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Purpose Major histocompatibility complex (MHC) class II deficiency is one of the combined immune deficiency disorders caused by defects in the MHC class II regulatory genes leading to abnormal T cells development and function. Therefore, patients mainly present with increased susceptibility to infections, diarrhea, and failure to thrive. In this report, we present one MHC class II deficient patient with a novel presentation with Hemophagocytic Lymphohistiocytosis (HLH). Methods Immunophenotyping of lymphocyte subpopulations and HLA-DR expression was assess by flow cytometry. Gene mutational analysis was performed by whole exome and Sanger sequencing. Results We reported a 7-year-old girl, who was diagnosed at age of 2 years with MHC class II deficiency by genetic testing and flow cytometry. Two years later, she developed disseminated BCGitis which was treated with proper antimicrobial agents. At the age of 7 years, she presented with clinical features fulfilling 6 diagnostic criteria of HLH including evidence of hemophagocytic activity in bone marrow aspiration. Accordingly, the diagnosis of HLH was established and the patient was started on IV Dexamethasone, Anakinra and IVIG. Eventually, patient started to improve and was discharged in good condition. Few months later, the patient was readmitted with severe pneumonia and sepsis leading to death. Conclusion Patients with MHC class II deficiency might present with disseminated BCGitis especially if the patient has severe T cell lymphopenia. Additionally, this immune defect might be added to the list of inborn errors of immunity that can be complicated with HLH. [ABSTRACT FROM AUTHOR]

Chronic use of human recombinant erythropoietin (r-HuEPO) is accompanied by serious vascular side effects related to the rise in blood viscosity and shear stress. We investigated the direct effects of r-HuEPO on endothelium and nitric oxide (NO)-dependent vasodilatation induced by shear stress of cannulated and pressurized rat mesenteric resistance arteries. Intravascular flow was increased in the presence or absence of the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 10-4 mol/L). In the presence of r-HuEPO, the flow-dependent vasodilatation was attenuated, while L-NAME completely inhibited it. The association of r-HuEPO and L-NAME caused a vasoconstriction in response to the rise in intravascular flow. Bosentan (10-5 mol/L), an inhibitor of endothelin-1 (ET-1) receptors, corrected the attenuated vasodilatation observed with r-HuEPO and inhibited the vasoconstriction induced by flow in the presence of r-HuEPO and L-NAME. r-HuEPO and L-NAME exacerbated ET-1 vasoconstriction. At shear stress values of 2 and 14 dyn/[cm.sup.2] (1 dyn = 10-5 N), cultured EA.hy926 endothelial cells incubated with r-HuEPO, L-NAME, or both released greater ET-1 than untreated cells. In conclusion, r-HuEPO diminishes flow-induced vasodilatation. This inhibitory effect seems to implicate ET-1 release. NO withdrawal exacerbates the vascular effects of ET-1 in the presence of r-HuEPO. These findings support the importance of a balanced endothelial ET-1:NO ratio to avoid the vasopressor effects of r-HuEPO. Key words: erythropoietin, shear stress, vascular flow, nitric oxide, endothelin-1, L-NAME, culture cells, bosentan. L'utilisation chronique d'erythropoietine recombinante humaine (EPOrHu) s'accompagne d'effets secondaires vasculaires graves lies a l'augmentation de la viscosite du sang et des contraintes de cisaillement. Nous avons examine les effets directs de l'EPOrHu sur l'endothelium et la vasodilatation dependante de NO induite par la contrainte de cisaillement d'arteres de resistance mesenteriques canulees et sous pression de rats. Le debit intravasculaire a augmente en presence ou en absence de l'inhibiteur de la NO-synthase, L-NAME (10-4 M). L'EPOrHu a attenue la vasodilatation dependante du debit, alors que L-NAME l'a totalement inhibee. L'association EPOrHu/L-NAME a cause une vasoconstriction en reponse a l'augmentation du debit intravasculaire. Le bosentan (10-5 M), un inhibiteur des recepteurs de l'endotheline-1 (ET-1), a corrige l'attenuation de la vasodilatation observee avec l'EPOrHu et inhibe la vasoconstriction induite par le debit en presence de EPOrHu/L-NAME. L'association EPOrHu/L-NAME a exacerbe la vasoconstriction induite par l'ET-1. Aux valeurs de cisaillement de 2 et 14 dyn/[cm.sup.2], les cellules endotheliales EA.hy926 cultivees, incubees avec l'EPOrHu, L-NAME, ou les deux, ont libere davantage d'ET-1 que les cellules non traitees. En conclusion, l'EPOrHu diminue la vasodilatation induite par le debit. Cet effet inhibiteur semble impliquer la liberation d'ET-1. L'elimination de NO amplifie les effets vasculaires de l'ET-1 en presence de l'EPOrHu. Ces resultats confirment l'importance d'un rapport ET-1/NO endothelial equilibre pour eviter les effets vasopresseurs de l'EPOrHu. Mots-cles : erythropoietine, contrainte de cisaillement, debit vasculaire, monoxyde d'azote, endotheline-1, L-NAME, cellules cultivees, bosentan. [Traduit par la Redaction], Introduction Human recombinant erythropoietin (r-HuEPO) is known to stimulate erythropoiesis and to treat anemia associated with chronic renal failure (Moreno et al. 2000). Its chronic use is often associated with [...]

Low‐calorie sweeteners are substitutes for sugar and frequently used by patients with cardiometabolic diseases. Erythritol, a natural low‐calorie sugar alcohol, was linked to cardiometabolic diseases in several recent metabolomics studies. However, the characterization of its role in disease development is lacking. Macrophage polarization orchestrates the immune response in various inflammatory conditions, most notably cardiometabolic disease. Therefore, the physiological effects of Erythritol on THP‐1 macrophages were investigated. We observed an increased cellular abundance of proinflammatory M1 macrophages, characterized by CD11c, TNF‐α, CD64, CD38, and HLA‐DR markers and decreased anti‐inflammatory M2 macrophages, characterized by mannose receptor CD206. The, Erythritol increased ROS generation, and the activation of the AKT pathway, cytosolic calcium overload, and cell cycle arrest at the G1 phase. Concomitantly, an increased population of necroptotic macrophages was observed. In conclusion, we provide evidence that Erythritol induced the proinflammatory phenotype in THP‐1 macrophages and this was associated with an increased population of necroptotic macrophages. Practical applications: This assessment provides evidence of the effects of Erythritol on macrophages, particularly THP‐1–derived macrophages. Our results support the role of Erythritol in driving the inflammation that is associated with cardiometabolic diseases and provide insights in the role of Erythritol as an inducer of necroptosis in THP‐1 derived macrophages that could be associated the disease. [ABSTRACT FROM AUTHOR]

Chemotherapy‐induced anemia (CIA) is a major obstacle in cancer management. Although the mechanisms governing CIA are poorly understood, recent efforts have identified suicidal erythrocyte (red blood cell, RBC) death as a possible cause of CIA. [6]‐Gingerol (GNG), a polyphenol extracted from Zingiber officinale plant, exhibits a wide array of biological activities including antimicrobial, antioxidant, anti‐inflammatory, immunomodulatory, and anticancer activities, in vitro and in vivo. However, the potential toxicity of GNG to human RBCs remains unexplored. RBCs from heparinized blood were isolated by centrifugation and exposed to antitumor concentrations (10–100 µM) of GNG for 24 hr at 37°C. Hemolysis was calculated from hemoglobin leakage in the supernatant (λmax = 405 nm), while cytofluorometric analysis of eryptosis employed Annexin‐V‐FITC to detect phosphatidylserine (PS) exposure, forward scatter (FSC) to estimate cell volume, Fluo4/AM to measure calcium activity, and H2DCFDA to assess oxidative stress. Moreover, zVAD(OMe)‐FMK, SB203580, necrostatin‐2, staurosporin, and D4476 were used to identify signaling pathways responsive to GNG. GNG induced significant hemolysis at 100 µM, independently of extracellular calcium, and increased Annexin‐V‐FITC fluorescence that was thoroughly abrogated without extracellular calcium. GNG also enhanced Fluo4 fluorescence and reduced FSC, but had no significant effect on DCF fluorescence. Importantly, the presence of D4476 significantly attenuated GNG‐induced hemolysis. In conclusion, GNG stimulates premature RBC death characterized by loss of membrane asymmetry, elevated cytosolic calcium, cell shrinkage, and casein kinase 1α activation. Blocking the activity of calcium channels or CK1α may, therefore, ameliorate the toxic effects of GNG on RBCs. Practical applications: This report presents a safety assessment of GNG as a chemotherapeutic agent and highlights the novel toxicity of GNG to human RBCs. Our findings provide novel insights that may lead to more efficient utilization of GNG in chemotherapy. Specifically, our data revealed the involvement of calcium channels and casein kinase 1α in mediating GNG‐induced premature RBC death, and, therefore, inverse agonists or inhibitors of either pathway may be used as pharmaceutical adjuvants to attenuate the toxic effects of GNG. [ABSTRACT FROM AUTHOR]