[Pathological diagnosis of Danon disease by endomyocardial biopsy].

Objective To investigate the clinicopathological features and differential diagnosis of Danon disease. Methods: Two cases of Danon disease were selected from Beijing Anzhen Hospital Affiliated to Capital Medical University from January 2019 to December 2019. The clinical history, histological, immunohistochemical, ultrastructural and gene mutation analysis were collected. Results: Both of the patients were male, aged 21 and 19 years old, respectively. They were diagnosed with hypertrophic cardiomyopathy by clinicians. The histologic features of endocardial biopsies were hypertrophy and vacuolar degeneration of cardiomyocytes. Part of cardiomyocytes appeared as intracellular clear areas lacking myofibers. The nuclei were large, irregular and hyperchromatic. And lipofuscin was occasionally observed in the nuclei of cardiomyocytes. Ultrastructural feature of electron microscopic was glycogen accumulation. Genetic analysis identified two lysosome-associated membrane protein-2 (LAMP2) gene mutations. A 1-bp deletion in exon 8 (c.973delC) was found in patient 1, leading to a frame-shift mutation. A 3-bp duplication in exon 5 (c.719_721dupAGC) was found in patient 2, leading to an insertion mutation. Conclusions: Danon disease is a rare disease characterized by hypertrophic cardiomyopathy. It is caused by mutations in the LAMP2 gene. Vacuolar degeneration of cardiomyocytes, glycogen accumulation under electron microscope and the mutation of LAMP2 gene are the critical features of Danon disease. Familiar with its clinicopathological characteristics would be helpful to avoid the misdiagnosis of Danon disease.

Changes in the PD-1 and PD-L1 expressions of splenic dendritic cells in multiple-organ dysfunction syndrome mice and their significance.

The aim of this study was to evaluate the expression of surface molecules in splenic dendritic cells (DC) in multiple-organ dysfunction syndrome (MODS) mice and their effects on the immunosuppression of sepsis and MODS. One hundred thirty C57BL/6 mice were divided into 7 groups: 6, 12, 24, 48 h, 5-7 days, 10-12 days, and the normal control group. The sepsis-MODS mouse model was established by zymson injection into the peritoneal cavity. Histopathological changes in the spleen were evaluated by hematoxylin and eosin (HE) staining. After enrichment with BDTM IMag, the expressions of PD-1, PD-L1, MHC-II (I-A(b)), and CD86 in splenic DCs were examined by flow cytometry, and their relationship with sepsis development and MODS was analyzed. The histological structures of the spleen were damaged in the 24-, 48-h, and 10-12-day groups. PD-L1 expression increased 6 h after zymosan injection, decreased to normal levels at 24 and 48 h, and increased at 5-7 days, peaking at 10-12 days. The change in PD-1 expression roughly paralleled that of PD-L1. MHC-II and CD86 increased at 6 and 12 h, and dropped to normal levels at 10-12 days. In the early stage of injury, splenic DCs were mainly activated, whereas in the later stage, the expressions of the negative co-stimulatory molecules, PD-L1 and PD- 1, were upregulated, similar to tolerogenic DCs. Splenic DCs might suppress the stimulation of T lymphocytes in MODS mice through the PD-L1/PD-1 pathway, which would induce immunosuppression and the pathogenesis of MODS.

Treatment with Fms-like tyrosine kinase 3 ligand reverses lung dendritic cell immunoparalysis and ameliorates zymosan-induced secondary lung injury in mice.

Depletion and dysfunction of dendritic cells in the lung can induce local immunoparalysis, which often leads to multiple organ dysfunction syndrome (MODS)-associated mortality. A therapeutic strategy that reverses this immunoparalysis is required. In the present study, we examined the effects of in vivo Fms-like tyrosine kinase 3 ligand (Flt3L) treatment on zymosan (zym)-induced secondary lung injury and dendritic cell (DC) immunoparalysis. BALBc mice were divided randomly into four groups (20/group): (1) sham [intraperitoneal (i.p.) saline] + vehicle [subcutaneous (s.c.) 0·01% mouse serum albumin]; (2) sham + Flt3L (s.c.); (3) zym (i.p.) + vehicle; and (4) zym + Flt3L. Injections were for 9 consecutive days; 12 days later we examined: survival rate (monitored for 12 days); lung tissue histopathology (haematoxylin and eosin staining); plasma indices of lung function (pH, PaO(2) , PaCO(2) , HCO(3) (-) ); DC subsets in lung tissue; and lung DCs production of interleukin (IL)-12p70 and IL-10. Zym administration resulted in increased mortality associated with significant lung histopathological changes and abnormal blood gas indices; however, these pathological changes were ameliorated by Flt3L treatment. Zym injections also resulted in significant reductions in DC subsets recovered from lungs [CD11c(+) major histocompatibility complex (MHC)-II/I-A(d+) , CD11c(+) CD11b(+) and CD11c(+) B220(+) ]. Importantly, in-vivo Flt3L treatment reversed these trends for DC immunoparalysis by increasing the percentages of recovered DC subsets concomitant with increased DC production of IL-12 p70 and decreased IL-10 production. These results suggest that Flt3L may have therapeutic potential for reversing DC immunoparalysis and ameliorating lung injury secondary to MODS.