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Videos

TLR9 activation in nonalcoholic steatohepatitis

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. 

 


Translating a rodent behavioral assay for humans

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.


James Allison

James Allison of the MD Anderson Cancer Center has made key discoveries on the regulation of T cell activation and modulation, including identification and characterization of the T cell antigen receptor and the T cell coreceptors CD28 and cytotoxic T lymphocyte antigen-4 (CTLA-4). He was awarded the 2015 Lasker~DeBakey Clinical Medical Research Award in honor of his discovery and subsequent development of CTLA-4–targeted monoclonal antibody therapy to unleash the immune response to cancer. In an interview with JCI Editor at Large Ushma Neill, Allison discusses his decision to pursue a PhD instead of an MD and his early experiences in applying biochemical techniques to immunological questions. Additionally, Allison talks about the process of moving anti–CTLA-4 therapy into the clinic.

 


Linking intranasal group A Streptococcus infection to CNS complications

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. 


Protecting positively selected B cell clones from apoptosis

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.

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