The Author’s Take 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.
Broadly neutralizing antibodies (BnAbs) represent a promising strategy for targeting rapidly mutating viruses, such as HIV-1. BnAbs recognize conserved epitopes and display unique characteristics that suggest that their development may be limited by immune tolerance. In this episode, Baton Haynes discusses the identification and characterization of a BnAb in an HIV-1-infected individual that developed the autoimmune disease systemic lupus erythematosus. The BnAb targeted both the HIV-1 envelope and human antigens, including dsDNA, supporting the hypothesis that lax immune control allows for maturation and production of BnAbs.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly forms of cancer, primarily due to the resistance of PDAC tumors to current therapeutic strategies. Several lines of evidence suggest that ineffective delivery of chemotherapy agents to tumor cells in the pancreas contributes to PDAC-associated treatment resistance. In this episode, Eugene Koay and Jason Fleming discuss the results of their clinical study that links pancreatic transport properties collected from PDAC patient CT scans with survival and response to the chemotherapy agent gemcitabine.
Familial Alzheimer's disease (FAD) is an early on-set, hereditary form of neurological disease with variable pathophysiology that is often associated with loss of cerebellar function and amyloid plaque formation. Diego Sepulveda-Falla and colleagues investigated how a particular PS1 mutation (PS1-E280A), present in large Columbian kindred of FAD patients, promotes disease. Postmortem evaluation of cerebellar tissue from patients revealed that PS1-E280A is associated with Purkinje cell loss, an abundance of abnormal mitochondria and loss of calcium transport proteins. Furthermore, cell culture and murine models of PS1-E280A FAD revealed that PS1alterations disrupt calcium homeostasis and mitochondrial transport within cerebellar neurons, resulting in increased amyloid plaque formation and cerebellar dysfunction.
Nonsense mutations that lead to PAX6 haploinsufficiency cause congenital aniridia, a panocular condition that results in severe vision defects. Cheryl Gregory-Evans and colleagues hypothesized that suppression of nonsense mutations could increase PAX6 levels and prevent post-natal eye damage. They developed a topical formulation of ataluren that not only inhibited disease progression, but also reversed ocular malformations and restored retinal responses in Pax6-deficient mice.
In order to protect the body from viruses and cancer, T cells must perform multiple functions, a feature that is often lost during chronic infection. Jonathan Schneck and colleagues examined the molecular mechanisms that maintain T cell polyfunctionality. They found that MAPK/ERK signaling was upregulated in polyfunctional T cells and that activation of this pathway was altered in response to different levels of antigen. Importantly, high levels of antigen increased levels of sprouty-2 (SPRY2), a negative regulator of MAPK/ERK signaling. High levels of SPRY2 were observed in HIV-specific T cells and inhibition of SPRY2 expression increased polyfunctional responses to HIV. These findings suggest that SPRY2 could be targeted to increase T cell polyfunctionality in the context of chronic viral infections.
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