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BACKGROUND: Bidirectional interactions between eosinophils and mast cells (MCs) have been reported in various allergic diseases. Bone marrow (BM) eosinophilia, and to a lesser extent blood eosinophilia, is common in systemic mastocytosis (SM), but its significance remains unknown. OBJECTIVE: To describe blood and BM eosinophil characteristics in SM. METHODS: A large collection of BM biopsies was analyzed using immunohistochemical staining and whole-slide imaging. Eosinophil and extracellular granules were detected by eosinophil peroxidase (EPX) staining, and MCs by KIT staining. Complementary analyses were conducted using flow cytometry and immunofluorescence. RESULTS: Eosinophil infiltrates and large areas of eosinophil degranulation were observed within or around BM MC infiltrates in SM. EPX staining surface, highlighting intact eosinophils and eosinophil degranulation, was higher in non-advanced-SM (n=37 BM biopsies) compared to both controls (n=8, p=0.0003) and to advanced SM (n=24, p=0.014). In non-advanced SM, positive correlations were observed between serum tryptase levels and percentages of eosinophil counts in BM aspirations (Spearman r coefficient r=0.38, p=0.038), eosinophils count in BM biopsies (r=0.45, p=0.007), EPX staining (r=0.37, p=0.035) and eosinophil degranulation (r=0.39, p=0.023). Eosinophil counts in BM biopsies also correlated with MC counts (r=0.47, p=0.006) and KIT staining surface (r=0.49, p=0.003). BM MCs expressed interleukin-5 receptor and other usual eosinophil cytokine/chemokine receptors, and blood eosinophils display several increased surface markers compared to controls, suggesting an activated state. CONCLUSION: Our data suggest a possible crosstalk between MCs and eosinophils, supporting MC tryptase release and MC activation-related symptoms. This suggests a rationale for targeting eosinophils in non-advanced-SM not fully controlled by other therapies.
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Acute chest syndrome (ACS) is a leading cause of morbimortality in sickle cell disease (SCD). In this prospective observational study, we investigated sputum interleukin-6 (IL-6) level as an ACS severity marker during 30 ACS episodes in 26 SCD children. Sputum IL-6 levels measured within the first 72 h of hospitalisation for ACS were significantly higher in patients with oxygen requirement ≥2 L/min, ventilation (invasive and/or non-invasive) length ≥5 days, bilateral and/or extensive opacities on chest X-ray or erythrocytapheresis requirement. Sputum IL-6 could serve as an ACS severity marker to help identify patients requiring targeted anti-inflammatory treatments such as tocilizumab.
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Síndrome Torácico Agudo , Anemia de Células Falciformes , Biomarcadores , Interleucina-6 , Índice de Severidad de la Enfermedad , Esputo , Humanos , Anemia de Células Falciformes/complicaciones , Síndrome Torácico Agudo/etiología , Niño , Interleucina-6/análisis , Interleucina-6/sangre , Masculino , Femenino , Adolescente , Esputo/metabolismo , Estudios Prospectivos , PreescolarRESUMEN
Plasma histamine levels are increased in patients with sickle cell disease (SCD), potentially promoting endothelial P-selectin expression and vaso-occlusion via histamine type 2 (H2) receptors. We conducted a prospective, non-comparative, single-centre study to determine whether famotidine, a H2 receptor antagonist, reduces P-selectin expression in SCD children. The median plasma P-selectin level was significantly reduced after 29 days of oral famotidine (53.2 ng/mL [IQR: 46.7-63.4] vs. 69.9 ng/mL [IQR: 53.6-84.2], median difference -10.2 ng/mL [IQR: -21.8 to -2.7], p = 0.005) in 28 patients. No effect was observed on other adhesion molecules, inflammation or haemolysis markers, except decreased reticulocyte count. No adverse events deemed related to famotidine were observed. Randomized controlled trials are now needed to assess the efficacy of famotidine in preventing vaso-occlusion in SCD.
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Anemia de Células Falciformes , Famotidina , Niño , Humanos , Famotidina/uso terapéutico , Selectina-P/metabolismo , Histamina , Estudios ProspectivosRESUMEN
Here, we report a dramatic efficacy of cannabidiol in an adolescent with SCD suffering from chronic pain refractory to other analgesics, with complete regression of chronic pain and rapid plasma histamine level normalization after treatment.
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BACKGROUND: Gain-of-function variants of JAK1 drive a rare immune dysregulation syndrome associated with atopic dermatitis, allergy, and eosinophilia. OBJECTIVES: This study sought to describe the clinical and immunological characteristics associated with a new gain-of-function variant of JAK1 and report the therapeutic efficacy of Janus kinase (JAK) inhibition. METHODS: The investigators identified a family affected by JAK1-associated autoinflammatory disease and performed clinical assessment and immunological monitoring on 9 patients. JAK1 signaling was studied by flow and mass cytometry in patients' cells at basal state or after immune stimulation. A molecular disease signature in the blood was studied at the transcriptomic level. Patients were treated with 1 of 2 JAK inhibitors: either baricitinib or upadacitinib. Clinical, cellular, and molecular response were evaluated over a 2-year period. RESULTS: Affected individuals displayed a syndromic disease with prominent allergy including atopic dermatitis, ichthyosis, arthralgia, chronic diarrhea, disseminated calcifying fibrous tumors, and elevated whole blood histamine levels. A variant of JAK1 localized in the pseudokinase domain was identified in all 9 affected, tested patients. Hyper-phosphorylation of STAT3 was found in 5 of 6 patients tested. Treatment of patients' cells with baricitinib controlled most of the atypical hyper-phosphorylation of STAT3. Administration of baricitinib to patients led to rapid improvement of the disease in all adults and was associated with reduction of systemic inflammation. CONCLUSIONS: Patients with this new JAK1 gain-of-function pathogenic variant displayed very high levels of blood histamine and showed a variable combination of atopy with articular and gastrointestinal manifestations as well as calcifying fibrous tumors. The disease, which appears to be linked to STAT3 hyperactivation, was well controlled under treatment by JAK inhibitors in adult patients.
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Dermatitis Atópica , Inhibidores de las Cinasas Janus , Neoplasias , Adulto , Humanos , Inhibidores de las Cinasas Janus/uso terapéutico , Dermatitis Atópica/tratamiento farmacológico , Histamina , Neoplasias/tratamiento farmacológico , Janus Quinasa 1/genéticaAsunto(s)
Síndrome Torácico Agudo , Anemia de Células Falciformes , Hemoglobinopatías , Humanos , Niño , Interleucina-6 , Pronóstico , Estudios Prospectivos , EsputoRESUMEN
Monocytes are considered crucial actors of inflammation in sickle cell disease (SCD), being responsible for an increased production of proinflammatory cytokines such as tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß), and IL-6. Although a role of free heme released by intravascular hemolysis has been suspected, the mechanisms underlying monocyte activation in patients with SCD remain unknown. Using purified human hemoglobin (Hb), we demonstrate herein, that cell-free HbS, unlike HbA or heme, is responsible for a major enhancement in the expression of proinflammatory cytokines by human monocytes. This effect was found mediated by direct interaction with the Toll-like receptor 4 (TLR4)/myeloid differentiation factor 2 (MD-2) complex, resulting in the activation of both the nuclear factor-κB (NF-κB) and type I interferon pathways. In Townes SCD mice, injection of HbS, unlike HbA, was responsible for an increased production of proinflammatory cytokines, which was prevented by the TLR4 inhibitor, TAK-242. Our results reveal a novel mechanism of monocyte activation and systemic inflammation in SCD, which opens new promising therapeutic perspectives targeting the HbS-TLR4 interaction.
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Anemia de Células Falciformes , Receptor Toll-Like 4 , Humanos , Ratones , Animales , Receptor Toll-Like 4/metabolismo , Monocitos/metabolismo , Transducción de Señal , FN-kappa B/metabolismo , Citocinas/metabolismo , Inflamación/metabolismo , Anemia de Células Falciformes/metabolismo , Hemo/metabolismoRESUMEN
Neuropilin-1 (NRP-1), the major co-receptor of vascular endothelial growth factor receptor-2 (VEGFR-2), may also independently act with VEGF-A165 to stimulate tumour growth and metastasis. Therefore, there is great interest in compounds that can block VEGF-A165/NRP-1 interaction. Peptidomimetic type inhibitors represent a promising strategy in the treatment of NRP-1-related disorders. Here, we present the synthesis, affinity, enzymatic stability, molecular modeling and in vitro binding evaluation of the branched urea-peptide hybrids, based on our previously reported Lys(hArg)-Dab-Oic-Arg active sequence, where the Lys(hArg) branching has been modified by introducing urea units to replace the peptide bond at various positions. One of the resulting hybrids increased the affinity of the compound for NRP-1 more than 10-fold, while simultaneously improving resistance for proteolytic stability in serum. In addition, ligand binding to NRP-1 induced rapid protein stock exocytotic trafficking to the plasma membrane in breast cancer cells. Examined properties characterize this compound as a good candidate for further development of VEGF165/NRP-1 inhibitors.
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Neuropilina-1/metabolismo , Oligopéptidos/farmacología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Sitios de Unión , Línea Celular Tumoral , Células Cultivadas , Exocitosis/efectos de los fármacos , Humanos , Ligandos , Oligopéptidos/química , Unión Proteica/efectos de los fármacos , Urea/químicaRESUMEN
BACKGROUND: The implication of lymphocytes in sickle cell disease pathogenesis is supported by a number of recent reports. These studies provided evidence for the activation of invariant natural killer T (iNKT) cells in adult patients, but did not investigate the involvement of other innate-like T cell subsets so far. METHODS: Here we present a monocentric prospective observational study evaluating the number and functional properties of both circulating conventional and innate-like T cells, namely iNKT, Mucosal-Associated Invariant T (MAIT) and gammadelta (γδ) T cells in a cohort of 39 children with sickle cell disease. RESULTS: Relative to age-matched healthy controls, we found that patients had a higher frequency of IL-13- and IL-17-producing CD4+ T cells, as well as higher MAIT cell counts with an increased frequency of IL-17-producing MAIT cells. Patients also presented increased Vδ2 γδ T cell counts, especially during vaso-occlusive crisis, and a lower frequency of IFNγ-producing Vδ2 γδ T cells, except during crisis. iNKT cell counts and the frequency of IFNγ-producing iNKT cells were unchanged compared to controls. Our study revealed positive correlations between 1) the frequency of IFNγ-producing CD4+, CD8+ and Vδ2 γδ T cells and the number of hospitalizations for vaso-occlusive crisis in the previous year; 2) the frequency of IFNγ-producing iNKT cells and patients' age and 3) the frequency of IL-17-producing Vδ2 γδ T cells and hemoglobin S level. CONCLUSION: These results strongly suggest a role of innate-like T cells in sickle cell disease pathophysiology, especially that of IL-17-producing MAIT and γδ T cells.
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Anemia de Células Falciformes/inmunología , Inmunidad Innata/inmunología , Células T Invariantes Asociadas a Mucosa/inmunología , Células T Asesinas Naturales/inmunología , Subgrupos de Linfocitos T/inmunología , Adolescente , Anemia de Células Falciformes/metabolismo , Niño , Femenino , Humanos , Masculino , Células T Invariantes Asociadas a Mucosa/metabolismo , Células T Asesinas Naturales/metabolismo , Estudios Prospectivos , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Subgrupos de Linfocitos T/metabolismoRESUMEN
Invariant NKT (iNKT) cells differentiate in the thymus into three distinct lineages defined by their cytokine and transcription factor expression. Signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) is essential for early stages of iNKT cell development, but its role during terminal differentiation of iNKT1, iNKT2, or iNKT17 cells remains unclear. Taking advantage of SAP-deficient mice expressing a Vα14-Jα18 TCRα transgene, we found that SAP is critical not only for IL-4 production but also for the terminal differentiation of IL-4-producing iNKT2 cells. Furthermore, without SAP, the IL-17 producing subset is expanded, while IFN-γ-producing iNKT1 differentiation is only moderately compromised. Lack of SAP reduced the expression of the transcription factors GATA-3 and promyelocytic leukemia zinc finger, but enhanced the levels of retinoic acid receptor-related orphan receptor γt. In the absence of SAP, lineage commitment was actually shifted toward the emergence of iNKT17 over iNKT2 cells. Collectively, our data unveil a new critical regulatory function for SAP in thymic iNKT cell fate decisions.