Sir Marc Feldmann’s research over the last 30 years has focused on the understanding of autoimmune disease, specifically the treatment of rheumatoid arthritis (RA). Sir Marc, now at the Kennedy Institute of Rheumatology at Oxford University, championed the importance of antigen presentation and cytokines in autoimmunity, a concept that led to TNF-α blockade. This idea was considered heretical in the 1980s until he and Sir Ravinder Maini led clinical trials showing that blocking TNF-α effectively treated rheumatoid arthritis refractory to previous therapy. The TNF-α antibodies Remicade, Humira, and Enbrel are now the cornerstone of a $25 billion industry. For stories about getting Pharma to speed delivery to patients and the power of persistence, watch the full interview.
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.
The simple fact that you can understand the words on this page, and that you might remember any of this interview tomorrow, is thanks to the simultaneous and precise coordination of communication between the billions of neurons in your brain and peripheral nervous system. Herein, the JCI speaks with Thomas Südhof of Stanford University, who has been at the center of unlocking the secrets of neurotransmission. His work over the last 30 years has elucidated much of what we know about the molecular mechanisms of neurotransmission in synaptic signaling. For this body of work, Südhof has recently shared in the 2013 Nobel Prize in Physiology or Medicine and the 2013 Albert Lasker Basic Medical Research Award.
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.
Damage to the glomerulus, which mediates the kidney's filtering function, causes plasma protein to spill into the urine, a sign of kidney failure and cardiovascular disease. Calcium influx into the podocytes, the cells that form the filtration barrier of the glomerulus, is known to damage the glomerulus, but the ion channel that mediates this influx was unknown. In this episode, Anna Greka and colleagues discuss their recent work demonstrating that inhibition of the TRPC5 ion channel protects mice from kidney damage by preventing calcium influx into the podocytes, and blocks the cytoskeletal alterations in the podocytes that disrupts the filtration barrier in the glomerulus.