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Late-onset inflammatory toxicities resembling hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) occur after chimeric antigen receptor T cell (CAR T cell) infusion and represent a therapeutic challenge. Given the established link between perforin deficiency and primary HLH, we investigated the role of perforin in anti-CD19 CAR T cell efficacy and HLH-like toxicities in a syngeneic murine model. Perforin contributed to both [CD8.sup.+] and [CD4.sup.+] CAR T cell cytotoxicity but was not required for in vitro or in vivo leukemia clearance. Upon CAR-mediated in vitro activation, perforin-deficient CAR T cells produced higher amounts of proinflammatory cytokines compared with WT CAR T cells. Following in vivo clearance of leukemia, perforin-deficient CAR T cells reexpanded, resulting in splenomegaly with disruption of normal splenic architecture and the presence of hemophagocytes, which are findings reminiscent of HLH. Notably, a substantial fraction of patients who received anti-CD22 CAR T cells also experienced biphasic inflammation, with the second phase occurring after the resolution of cytokine release syndrome, resembling clinical manifestations of HLH. Elevated inflammatory cytokines such as IL-1[beta] and IL-18 and concurrent late CAR T cell expansion characterized the HLH-like syndromes occurring in the murine model and in humans. Thus, a murine model of perforin-deficient CAR T cells recapitulated late-onset inflammatory toxicities occurring in human CAR T cell recipients, providing therapeutically relevant mechanistic insights., Introduction Chimeric antigen receptor T cells (CAR T cells) are highly effective against B cell malignancies (1-8) but are frequently associated with cytokine-mediated toxicities or hyperinflammatory conditions (9, 10). The [...]

The congenital sideroblastic anemias (CSAs) can be caused by primary defects in mitochondrial iron-sulfur (Fe-S) cluster biogenesis. HSCB (heat shock cognate B), which encodes a mitochondrial cochaperone, also known as HSC20 (heat shock cognate protein 20), is the partner of mitochondrial heat shock protein A9 (HSPA9). Together with glutaredoxin 5 (GLRX5), HSCB and HSPA9 facilitate the transfer of nascent 2-iron, 2-sulfur clusters to recipient mitochondrial proteins. Mutations in both HSPA9 and GLRX5 have previously been associated with CSA. Therefore, we hypothesized that mutations in HSCB could also cause CSA. We screened patients with genetically undefined CSA and identified a frameshift mutation and a rare promoter variant in HSCB in a female patient with non-syndromic CSA. We found that HSCB expression was decreased in patient-derived fibroblasts and K562 erythroleukemia cells engineered to have the patient-specific promoter variant. Furthermore, gene knockdown and deletion experiments performed in K562 cells, zebrafish, and mice demonstrate that loss of HSCB results in impaired Fe-S cluster biogenesis, a defect in RBC hemoglobinization, and the development of siderocytes and more broadly perturbs hematopoiesis in vivo. These results further affirm the involvement of Fe-S cluster biogenesis in erythropoiesis and hematopoiesis and define HSCB as a CSA gene., Introduction The congenital sideroblastic anemias (CSAs) are a group of uncommon inherited blood disorders characterized by abnormal iron accumulation in the mitochondria of erythroid cells. As the normal location of [...]

Rationale Detecting weaning-induced pulmonary oedema (WIPO) is important because its treatment might prompt extubation. For this purpose, lung ultrasound might be an attractive tool, since it demonstrates pulmonary oedema through the appearance of B-lines. Objectives To test the ideal profile (increase in the number of B-lines) for diagnosing WIPO. Methods Before and at the end of 62 spontaneous breathing trials (SBT) performed in 42 patients, we prospectively assessed lung ultrasound on four anterior chest wall points. B-lines were counted before and at the end of SBT. We looked for the threshold of B-line increase (Delta-B-lines) that provided the best diagnostic accuracy, compared to the reference diagnosis of WIPO established by experts blinded to lung ultrasound. Results SBT failed in 33 cases. WIPO occurred in 17 cases and all failed. The best diagnostic accuracy was reached with a Delta-B-lines [greater than or equal to] 6. Among WIPO, the number of B-lines increased by [greater than or equal to] 6 in 15 cases (including 13 cases with an increase of [greater than or equal to] 8 B-lines). Among the 16 cases with SBT failure but without WIPO, the Delta-B-lines was [greater than or equal to] 6 in two cases. Among the 33 cases with SBT failure, this profile diagnosed WIPO with a sensitivity of 88% (64-98) and a specificity of 88% (62-98) [area under the receiver operating characteristic curve 0.91 (0.75-0.98)]. Among the 29 cases with SBT success, a Delta-B-lines [greater than or equal to] 6 occurred in two cases. Conclusions This study suggests that a Delta-B-lines [greater than or equal to] 6 on four anterior points allows the diagnosis of WIPO with the best accuracy. This should be confirmed in larger populations., Author(s): Alexis Ferré [sup.1] [sup.2], Max Guillot [sup.1] [sup.2], Daniel Lichtenstein [sup.3], Gilbert Mezière [sup.4], Christian Richard [sup.1] [sup.2], Jean-Louis Teboul [sup.1] [sup.2], Xavier Monnet [sup.1] [sup.2] Author Affiliations: (1) [...]