Type 1 diabetes (T1D) results from autoimmune-mediated destruction of insulin-producing pancreatic β cells. While there is a genetic component to T1D, there is no reliable way to identify which genetically at-risk individuals will develop autoantibodies. In this episode, Mark Harris, Ahmed Mehdi, and Ranjeny Thomas discuss their work, which identifies a gene expression signature during infancy that when combined with HLA risk score predicts later seroconversion in genetically at-risk subjects. Use of this signature has potential to improve early diagnosis and treatment intervention for those at risk of developing T1D.
Eosinophilic esophagitis (EoE) is a chronic allergic disorder that presents with difficulty swallowing, vomiting, failure to thrive, and food impaction in adulthood. Several EoE-associated pathways have been identified; however, the underlying genetic causes of this disorder are poorly understood. In this episode, Marc Rothenberg and colleagues used whole-exome sequencing and identified EoE-associated variants in the mitochondrial oxioreductases DHTKD1 and OGDHL. In T cells, loss of DHTKD1 function increased ROS and viperin, which promotes Th2 cytokine production. Moreover, viperin was increased in esophageal biopsies from EoE patients. Together, these results implicate mitochondrial dysfunction in EoE pathogenesis.
Alport syndrome is a rare hereditary renal disease that is characterized by blood and protein in the urine, hypertension, progressive kidney failure, hearing loss, and eye abnormalities. While it is possible to diagnose the disease early, current therapies are unable to prevent end-stage kidney failure. In this episode, Lina Shehadeh and colleagues determined that osteopontin is highly upregulated in the renal tubules of a mouse model of Alport syndrome and promotes excessive cholesterol influx to the kidney. Deletion of the osteopontin-encoding gene ameliorated Alport-associated disease manifestations and improved lifespan. Together, these results identify osteopontin as a driver of renal dysfunction in Alprot syndrome and provides potential therapeutic targets to be further explored.
The transmembrane protein GARP serves as a receptor for latent TGF-β, resulting in activation of this cytokine. GARP is expressed on the surface of Tregs, tumors, and platelets and has been implicated in cancer immune invasion. In this episode, Zihai Li and colleagues reveal that the GARP-TGF-β complex is present on activated, but not resting, human and murine B cells. Using multiple murine genetic models, the authors determined that this complex is essential for maintaining immune tolerance and for preventing autoimmune disease. These results support further exploration of B cell GARP as a therapeutic target and possible diagnostic tool.
Sepsis is a life-threatening complication of infection that results in over 250,000 deaths per year in the United States. There is a strong correlation between reduced levels of lymphocytes, such as CD8+ and CD4+ T cells, and increased mortality; therefore, strategies aimed to increase these cells have therapeutic potential. The cytokine IL-7 prevents lymphocyte death, increases lymphocyte proliferation, and has been shown to improve intestinal lymphocyte counts in patients with HIV-1. In this episode, Richard Hotchkiss details the results from a prospective, randomized, double-blind, placebo-controlled trial of recombinant human IL-7 in patients with septic shock and severe lymphocytopenia. IL-7 reversed the loss of lymphocytes in septic patients, suggesting that this approach be further explored.