This series showcases video summaries of new findings published in The Journal of Clinical Investigation. This format allows authors to to provide a personally guided tour of their results and makes the research more accessible to a broad readership. The JCI accepts videos from authors of recently accepted manuscripts. Instructions can be found on the Author's Take Guidelines page.
The pulmonary disease tuberculosis (TB) is a global health problem that results from Mycobacterium tuberculosis (Mtb) infection. As parasitic helminth worms are endemic to areas with high rates of TB, helminths are thought to enhance susceptibility to Mtb. In this episode, Shabaana Khader and colleagues demonstrate that helminth coinfection exacerbates TB by promoting formation of arginase-1-expressing inflammatory granulomas, resulting in increased lung damage. Moreover, inflammatory phenotypes associated with coinfection were reversed in a murine co-infection model by treatment with anti-helminthic agents. This study provides mechanistic insight into the link between helminth coinfection and TB disease severity.
Granulomatosis with polyangiitis (GPA) is a form of autoimmune vasculitis that is associated with the presence of anti-neutrophil cytoplasmic antibodies (ANCAs) directed against proteinase 3 (PR3). In this episode, Véronique Witko-Sarsat, Nathalie Thieblemont, and Katherine Martin discuss their work, which shows that PR3 expression is enhanced on the surface of apoptotic neutrophils from GPA patients. PR3-expressing apoptotic neutrophils were found to promote pro-inflammatory responses and prevent the development of regulatory T cells. Moreover, the authors show that this immune dysregulation was also present in GPA patients. Together, the results of this study provide important insight into the pathogenesis of GPA.
Retinitis pigmentosa (RP) is hereditary retinal degenerative disease that is characterized by progressive loss of photoreceptor function. In human trials, gene therapy has been shown to improve vision; however, this benefit has not been sustainable. It is not clear if the lack of long-term benefit is due to the advanced stage of the disease at the time of therapy or due to inefficient delivery of the functional gene. In this episode, Stephen Chang and Susanne Koch discuss the development of a murine RP model that allows induction of the corrected gene at various stages of disease. The results of their study indicate that gene therapy can treat RP even at advanced stages and that future studies should focus on improving gene delivery.
Epigenetic modifications, such as histone acetylation, are dysregualted in Alzheimer’s disease (AD) and other neurodegenerative disorders, resulting altered patterns of neuronal gene expression and cognitive decline. In this episode, Eva Benito-Garagorri reveals that the small molecule histone-deacetylase (HDAC) suberoylanilide hydroxamic acid (SAHA) improves cognitive function and restores neuronal gene expression patterns in murine models of aging and neurodegeneration. Importantly, oral administration of SAHA provided these beneficial effects in neurons and did not affect non-neuronal cells. The results of this study suggest that SAHA should be further explored for the treatment of neurodegenerative disorders and age-related cognitive decline.
An inability to properly sustain blood cell production results in the development of hematopoietic disorders. Epigenetic regulators have been shown to be involved in the function of hematopoietic stem and progenitor cells; however, dysfunction of these enzymes is associated with development of malignancies. In this episode Stephen Nimer and colleagues identify the type II arginine methyltransferase PRMT5 as an important regulator of adult hematopoiesis. Mice lacking PRMT5 developed fatal pancytopenia due to reduced proliferation of hematopoietic progenitor cells as the results of impaired cytokine signaling and increased p53 signaling. Hematopoietic stem cell populations were not initially reduced in these animals; however, this population was unable to restore blood cell populations in lethally irradiated mice. Together, the results of this study provide important insight into the role of PRMT5-mediated gene expression in maintaining hematopoietic homeostasis.
Copyright © 2015 American Society for Clinical Investigation