No lack of regulatory B cells in patients with Multiple Sclerosis

International audienc

Stratégies thérapeutiques anti-VIH (du curatif au préventif)

AIX-MARSEILLE2-BU Pharmacie (130552105) / SudocSudocFranceF

Regulatory B Cells and Tolerance in Transplantation: From Animal Models to Human

International audienceUntil recently, the role of B cells in transplantation was thought to be restricted to producing antibodies that have been clearly shown to be deleterious in the long-term, but, in fact, B cells are also able to produce cytokine and to present antigen. Their role as regulatory cells in various pathological situations has also been highlighted, and their role in transplantation is beginning to emerge in animal, and also in human, models. This review summarizes the different studies in animals and humans that suggest a B-cell regulatory role in the transplant tolerance mechanisms

Biomarkers and possible mechanisms of operational tolerance in kidney transplant patients

International audienceA small number of patients do not reject their graft after weaning from immunosuppressive treatment. Here, we analyze the studies carried out to try to understand the mechanisms involved in this operational transplant tolerance and evaluate the hypotheses proffered on these potential mechanisms

B cells in operational tolerance

International audienc

Structural insights into the catalytic mechanism of granzyme B upon substrate and inhibitor binding

International audienceHuman granzyme B (hGzmB), which is present in various immune cells, has attracted much attention due to its role in various pathophysiological conditions. The hGzmB activity is triggered at a catalytic triad (His59, Asp103, Ser198), cleaving its specific substrates. To date, the drug design strategy against hGzmB mainly targets the catalytic triad, which causes the non-specificity problem of inhibitors due to the highly conserved active site in serine proteases. In the present work, microsecond classical molecular dynamics simulations are devoted to exploring the structural dynamics of the hGzmB catalytic cycle in the presence of Ac-IEPD-AMC, a known substrate (active hGzmB), and Ac-IEPD-CHO, a known inhibitor (inactive hGzmB). By comparing active and inactive forms of hGzmB in the six different stages of the hGzmB catalytic cycle, we revealed, for the very first time, an additional network of interactions involving Arg216, a residue located outside the conventional binding site. Upon activation, the His59•••Asp103 hydrogen bond is broken due to the formation of the Asp103•••Arg216 salt bridge, expanding the active site to facilitate the substrate-binding. On the contrary, the binding of inhibitor Ac-IEPD-CHO to hGzmB prevents the Arg216-mediated interactions within the catalytic triad, thus preventing hGzmB activity. In silico Arg216Ala mutation confirms the role of Arg216 in enzyme activity, as the substrate Ac-IEPD-AMC failed to bind to the mutated hGzmB. Importantly, as Arg216 is not conserved amongst the various granzymes, the current findings can be a major step to guide the design of hGzmB specific therapeutics

Identification of a common transcriptional signature for regulatory B cells in Humans and Mice

International audienceRegulatory B cells (Bregs) have been described in mice and humans for their ability to regulate inflammation through a variety of mechanisms in different pathological situations. Up to date, no consensual and common Breg phenotype has been described, and whether there is a Breg lineage commitment or if they acquire their function under certain environmental conditions remains unknown. To address these points, we performed a sample size weighted meta-analysis of publicly available transcriptomic data from 4 different Bregs studies in humans and 6 Bregs studies in mice

Olfactory control of reproductive function

National audienc

Phenotype and functions of B cells in patients with acute brain injuries

International audienceBackground: Brain injuries (BI) induce a state of systemic immunosuppression, leading to a high risk of pneumonia. In this pilot study, we investigated the status of B cell compartment in BI patients.Methods: A prospective observational study was performed in 2 intensive care units in a university hospital. Blood samples were collected in 14 patients at day 1 and day 7 after acute BI. The phenotype and the ability of B cells to secrete IL-10 were compared to 11 healthy volunteers (HV).Results: Among the circulating lymphocytes, the frequency of B cells was significantly higher in BI patients compared to HV (p < 0.001). B cells from BI patients displayed an activated profil on day 7 after BI, reflected by a significantly higher proportion of CD27 + memory (p = 0.01) and CD27 + IgD − switched memory B cells (p = 0.02), as well as a significantly higher blood level of IgA (p = 0.001) and IgM (p < 0.001) as compared to day 1. The frequency of IL-10 secreting B cells (IL-10 + B cells) on day 1 and day 7 was significantly lower in BI patients compared to HV (p < 0.05). Interestingly, we observed that all BI patients with high frequency of IL-10 + B cells on day 1 displayed an episode of pneumonia, and had a longer duration of mechanical ventilation and ICU stay compared to BI patients with low proportion of IL-10 + B cells.Conclusion: This study provides an extensive description of the phenotype and function of B cells in BI patients. Our results suggest that IL-10 + B cells could play a major role in immunosuppression after BI

A common gene signature across multiple studies relate biomarkers and functional regulation in tolerance to renal allograft

International audiencePatients tolerant to a kidney graft display a specific blood cell transcriptional pattern but results from five different studies were inconsistent, raising the question of relevance for future clinical application. To resolve this, we sought to identify a common gene signature, specific functional and cellular components, and discriminating biomarkers for tolerance following kidney transplantation. A meta-analysis of studies identified a robust gene signature involving proliferation of B and CD4 T cells, and inhibition of CD14 monocyte related functions among 96 tolerant samples. This signature was further supported through a cross-validation approach, yielding 92.5% accuracy independent of the study of origin. Experimental validation, performed on new tolerant samples and using a selection of the top-20 biomarkers, returned 91.7% of good classification. Beyond the confirmation of B-cell involvement, our data also indicated participation of other cell subsets in tolerance. Thus, the use of the top 20 biomarkers, mostly centered on B cells, may provide a common and standardized tool towards personalized medicine for the monitoring of tolerant or low-risk patients among kidney allotransplant recipients. These data point to a global preservation of genes favoring the maintenance of a homeostatic and 'healthy' environment in tolerant patients and may contribute to a better understanding of tolerance maintenance mechanisms