No abstract

The meninges contain adaptive immune cells that provide immunosurveillance of the CNS. These cells are thought to derive from the systemic circulation. Through single-cell analyses, confocal imaging, bone marrow chimeras, and parabiosis experiments, we show that meningeal B cells derive locally from the calvaria, which harbors a bone marrow niche for hematopoiesis. B cells reach the meninges from the calvaria through specialized vascular connections. This calvarial–meningeal path of B cell development may provide the CNS with a constant supply of B cells educated by CNS antigens. Conversely, we show that a subset of antigen-experienced B cells that populate the meninges in aging mice are blood-borne. These results identify a private source for meningeal B cells. which may help maintain immune privilege within the CNS.

No abstract

Progression of fatty liver to non-alcoholic steatohepatitis (NASH) is a rapidly growing health problem. Presence of inflammatory infiltrates in the liver and hepatocyte damage distinguish NASH from simple steatosis. However, the underlying molecular mechanisms involved in the development of NASH remain to be fully understood. Here we perform transcriptional and immune profiling of NASH patients before and after lifestyle intervention (LSI). Analysis of liver microarray data from a cohort of patients with histologically assessed NAFLD reveals a hepatic gene signature, which is associated with NASH and is sensitive to regression of NASH activity upon LSI independently of body weight loss. Enrichment analysis reveals the presence of immune-associated genes linked to inflammatory responses, antigen presentation and cytotoxic cells in the NASH-linked gene signature. In an independent cohort, NASH is also associated with alterations in blood immune cell populations, including conventional dendritic cells (cDC) type 1 and 2, and cytotoxic CD8 T cells. Lobular inflammation and ballooning are associated with the accumulation of CD8 T cells in the liver. Progression from simple steatosis to NASH in a mouse model of diet-driven NASH results in a comparable immune-related hepatic expression signature and the accumulation of intra-hepatic cDC and CD8 T cells. These results show that NASH, compared to normal liver or simple steatosis, is associated with a distinct hepatic immune-related gene signature, elevated hepatic CD8 T cells, and altered antigen-presenting and cytotoxic cells in blood. These findings expand our understanding of NASH and may identify potential targets for NASH therapy.