Commentary
Abstract
Minor histocompatibility antigens (mHAgs) selectively expressed by cells or cell subsets of the hematopoietic system are targets of the T cell–mediated graft-versus-leukemia response that develops following allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of hematological malignancies. This observation has served as the rationale for utilizing mHAg-specific immunotherapy for the treatment of particular patients. However, at present, only a select and small number of patients could potentially benefit from mHAg-based immunotherapy. A report from de Rijke et al. in this issue of the JCI describes a new hematopoietic lineage–specific HLA-B7–restricted mHAg associated with remission of chronic myeloid leukemia. This result represents another example of an mHAg-mediated graft-versus-leukemia response, thereby expanding the number of patients eligible for mHAg-based immunotherapy in the setting of HSCT.
Authors
Eric Spierings, Els Goulmy
Abstract
The recent discovery of the Gi protein–coupled receptor GPR109A (HM74A in humans; PUMA-G in mice) as a receptor for nicotinic acid has provided the opportunity to gain greater understanding of the underlying biology contributing to the clinical efficacy (increases in HDL, decreases in VLDL, LDL, and triglycerides) and the characteristic side-effect profile of nicotinic acid. GPR109A has been proven to be the molecular target for the actions of nicotinic acid on adipose tissue, and in this issue of the JCI, Benyó et al. have confirmed the involvement of GPR109A in the nicotinic acid–induced flushing response, a common side effect. The involvement of GPR109A in both the desirable and undesirable clinical actions of nicotinic acid raises interesting questions regarding the function of this receptor.
Authors
Nicholas B. Pike
Abstract
A life-saving response to hypoglycemia requires rapid sensing of decreases in glycemia and consequent brisk glucagon secretion. Preceding studies have shown that mice lacking glucose transporter type 2 (GLUT2) lose this response. In this issue of the JCI, Marty et al. report that glucose sensing and consequent pancreatic glucagon secretion are restored by re-expression of GLUT2 in glial but not neuronal cells. A new, glucose-sensing role is ascribed to GLUT2-expressing glial cells.
Authors
Amira Klip, Meredith Hawkins
Abstract
Glucagon-like peptide–1 (GLP-1) has a diverse set of peripheral actions which all serve to promote enhanced glucose tolerance, and for this reason it has become the basis for new treatments for type 2 diabetes. In this issue of the JCI, Knauf et al. provide clear evidence that GLP-1 signaling in the CNS is also linked to the control of peripheral glucose homeostasis by inhibiting non–insulin-mediated glucose uptake by muscle and increasing insulin secretion from the pancreas. The authors’ work points to an important need to integrate diverse GLP-1 signaling actions and peripheral GLP-1 function in order to better understand both normal and abnormal glucose homeostasis.
Authors
David A. D’Alessio, Darleen A. Sandoval, Randy J. Seeley
Abstract
Cytokines secreted by cells that mediate the innate and adaptive immune responses play a critical role in regulating the synthesis of ECM components by fibroblasts. Overexpression and deposition of ECM components are dominant features of fibrotic diseases, including hepatic fibrosis. The contribution of CD4+ Th2 cells to hepatic fibrosis has been well described. Now, in this issue of the JCI, Novobrantseva et al. provide data to suggest that hepatic B cells also play a role in liver injury. In a carbon tetrachloride–induced mouse model of hepatic fibrosis, T cell–deficient mice developed severe liver fibrosis; however, in B cell–deficient animals, hepatic fibrosis was attenuated. This study provides new insight into our understanding of the cells involved in mediating the adaptive immune response that leads to hepatic fibrosis.
Authors
Rashpal K. Bhogal, Constantin A. Bona
Abstract
There is a strong link between high fat intake and obesity. In addition to its high caloric density, dietary fat has a hyperphagic effect, in part as a result of its high palatability. The recent identification by Laugerette et al. of CD36 as a taste receptor for fatty acids provides insight into the molecular basis of our preference for fat. As we gain more information regarding the function of this receptor, we may be able to devise better strategies to address the addictive potential of dietary fat.
Authors
Nada A. Abumrad
Abstract
Autosomal-dominant pure hereditary spastic paraplegia (AD-HSP) is characterized by the degeneration of long axons in corticospinal tracts and dorsal columns, resulting in spasticity and difficulty walking. Mutations in the SPG4 gene product spastin are the predominant genetic lesions associated with this inherited disease. In this issue, Orso et al. examine and reconcile existing Drosophila mutants of spastin and generate a new model for HSP by overexpression of a fly spastin transgene that carries a mutation prevalent in human AD-HSP. Expression of this mutant spastin protein produces pathology in flies reminiscent of the human disease, including adult locomotion defects, in addition to causing aberrant synaptic morphology and altered microtubule stability. Both movement and synaptic defects in fly mutants were ameliorated by treatment with the microtubule-modifying agent vinblastine. The results are consistent with disease-causing mutations in human spastin producing dominant-negative proteins and confirm the usefulness of Drosophila genetic techniques to understand HSP and other neurodegenerative diseases.
Authors
Ellen B. Penny, Brian D. McCabe
Abstract
Classically, 7 transmembrane receptors transduce extracellular signals by coupling to heterotrimeric G proteins, although recent in vitro studies have clearly demonstrated that they can also signal via G protein–independent mechanisms. However, the physiologic consequences of this unconventional signaling, particularly in vivo, have not been explored. In this issue of the JCI, Zhai et al. demonstrate in vivo effects of G protein–independent signaling by the angiotensin II type 1 receptor (AT1R). In studies of the mouse heart, they compare the physiologic and biochemical consequences of transgenic cardiac-specific overexpression of a mutant AT1R incapable of G protein coupling with those of a wild-type receptor. Their results not only provide the first glimpse of the physiologic effects of this newly appreciated mode of signaling but also provide important and previously unappreciated clues as to the underlying molecular mechanisms.
Authors
Keshava Rajagopal, Robert J. Lefkowitz, Howard A. Rockman
Abstract
Discovery of mutated genes that cause various types of primary immunodeficiencies has significantly advanced our understanding of the pathogenesis of these diseases and of the functions of normal gene products. However, it is becoming abundantly clear that the phenotypic presentation of mutations in a given gene can be quite different, depending upon the location and type of mutation but also probably upon other genetic factors and environmental influences. In this issue of the JCI, de Villartay et al. describe a third phenotype for mutations in recombination activating gene 1 (RAG1), in addition to the already known phenotypes of SCID and Omenn syndrome.
Authors
Rebecca H. Buckley
Abstract
An important physiological response to changes in local or systemic oxygenation is the modulation of vascular tone, which is mediated in part by changes in the activities of the 3 NO synthase (NOS) isoforms. In arterial smooth muscle cells, acute hypoxia induces increased vascular tone, which is attenuated if hypoxia persists. In this issue of the JCI, Ward et al. demonstrate that changes in O2 concentration have effects on neuronal NOS enzymatic activity and gene expression that contribute to vascular homeostasis under conditions of acute and chronic hypoxia.
Authors
Gregg L. Semenza
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