Antibody therapy reduces asthma in mice
Asthma rates are rapidly increasing, particularly in children. Although asthma is mediated in part by activation of special immune cells called Th2 cells, the precise causes are unclear. Now, in a study appearing in the March issue of the Journal of Clinical Investigation, Jörg Köhl and colleagues from the Cincinnati Children's Hospital Research Foundation report that a small allergy-inducing protein called C5a produced in the lungs can prevent or induce asthma, depending upon the timing of allergen exposure. The authors blocked the C5a receptor (C5aR) by either giving normal mice an antibody against C5aR, or by genetically deleting C5aR. The researchers then determined the animal's response to inhalation of one of two allergens: egg ovalbumin (OVA), which fails to induce asthma; or house dust mites, which induce asthma-like symptoms relevant to human disease. The authors found that mice in which C5aR was blocked or deleted prior to exposure to either allergen developed asthma-like symptoms such as a strong Th2 cell response, mucus production, and airway inflammation. To identify the mechanism by which C5aR signaling prevents this response, the researchers looked at immune cells called dendritic cells (DCs) in the mouse lungs. C5aR blockade was found to directly increase the ratio of pro-asthma "mDCs" to anti-asthma "pDCs" leading to Th2 sensitization, in the absence of allergen, but even more so following allergen exposure, demonstrating that C5aR prevents cell activation and recruitment. Paradoxically, when C5aR was blocked after allergen exposure, the allergic response was dramatically prevented, and the severity of asthma-like symptoms was reduced, suggesting that C5aR increases the body's response to asthma-inducing stimuli only in an established allergic environment.
In an accompanying commentary, Bart N. Lambrecht from Erasmus University Medical Center in The Netherlands states that these studies "show that C5aR blockade promotes Th2 sensitization upon first exposure to inhaled allergen, whereas C5aR blockade during established inflammation suppresses the cardinal features of asthma."
TITLE: A regulatory role for the C5a anaphylatoxin in type 2 immunity in asthma
AUTHOR CONTACT:
Jörg Köhl
Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio, USA
Phone: (513) 636-1219; Fax: (513) 636-5355; E-mail: joerg.koehl@chmcc.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=26582
ACCOMPANYING COMMENTARY:
TITLE: An unexpected role for the anaphylatoxin C5a receptor in allergic sensitization
AUTHOR CONTACT:
Bart N. Lambrecht
Erasmus University Medical Center, Rotterdam, The Netherlands
Phone: 31-10-408-77-03; Fax: 31-10-408-94-53; E-mail: B.Lambrecht@erasmusmc.nl
View the PDF of this article at: https://www.the-jci.org/article.php?id=27876
HEMATOLOGY
Anemia and cancer therapy: clues to making new blood cells
Under normal conditions red blood cells are made by a process called erythropoiesis in the bone marrow. However, during stressful conditions, such as acute anemia, the spleen produces these important oxygen-carrying cells. The major hormone controlling this process is erythropoietin (Epo) and its cell receptor, EpoR. In a new study appearing in the March issue of the Journal of Clinical Investigation, researcher Don M. Wojchowski and colleagues from Maine Medical Center Research Institute show that activation of a signaling molecule called Stat5 by EpoR distinguishes stress-associated erythropoiesis from normal erythropoiesis. The authors used genetically modified mice in which the EpoR is mutated to not interact with Stat5. Erythropoiesis under non-stress conditions was normal in these mutant mice. However, after bone marrow transplant (stress) to induce anemia, the mutant mice were unable to generate new blood cells, demonstrating that Stat5 is essential for the stress response. The authors confirmed these results in mice that had been treated with 5- fluorouracil, a frequently used drug for cancer treatment that impairs the development of new blood cells and can cause anemia in cancer patients.
In an accompanying commentary, Gregory D. Longmore from Washington University, St. Louis, Missouri, points out that "In many ways these mice could be viewed as models for otherwise normal adult humans who exhibit exaggerated or unexpected responses to inflammation, infectious agents, or cancer progression."
TITLE: Signals for stress erythropoiesis are integrated via an erythropoietin receptor–phosphotyrosine-343–Stat5 axis
AUTHOR CONTACT:
Don M. Wojchowski
Maine Medical Center Research Institute, Scarborough, Maine, USA
Phone: (207) 885-8258; Fax: (207) 885-8179; E-mail: wojchd@mmc.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=25227
ACCOMPANYING COMMENTARY:
TITLE: A unique role for Stat5 in recovery from acute anemia
AUTHOR CONTACT:
Gregory D. Longmore
Washington University, St. Louis, Missouri, USA
Phone: (314) 362-8834; Fax: (314) 362-8826; E-mail: glongmor@im.wustl.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=27988
GENETICS
More than skin deep: preventing premature aging at the subcellular level
Laminopathies are diseases caused by mutations in the LMNA gene, which encodes lamins A and C, and are characterized by "progeroid" symptoms such as premature aging and muscular weakness. Lamins are structural proteins that support the membrane envelope of the cell nucleus. In a study appearing in the March issue of the Journal of Clinical Investigation, researcher Loren G. Fong and colleagues at the University of California, Los Angeles, show that, surprisingly, mice that express intact lamin C but do not express lamin A or prelamin A, the latter of which can be cleaved to form mature lamin A, are healthy. The authors created these "lamin C–only mice" using two different model systems. The first method involved mutating the Lmna mouse gene. In addition, the researchers treated normal mice with short DNA molecules to block expression of a prelamin A-processing enzyme called Zmpste24, resulting in failure to produce mature lamin A, accompanied by a buildup of prelamin A. The first group of lamin C–only mice showed normal growth rates, muscle function, and life span, suggesting that lamin C is sufficient to produce a normal mouse under these experimental conditions. However, the Zmpste24 group of mice, displayed premature aging symptoms similar to humans with laminopathy. The results of this study show that prelamin A buildup, and not merely absence of mature lamin A, contributes to progeroid diseases.
In an accompanying commentary, Tom Misteli of the National Cancer Institute points out that "these elegantly reinforced findings shed light on the cellular behavior of lamin, and that lamin C is able to functionally substitute for lamin A."
TITLE: Prelamin A and lamin A appear to be dispensable in the nuclear lamina
AUTHOR CONTACT:
Loren G. Fong
University of California, Los Angeles, California, USA
Phone: (310) 267-4380; Fax: (310) 267-2722; E-mail: lfong@mednet.ucla.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=27125
ACCOMPANYING COMMENTARY:
TITLE: Good news in the nuclear envelope: loss of lamin A might be a gain
AUTHOR CONTACT:
Tom Misteli
National Cancer Institute, Bethesda, Maryland, USA
Phone: (301) 402-3959; Fax: (301) 496-4951; E-mail: mistelit@mail.nih.gov
View the PDF of this article at: https://www.the-jci.org/article.php?id=27820
NEPHROLOGY
When you gotta go: genetically modified mice reveal how the urinary tract develops
The ureters are tube-like structures of the urinary tract that direct urine from the kidneys to the bladder. Researcher Andreas Kispert and colleagues from the Medizinische Hochschule Hannover in Germany have identified a role for a special protein called Tbx18 that is selectively expressed in ureter mesenchyme (tissue that will eventually develop into smooth muscle cells to conduct urine through adult ureters) and is important for embryonic ureter patterning and maturation (differentiation) of epithelial cells. The authors generated mutant mice that did not express the Tbx18 gene and found that the animals developed altered ureter structure and impaired ureter function similar to children born with genetic urinary tract defects. The mice also developed a symptom known as "functional obstruction" in which defective urine transport occurs in the absence of physical blockage. Examination of thin tissue sections of the developing ureters from the mutant mice showed a deficiency of smooth muscle, a feature thought to be involved in functional obstruction in humans. The study appears in the March issue of the Journal of Clinical Investigation.
In an accompanying commentary, Cathy Mendelsohn from Columbia University in New York writes that "the studies reported here suggest that Tbx18 may be a mesenchymal signal to control ureter differentiation and is an important regulator of the patterning of the urinary tract."
TITLE: Tbx18 regulates the development of the ureteral mesenchyme
AUTHOR CONTACT:
Andreas Kispert
Medizinische Hochschule Hannover, Hannover, Germany
Phone: 49-511-5324017; Fax: 49-511-5324283; E-mail: kispert.andreas@mh-hannover.de
View the PDF of this article at: https://www.the-jci.org/article.php?id=26027
ACCOMPANYING COMMENTARY:
TITLE: Going in circles: conserved mechanisms control radial patterning in the urinary and digestive tracts
AUTHOR CONTACT:
Cathy Mendelsohn
Columbia University, New York, New York, USA
Phone: (212) 305-1591; Fax: (212) 305-6851; E-mail: clm20@columbia.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=27985
ENDOCRINOLOGY
Identification of a human mutation that reduces height and increases appetite
In a study published in the March issue of the Journal of Clinical Investigation, Jacques Pantel and colleagues from the INSERM in France identify two separate families characterized by puberty-onset obesity and short stature that have an identical ghrelin receptor mutation that causes this receptor to lose its constitutive activity. The study provides insights into the previously unknown biological relevance of the activity of this receptor, which binds ghrelin, a hormone produced by the stomach to increase food intake and body weight. The ghrelin receptor is a member of a family of snake-shaped proteins called 7-transmembrane segment (7TM) receptors. In the present study the researchers used genetic statistical modeling to track the presence of the mutation to short stature or obesity, and found that, in both families, the mutation lacking constitutive activity segregated with short stature in a dominant manner, in which 70% of family members who had the mutation were also short. Unfortunately, no direct relationship was found between the ghrelin mutation and obesity in these families. When the researchers expressed the normal and mutant forms of the ghrelin receptor in cells in the laboratory, they found that, unlike the normal receptor, the mutant receptor did not bind ghrelin well and showed low constitutive activity, demonstrating a functional effect of this mutation. Surprisingly, the mutant receptor was able to induce high levels of ghrelin signaling, revealing that although the mutation impairs constitutive activity, it dramatically enhances ghrelin responsiveness. Together the analyses reveal a physiological role for the continuous activity of the ghrelin receptor in height development in humans.
In an accompanying commentary, Thue W. Schwartz from the University of Copenhagen in Denmark notes, "These are landmark studies, as they for the first time clearly demonstrate that constitutive signaling of 7TM receptors is not just an in vitro artifact or epiphenomenon but rather serves important functions of these receptors in vivo."
TITLE: Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature
AUTHOR CONTACT:
Jacques Pantel
INSERM, Créteil Cedex, France
Phone: 33-149-81-28-56; Fax: 33-148-99-33-45; E-mail: jacques.pantel@im3.inserm.fr
View the PDF of this article at: https://www.the-jci.org/article.php?id=25303
ACCOMPANYING COMMENTARY:
TITLE: Ghrelin receptor mutations -- too little height and too much hunger
AUTHOR CONTACT:
Thue W. Schwartz
University of Copenhagen, Copenhagen, Denmark
Phone: 45-3532-7601; Fax: 45-3532-7610; E-mail: schwartz@molpharm.dk
View the PDF of this article at: https://www.the-jci.org/article.php?id=27999
CARDIOLOGY
Got milk? The dual roles of calcium in the heart
Calcium (Ca2+) has an important role in regulating heartbeat or cardiac excitation-contraction coupling (called ECC), but it also is involved throughout the body in signaling pathways that control protein activity and gene expression. A significant question in the field of cardiology is how Ca2+ can perform both of these functions in the heart. In a study appearing in the March issue of the Journal of Clinical Investigation, Donald M. Bers and colleagues from Loyola University Chicago in Illinois show that a receptor called InsP3R, which releases local stored Ca2+ into the cell, induces activation of a nuclear protein called CaMKII, resulting in heart failure–associated gene expression. The gene expression changes are induced through modification of another protein called histone deacetylase5 (HDAC5). Importantly, the researchers used several genetically mutant mice that did not have either InsP3R or CaMKII to demonstrate that these cardiac gene expression changes are not the result of fluctuations in global Ca2+ levels that are involved in regulating heartbeat. Further, the authors examined adult rabbit ventricular myocytes to show that InsP3R release of local Ca2+ into the nuclear envelope is followed by CaMKII activation, which acts on HDAC5 to cause HDAC5 to leave the nucleus.
In an accompanying commentary, Jeffery D. Molkentin from the Cincinnati Children's Hospital Medical Center in Ohio writes that, "As with most landmark studies, this study raises a number of important issues. Thus, the results of this convincing research have not only established a calcium-dependent regulatory paradigm, but they have also provided the conceptual framework for further parsing contractile versus reactive signaling Ca2+ in the heart."
TITLE: Local InsP3-dependent perinuclear Ca2+ signaling in cardiac myocyte excitation-transcription coupling
AUTHOR CONTACT:
Donald M. Bers
Loyola University Chicago, Maywood, Illinois, USA
Phone: (708) 216-1018; Fax: (708) 216-6308; E-mail: dbers@lumc.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=27374
ACCOMPANYING COMMENTARY:
TITLE: Dichotomy of Ca2+ in the heart: contraction versus intracellular signaling
AUTHOR CONTACT:
Jeffery D. Molkentin
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
Phone: (513) 636-3557; Fax: (513) 636-5958; E-mail: jeff.molkentin@cchmc.org
View the PDF of this article at: https://www.the-jci.org/article.php?id=27824
Journal
Journal of Clinical Investigation