. Cette étude vise à proposer des méthodes d’atténuation efficaces pour la protection des espèces restantes.Lebanon is part of the hot spot of Mediterranean biodiversity and is well known for its large number of living species, particularly terrestrial ones. Uncontrolled urbanisation is the main cause of fragmentation of the habitats of these species. This research proposes GIS and landscape analysis as tools for understanding the process of fragmentation in the Metropolitan Area of Beyrouth over the last thirty years. Satellite images taken in 1985 and 2016 were processed by GIS and fragmentation indices were calculated using Fragstat4.2. Five sites were studied at a fine scale so as to identify the causes of this parcelling, which is on the increase. The results show increasing fragmentation of green spaces, considerable segregation between these patches and the breakdown of their connections. The aim of this study is to offer efficient mitigation methods for the protection of the remaining species

Direct and Indirect Effect of TGFβ on Treg Transendothelial Recruitment in HCC Tissue Microenvironment

The balance between anti-tumor and tumor-promoting immune cells, such as CD4+ Th1 and regulatory T cells (Tregs), respectively, is assumed to dictate the progression of hepatocellular carcinoma (HCC). The transforming growth factor beta (TGFβ) markedly shapes the HCC microenvironment, regulating the activation state of multiple leukocyte subsets and driving the differentiation of cancer associated fibroblasts (CAFs). The fibrotic (desmoplastic) reaction in HCC tissue strongly depends on CAFs activity. In this study, we attempted to assess the role of TGFβ on transendothelial migration of Th1-oriented and Treg-oriented CD4+ T cells via a direct or indirect, CAF-mediated mechanisms, respectively. We found that the blockage of TGFβ receptor I-dependent signaling in Tregs resulted in impaired transendothelial migration (TEM) of these cells. Interestingly, the secretome of TGFβ-treated CAFs inhibited the TEM of Tregs but not Th1 cells, in comparison to the secretome of untreated CAFs. In addition, we found a significant inverse correlation between alpha-SMA and FoxP3 (marker of Tregs) mRNA expression in a microarray analysis involving 78 HCCs, thus suggesting that TGFβ-activated stromal cells may counteract the trafficking of Tregs into the tumor. The apparent dual behavior of TGFβ as both pro- and anti-tumorigenic cytokines may add a further level of complexity to the mechanisms that regulate the interactions among cancerous, stromal, and immune cells within HCC, as well as other solid tumors, and contribute to better manipulation of the TGFβ signaling as a therapeutic target in HCC patients

Angiogenesis in NENs, with a focus on gastroenteropancreatic NENs: from biology to current and future therapeutic implications

Neuroendocrine neoplasms (NENs) are highly vascularized malignancies arising from cells of the diffuse neuroendocrine system. An intricated cross-talk exists between NEN cells and the tumor microenvironment, and three main molecular circuits (VEGF/VEGFR pathway, FGF-dependent signaling and PDGF/PDGFR axis) have been shown to regulate angiogenesis in these neoplasms. Multiple randomized trials have investigated antiangiogenic agents over the past two decades, and sunitinib is currently approved for the treatment of advanced, progressive, G1/G2 pancreatic NENs. In recent years, two phase III clinical trials have demonstrated the efficacy and safety of surufatinib, a multi-tyrosine kinase angioimmune inhibitor, in patients with well-differentiated pancreatic and extrapancreatic NENs, and two studies of this agent are currently underway in Europe and US. The HIF-2 alpha inhibitor belzutifan has recently received regulatory approval for the treatment of tumors arising in the context of Von-Hippel Lindau syndrome including pancreatic NENs, and a study of this drug in patients with sporadic tumors is presently ongoing. Combinations of antiangiogenic agents with chemotherapeutics and targeted drugs have been tested, with accumulating toxicities being a matter of concern. The potential of antiangiogenic agents in fine-tuning the immune microenvironment of NENs to enhance the activity of immune checkpoint inhibitors has been only partially elucidated, and further research should be carried out at this regard. Here, we review the current understanding of the biology of angiogenesis in NENs and provide a summary of the latest clinical investigations on antiangiogenic drugs in this malignancy

Lack of MHC class II molecules favors CD8 + T- cell infiltration into tumors associated with an increased control of tumor growth

International audienceRegulatory T-cells (Tregs) are crucial for the maintenance of immune tolerance and homeostasis as well as forpreventing autoimmune diseases, but their impact on the survival of cancer patients remains controversial. Inthe TC-1 mouse model of human papillomavirus (HPV)-related carcinoma, we have previously demonstratedthat the therapeutic efficacy of the CyaA-E7-vaccine, targeting the HPV-E7 antigen, progressively declineswith tumor growth, in correlation with increased intratumoral recruitment of Tregs. In the present study, wedemonstrated that these TC-1 tumor-infiltrating Tregs were highly activated, with increased expression ofimmunosuppressive molecules. Both intratumoral effector CD4C T-cells (Teffs) and Tregs expressed highlevels of PD-1, but anti-PD-1 antibody treatment did not impact the growth of the TC-1 tumor nor restorethe therapeutic effect of the CyaA-E7 vaccine. To analyze the mechanisms by which Tregs are recruited tothe tumor site, we used MHC-II KO mice with drastically reduced numbers of CD4C effector T-cells. Wedemonstrated that these mice still had significant numbers of Tregs in their lymphoid organs which wererecruited to the tumor. In MHC-II KO mice, the growth of the TC-1 tumor was delayed in correlation with astrong increase in the intratumoral recruitment of CD8C T-cells. In addition, in mice that spontaneouslyrejected their tumors, the infiltration of E7-specific CD8C T-cells was significantly higher than in MHC-II KOmice with a growing tumor. These results demonstrate that tumor-specific CD8C T-cells can be efficientlyactivated and recruited in the absence of MHC class II molecules and of CD4C T-cell help

BAFF enhances chemotaxis of primary human B cells: a particular synergy between BAFF and CXCL13 on memory B cells

International audienc