Single cell RNA sequencing reveals ferritin as a key mediator of autoimmune pre-disposition in a mouse model of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a devastating autoimmune disorder characterized by failure of self-tolerance with resultant production of autoreactive antibodies. The etiology of this syndrome is complex, involving perturbations in immune cell signaling and development. The NZBWF1 mouse spontaneously develops a lupus-like syndrome and has been widely used as a model of SLE for over 60 years. The NZBWF1 model represents the F1 generation of a cross between New Zealand Black (NZB) and New Zealand White (NZW) mice. In order to better understand the factors that contribute to the development of autoimmunity, single cell RNA sequencing was conducted using the bone marrow from female NZBWF1 mice prior to the development of overt disease. The results were contrasted with single cell RNA sequencing results from the two parental strains. The expected findings of B cell abundance and upregulation, and evidence of interferon signaling were validated in this model. In addition, several novel areas of inquiry were identified. Most notably, the data showed a marked upregulation of the ferritin light chain across all cell types in the NZBWF1 mice compared to parental controls. This data can serve as a gene expression atlas of all hematopoietic cells in the NZBWF1 bone marrow prior to the development of autoimmunity.

Norrie disease with a spontaneously shrinking choroid plexus abnormality: a case report.

Background: Norrie disease is a genetic disorder of the retina characterized by impaired retinal vascular development leading to retinal detachment and blindness. Non-retinal manifestations of the disorder include intellectual disability and seizure disorders. However, to date, no association with neurological mass lesions has been described.Materials and methods: Case reporResults: Here, we report a case of a patient with Norrie disease who presented with an enhancing mass of the choroid plexus that spontaneously diminished in size. Conclusion: This report suggests watchful waiting as a reasonable clinical approach to choroid plexus lesions in patients with Norrie disease.

In silico analysis identifies a putative cell-of-origin for BRAF fusion-positive cerebellar pilocytic astrocytoma.

Childhood cancers are increasingly recognized as disorders of cellular development. This study sought to identify the cellular and developmental origins of cerebellar pilocytic astrocytoma, the most common brain tumor of childhood. Using publicly available gene expression data from pilocytic astrocytoma tumors and controlling for driver mutation, a set of developmental-related genes which were overexpressed in cerebellar pilocytic astrocytoma was identified. These genes were then mapped onto several developmental atlases in order to identify normal cells with similar gene expression patterns and the developmental trajectory of those cells was interrogated. Eight known neuro-developmental genes were identified as being expressed in cerebellar pilocytic astrocytoma. Mapping those genes or their orthologs onto mouse neuro-developmental atlases identified overlap in their expression within the ventricular zone of the cerebellar anlage. Further analysis with a single cell RNA-sequencing atlas of the developing mouse cerebellum defined this overlap as occurring in ventricular zone progenitor cells at the division point between GABA-ergic neuronal and glial lineages, a developmental trajectory which closely mirrors that previously described to occur within pilocytic astrocytoma cells. Furthermore, ventricular zone progenitor cells and their progeny exhibited evidence of MAPK pathway activation, the paradigmatic oncogenic cascade known to be active in cerebellar pilocytic astrocytoma. Gene expression from developing human brain atlases recapitulated the same anatomic localizations and developmental trajectories as those found in mice. Taken together, these data suggest this population of ventricular zone progenitor cells as the cell-of-origin for BRAF fusion-positive cerebellar pilocytic astrocytoma.

Tumor necrosis factor-α impairs cerebral blood flow in pregnant rats: role of vascular ß-epithelial Na+ channel.

Preeclampsia is a pregnancy-related disorder characterized by hypertension, vascular dysfunction and an increase in circulating inflammatory factors including the cytokine, tumor necrosis factor-α (TNF-α). Studies have shown that placental ischemia is associated with 1) increased circulating TNF-α, 2) attenuated pressure-induced cerebral vascular tone, and 3) suppression of ß-epithelial Na+ channel (ßENaC) protein in cerebral vessels. In addition to its role in epithelial Na+ and water transport, ßENaC is an essential signaling element in transduction of pressure-induced (aka "myogenic") constriction, a critical mechanism of blood flow autoregulation. While cytokines inhibit expression of certain ENaC proteins in epithelial tissue, it is unknown if the increased circulating TNF-α associated with placental ischemia mediates the loss of cerebrovascular ßENaC and cerebral blood flow regulation. Therefore, the purpose of this study was to test the hypothesis that increasing plasma TNF-α in normal pregnant rats reduces cerebrovascular ßENaC expression and impairs cerebral blood flow (CBF) regulation. In vivo TNF-α infusion (200 ng/day, 5 days) inhibited cerebrovascular expression of ßENaC and impaired CBF regulation in pregnant rats. To determine the direct effects of TNF-α and underlying pathways mediating vascular smooth muscle cell ßENaC reduction, we exposed cultured VSMCs (A10 cell line) to TNF-α (1-100 ng/mL) for 16-24 h. TNF-α reduced ßENaC protein expression in a concentration-dependent fashion from 0.1 to 100 ng/mL, without affecting cell death. To assess the role of canonical MAPK signaling in this response, VSMCs were treated with p38MAPK or c-Jun kinase (JNK) inhibitors in the presence of TNF-α. We found that both p38MAPK and JNK blockade prevented TNF-α-mediated ßENaC protein suppression. These data provide evidence that disorders associated with increased circulating TNF-α could lead to impaired cerebrovascular regulation, possibly due to reduced ßENaC-mediated vascular function.NEW & NOTEWORTHY This manuscript identifies TNF-α as a possible placental-derived cytokine that could be involved in declining cerebrovascular health observed in preeclampsia. We found that infusion of TNF-α during pregnancy impaired cerebral blood flow control in rats at high arterial pressures. We further discovered that cerebrovascular ß-epithelial sodium channel (ßENaC) protein, a degenerin protein involved in mechanotransduction, was reduced by TNF-α in pregnant rats, indicating a potential link between impaired blood flow and this myogenic player. We next examined this effect in vitro using a rat vascular smooth muscle cell line. TNF-α reduced ßENaC through canonical MAPK-signaling pathways and was not dependent on cell death. This study demonstrates the pejorative effects of TNF-α on cerebrovascular function during pregnancy and warrants future investigations to study the role of cytokines on vascular function during pregnancy.