In the vascular wall, endothelial nitric oxide synthase (eNOS) produces NO to regulate peripheral vascular resistance, tissue perfusion, and blood pressure. In resistance arteries, eNOS couples with α-globin and, through chemical reactions, modulates NO diffusion needed for vascular smooth muscle relaxation. While α-globin protein alone is known to be unstable, the mechanisms that enable α-globin protein expression remain elusive. Here, Lechauve et al. report that arterial endothelium expresses α hemoglobin–stabilizing protein, which acts as a critical chaperone protein for α-globin expression and vascular function.
Adam C. Straub, Mark T. Gladwin
The current inactivated influenza vaccines rely on the induction of neutralizing antibodies against the head domain of the viral hemagglutinin (HA). The HA head contains five immunodominant antigenic sites, all of which are subject to antigenic drift, thereby limiting vaccine efficacy. Bypassing the immune system’s tendency to focus on the most variable regions of the HA may be a step toward more broadly protective influenza vaccines. However, this requires a better understanding of the biological meaning of immunodominance, and of the hierarchy between different antigenic sites. In this issue of the JCI, Liu et al. determined the immunodominance of the five antigenic sites of the HA head in experimentally infected mice, guinea pigs, and ferrets. All three species exhibited different preferences for the five sites of the 2009 pandemic H1N1 strain. Moreover, human subjects exhibited yet a different pattern of immunodominance following immunization with the standard inactivated influenza vaccine. Together, these results have important implications for influenza vaccine design and interpretation of animal models.
Kristien Van Reeth
Bone metabolism is controlled by endocrine, paracrine, and inflammatory signals that continuously operate in health and disease. While these signals are critical for skeletal adaptation during development, longitudinal growth, and repair, disturbances such as sex hormone deficiency or chronic inflammation have unambiguously been linked to bone loss and skeletal fragility across species. In the current issue of the JCI, Khosla et al. evaluated the role of sympathetic outflow and present evidence to support the idea that the sympathetic nervous system regulates bone metabolism in humans, primarily via the β1-adrenergic receptor.
Lorenz C. Hofbauer, Holger Henneicke
Renin-expressing cells have been conserved through evolution and maintain blood pressure and fluid homeostasis. Lack of availability of tools to study the specifics of renin regulation has limited advances in this field. In the current issue of the Journal of Clinical Investigation, Martinez and colleagues used the genome-wide assessment of the chromatin status of cells and uncovered a unique set of super-enhancers that determine the identity of renin cells. The renin super-enhancers play a key role in the molecular memory of renin cell function, a mechanism at the core of preserving homeostasis.
Steven D. Crowley
Hepatitis B virus–specific (HBV-specific) T cells have been identified as main effector cells in HBV clearance. In contrast, B cells producing neutralizing antibodies against the HBV surface antigen (HBsAg) have been studied in little detail, mainly due to methodical limitations. In this issue of the JCI, two reports use a new technique to specifically detect and characterize HBsAg-specific B cells ex vivo. Indeed, these cells are present, but show phenotypic alterations and impaired function during acute and chronic HBV infection. Thus, HBsAg-specific B cells are a novel attractive target for antiviral strategies toward functional cure of chronic HBV infection.
Christoph Neumann-Haefelin, Robert Thimme
The polyamine metabolic pathway has been considered a rational target for antineoplastic therapy since it was discovered that polyamines are absolute requirements for tumor initiation, growth, and, in some instances, survival. Although several promising preclinical studies have demonstrated the critical nature of polyamines for tumor growth, the clinical success of agents targeting polyamine metabolism have been lacking. In the accompanying article, Bianchi-Smiraglia et al. identify both a new target and new drug that inhibits polyamine biosynthesis, reduces intracellular polyamines, and inhibits the growth of several models of human multiple myeloma. These results are both intriguing and provide promise for moving such a strategy to the clinic.
Robert A. Casero Jr.
In spite of a very robust body of literature and definitive data demonstrating the importance of the programmed cell death receptor-1 (PD-1) pathway in T cells and their function, the data on NK cell PD-1 expression have been highly variable and, particularly in the case of mouse NK cells, scarce. In this issue of the JCI, Hsu et al. present data demonstrating PD-1 expression on mouse NK cells only within tumors and show that PD-1 blockade elicits an antitumor NK cell–mediated response. This study indicates that, given the complexity of both the biology and study of NK cells, further work is needed to more clearly determine the role of the PD-1/PD-1 ligand (PD-L1) on NK cells.
Cordelia Dunai, William J. Murphy
About one-third of the US population will develop herpes zoster (HZ, commonly known as shingles) over a lifetime, while two-thirds will not. It is not clear exactly why certain people are susceptible to HZ; however, we may be coming closer to an answer. In this issue of the JCI, a study by Levin et al. provides important details concerning pathogenesis of and protection from HZ. The authors characterized differences in the immunologic responses induced by two HZ vaccines, the live attenuated zoster vaccine (ZV) and the more recently developed adjuvanted varicella-zoster virus (VZV) glycoprotein E (gE) subunit herpes zoster vaccine (HZ/su), in vaccine-naive subjects and those previously vaccinated with HZ. The observed differences in responses paralleled the observed clinical protection of the two zoster vaccines, with HZ/su being superior to HZ. Together, these results seem to explain immunologically why the new subunit vaccine outperforms the live vaccine. These differences may also provide clues as to why HZ develops in the first place.
Anne A. Gershon
Stephen T. Oh
Over 40 years ago, Loeb and colleagues proposed that errors in DNA replication produce a mutator phenotype that is involved in generating the multiple mutations required for tumor development. In this issue of the JCI, Li, Castrillon, and colleagues describe a mouse model containing a single base change in the gene encoding replicative DNA polymerase ε (POLE) that mimics the “ultramutator” phenotype recently reported in many human tumors. Their seminal accomplishment validates Loeb’s hypothesis and the use of mutational signatures to understand the origins and potentially the treatment of human tumors, and it offers an exciting opportunity to further explore the mechanisms responsible for normal DNA replication fidelity and their perturbations.
Thomas A. Kunkel
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