In this video collection, authors of findings published in The Journal of Clinical Investigation present personally guided tours of their results. The JCI accepts video submissions from authors of recently accepted manuscripts. Instructions can be found on the Author's Take Guidelines page.
The specialized endothelial cells of the blood-brain barrier (BBB) protect the brain from toxic substances, while allowing oxygen and other nutrients to pass through. The selectivity of the BBB also prevents delivery of therapeutic agents to the brain that could benefit patients with neurological diseases. In this episode, Margaret Bynoe reveals that activation of the A2A adenosine receptor (A2A AR) with the FDA-approved agonist Lexiscan reversibly reduced expression of the drug efflux transporters P-glycoprotein and BCRP1. Moreover, in mouse models, Lexisacn treatment resulted in a greater accumulation of chemotherapeutic drugs in the brain. The results of this study indicate that targeting A2A AR should be further explored for improving drug-delivery to the brain.
Nonalcoholic steatohepatitis (NASH) is the most common liver disease in the US and can lead to cirrhosis, cancer, and death; however, the drivers of NASH development are poorly understood. In this episode, Wajahat Mehal and colleagues reveal that levels of mitochondrial DNA, which activates TLR9, are elevated in plasma of mice and patients with NASH. Importantly, pharmacological or genetic inhibition of TLR9 blocked NASH development in mice fed a high-fat diet. The results of this study identify TLR9 activation via mitochondrial DNA as a driver of NASH and suggest targeting this pathway should be further explored for treatment of NASH.
While animal models of neurodegenerative diseases exhibit many of the features observed in patients, it remains a challenge to translate laboratory findings to effective clinical therapies. In this episode, Steve Finkbeiner, Pascal Sanchez, and Kate Possin discuss their collaboration to develop and evaluate a virtual version of the Morris water maze, which is frequently used to assess spatial learning and memory in rodents, for use in patients with mild Alzheimer’s disease-associated cognitive impairment. Careful comparison between a mouse model of Alzheimer’s disease in the Morris maze and patients with Alzheimer’s disease in the virtual version of the test revealed that with proper sample size and the evaluation of appropriate performance measures the Morris maze is a sensitive assay for detecting Alzheimer’s disease-related impairments across species.
Infection with group A Streptococcus (GAS) causes the common and treatable pharyngitis known as strep throat; however, these infections are also associated with autoimmune diseases of the central nervous system (CNS). A subset of children are at risk of developing pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), which are characterized by an abrupt onset of abnormal behaviors. In murine models, GAS has been shown to induce a robust Th17 response in nasal-associated lymphoid tissues. In this episode, Pat Cleary and Dritan Agalliu discuss their collaboration to investigate the link between the generation of GAS-specific Th17 cells and CNS autoimmunity. They determined that multiple intranasal GAS challenges in mice promotes migration and persistence of GAS-specific Th17 cells to the brain, leading to blood-brain barrier (BBB) breakdown and autoantibody access to the CNS. Moreover, they identified GAS-specific Th17 cells in the tonsils of patients naturally exposed to GAS. Together, these data provide insights into the immunopathology underlying GAS-associated neurological complications.
The affinity that B cells have for antigen is increased through an iterative process known as affinity maturation. This process involves the cycling of B cells cycle between somatic hypermutation and proliferation in the germinal center (GC) dark zone (DZ), allowing the acquisition of mutations that enhance antigen affinity, and clonal selection in the GC light zone (LZ). The oncogenic microRNA miR-155 is required for efficient affinity maturation and GC maintenance; however, the underlying molecular mechanisms are unclear. In this episode, Rinako Nakagawa and Elena Vigorito discuss their work, which reveals that miR-155 is highly expressed in positively selected c-MYC+ LZ B cells and inhibits JARID2 to prevent apoptosis of positively selected B cells. Together, the results of this study provide important insight in the GC response and how c-MYC and miR-155 may collaborate as oncogenes.