Interferons and Toxoplasma gondii shape PD-L1 regulation in retinal barrier cells: the critical role of proteases

IntroductionThe apicomplexan parasite Toxoplasma gondii establishes chronic infection in the central nervous system, including the retina, causing ocular toxoplasmosis (OT). This persistence relies on a fine balance between inflammatory and immunomodulatory mechanisms, especially in the immune-privileged ocular environment. We previously described the immunologic interactions between retinal cells, and particularly the roles of type I and III interferons. In this study, we investigated the regulatory dynamics of PD-L1, a central immunomodulatory receptor on immune cells.MethodsWe first investigated the mechanisms of PD-L1 regulation and the roles of type I and III interferons in an in vitro T. gondii infection model using mono- and co-culture systems of human microglia, astrocytes, and Müller cells. We also assessed PD-L1 expression in an outer blood-retina barrier model (oBRB) of differentiated retinal pigmented epithelial (RPE) cells. Additionally, we looked at retinal cell activation, PD-L1 expression and the roles of these interferons in a mouse model of OT.ResultsOur findings reveal new roles for type I and III interferons in regulating glial cell activation and PD-L1 expression in RPE, Müller, astrocytes and microglial cells. Notably, Müller cells, the most abundant glial cells in the retina, showed the highest baseline PD-L1 expression at both the mRNA and protein levels, and responded robustly to interferon stimulation. This points to a more prominent immunoregulatory role for Müller cells in the retina than previously recognized. Furthermore, we identified a parasite protease-dependent mechanism that reduces PD-L1 expression in our in vitro oBRB model potentially contributing to immune evasion and inflammation during OT. Finally, in a murine model of OT, we demonstrated that PD-L1 expression reached its peak on day 7 post-infection and that interferon neutralization plays a crucial role in regulating both PD-L1 expression and glial activation.DiscussionThe parasite T. gondii orchestrates the IFN type I and III dependent retinal immune interaction and downregulates PD-L1 in the oBRB by a protease-dependent mechanism, potentially contributing to immune evasion and inflammation in retinal infection. Our results can pave the way to fully elucidate retinal immune networks and PD-L1 regulation mechanisms, offering potential targets for therapeutic interventions in OT and other retinal inflammatory diseases

The hide and seek of Plasmodium vivax in West Africa: report from a large-scale study in Beninese asymptomatic subjects

International audienc

MOESM1 of The hide and seek of Plasmodium vivax in West Africa: report from a large-scale study in Beninese asymptomatic subjects

Additional file 1: Table S1. Pairwise comparison of recombinant protein indexes using correlation coefficients (r 2 )

MOESM2 of The hide and seek of Plasmodium vivax in West Africa: report from a large-scale study in Beninese asymptomatic subjects

Additional file 2: Fig. S1. Sequence alignment of the seven Plasmodium vivax sequence from nested-PCR. Sequence variations are highlighted by black boxes

How should we diagnose and treat blastic plasmacytoid dendritic cell neoplasm patients?

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive leukemia for which we developed a nationwide network to collect data from new cases diagnosed in France. In a retrospective, observational study of 86 patients (2000-2013), we described clinical and biological data focusing on morphologies and immunophenotype. We found expression of markers associated with plasmacytoid dendritic cell origin (HLA-DRhigh, CD303+, CD304+, and cTCL1+) plus CD4 and CD56 and frequent expression of isolated markers from the myeloid, B-, and T-lymphoid lineages, whereas specific markers (myeloperoxidase, CD14, cCD3, CD19, and cCD22) were not expressed. Fifty-one percent of cytogenetic abnormalities impact chromosomes 13, 12, 9, and 15. Myelemia was associated with an adverse prognosis. We categorized chemotherapeutic regimens into 5 groups: acute myeloid leukemia (AML)-like, acute lymphoid leukemia (ALL)-like, lymphoma (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP])-like, high-dose methotrexate with asparaginase (Aspa-MTX) chemotherapies, and not otherwise specified (NOS) treatments. Thirty patients received allogeneic hematopoietic cell transplantation (allo-HCT), and 4 patients received autologous hematopoietic cell transplantation. There was no difference in survival between patients receiving AML-like, ALL-like, or Aspa-MTX regimens; survival was longer in patients who received AML-like, ALL-like, or Aspa-MTX regimens than in those who received CHOP-like regimens or NOS. Eleven patients are in persistent complete remission after allo-HCT with a median survival of 49 months vs 8 for other patients. Our series confirms a high response rate with a lower toxicity profile with the Aspa-MTX regimen, offering the best chance of access to hematopoietic cell transplantation and a possible cure

How should we diagnose and treat blastic plasmacytoid dendritic cell neoplasm patients?

International audienceBlastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive leukemia for which we developed a nationwide network to collect data from new cases diagnosed in France. In a retrospective, observational study of 86 patients (2000-2013), we described clinical and biological data focusing on morphologies and immunophenotype. We found expression of markers associated with plasmacytoid dendritic cell origin (HLA-DRhigh, CD303+, CD304+, and cTCL1+) plus CD4 and CD56 and frequent expression of isolated markers from the myeloid, B-, and T-lymphoid lineages, whereas specific markers (myeloperoxidase, CD14, cCD3, CD19, and cCD22) were not expressed. Fifty-one percent of cytogenetic abnormalities impact chromosomes 13, 12, 9, and 15. Myelemia was associated with an adverse prognosis. We categorized chemotherapeutic regimens into 5 groups: acute myeloid leukemia (AML)-like, acute lymphoid leukemia (ALL)-like, lymphoma (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP])-like, high-dose methotrexate with asparaginase (Aspa-MTX) chemotherapies, and not otherwise specified (NOS) treatments. Thirty patients received allogeneic hematopoietic cell transplantation (allo-HCT), and 4 patients received autologous hematopoietic cell transplantation. There was no difference in survival between patients receiving AML-like, ALL-like, or Aspa-MTX regimens; survival was longer in patients who received AML-like, ALL-like, or Aspa-MTX regimens than in those who received CHOP-like regimens or NOS. Eleven patients are in persistent complete remission after allo-HCT with a median survival of 49 months vs 8 for other patients. Our series confirms a high response rate with a lower toxicity profile with the Aspa-MTX regimen, offering the best chance of access to hematopoietic cell transplantation and a possible cure

How should we diagnose and treat blastic plasmacytoid dendritic cell neoplasm patients?

Abstract Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive leukemia for which we developed a nationwide network to collect data from new cases diagnosed in France. In a retrospective, observational study of 86 patients (2000-2013), we described clinical and biological data focusing on morphologies and immunophenotype. We found expression of markers associated with plasmacytoid dendritic cell origin (HLA-DRhigh, CD303+, CD304+, and cTCL1+) plus CD4 and CD56 and frequent expression of isolated markers from the myeloid, B-, and T-lymphoid lineages, whereas specific markers (myeloperoxidase, CD14, cCD3, CD19, and cCD22) were not expressed. Fifty-one percent of cytogenetic abnormalities impact chromosomes 13, 12, 9, and 15. Myelemia was associated with an adverse prognosis. We categorized chemotherapeutic regimens into 5 groups: acute myeloid leukemia (AML)–like, acute lymphoid leukemia (ALL)–like, lymphoma (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP])–like, high-dose methotrexate with asparaginase (Aspa-MTX) chemotherapies, and not otherwise specified (NOS) treatments. Thirty patients received allogeneic hematopoietic cell transplantation (allo-HCT), and 4 patients received autologous hematopoietic cell transplantation. There was no difference in survival between patients receiving AML-like, ALL-like, or Aspa-MTX regimens; survival was longer in patients who received AML-like, ALL-like, or Aspa-MTX regimens than in those who received CHOP-like regimens or NOS. Eleven patients are in persistent complete remission after allo-HCT with a median survival of 49 months vs 8 for other patients. Our series confirms a high response rate with a lower toxicity profile with the Aspa-MTX regimen, offering the best chance of access to hematopoietic cell transplantation and a possible cure.</jats:p