EDITOR'S PICK: Maternal diet can increase development and severity of asthma in offspring
John Hollingsworth and colleagues, at Duke University Medical Center, Durham, have generated evidence in mice that a maternal diet rich in methyl donors, of which one source is the prenatal supplement folate, increases the chance that the developing fetus will suffer from asthma after birth.
In the study, the development and severity of allergic airway disease (the experimental equivalent of asthma) was found to be enhanced in mice born to mothers who had eaten a diet supplemented with methyl donors. In addition, enhanced development and severity of allergic airway disease was observed in mice born to those exposed to methyl donors in utero, i.e. the problems were inherited. Further analysis indicated that some genes in the mice exposed to methyl donors in utero were modified by methylation in a different way to mice not exposed to methyl donors in utero. This change in the pattern of methylation, altered the expression of the genes and is likely to be the underlying cause of the increased development and severity of allergic airway disease. Both the authors and, in an accompanying commentary, Rachel Miller, at Columbia University College of Physicians and Surgeons, New York, discuss the potential implications of this study in light of the fact that folate is a source of methyl donors and is an important prenatal supplement that helps prevent congential abnormalities. As they caution, it is important to determine if the same effects occur in humans before changing the current recommendations about prenatal supplementation.
TITLE: In utero supplementation with methyl donors enhances allergic airway disease in mice
AUTHOR CONTACT:
John W. Hollingsworth
Duke University Medical Center, Durham, North Carolina, USA.
Phone: (919) 684-4588; Fax: (919) 684-3067; E-mail: holli017@mc.duke.edu.
MEDIA CONTACT:
Mary Jane Gore
Duke Medicine News and Communications, Duke University Medical Center, Durham, North Carolina, USA.
Phone: 919-660-1309 (office) or 919-323-0179 (cell); E-mail : mary.gore@duke.edu.
William Allstetter
National Jewish Health, Denver, Colorado, USA.
Phone: (303) 398-1002; E-mail: allstetterw@njc.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=34378
ACCOMPANYING COMMENTARY TITLE: Prenatal maternal diet affects asthma risk in offspring
AUTHOR CONTACT:
Rachel L. Miller
Columbia University College of Physicians and Surgeons, New York, New York, USA.
Phone: (212) 305-7759; Fax: (212) 305-2277; Email: rlm14@columbia.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=37171
EDITOR'S PICK: Statins block one cause of pregnancy loss in mice
In women, the inflammatory condition antiphospholipid syndrome (APS) often causes pregnancy-related complications, including miscarriage, intrauterine growth restriction, and fetal death. It is caused by molecules known as antiphospholipid antibodies, which are made by cells of the immune system. Using a mouse model of the pregnancy-related complications of APS, in which human antiphospholipid antibodies are infused into pregnant mice, Guillermina Girardi and colleagues, at Weill Medical College of Cornell University, New York, have delineated a central mechanism by which antiphospholipid antibodies induce fetal loss. As two distinct statins were found to affect the molecular pathway identified and prevent pregnancy loss, the authors suggest that statins may be a good treatment for women with pregnancy complications caused by APS.
In an accompanying commentary, Hartmut Weiler, at the BloodCenter of Wisconsin, Milwaukee, provides more insight into the mechanistic pathways uncovered, which are distinct from those many thought were likely to be involved.
TITLE: Neutrophil activation by tissue factor/Factor VIIa/PAR2 axis mediates fetal death in a mouse model of antiphospholipid syndrome
AUTHOR CONTACT:
Guillermina Girardi
Weill Medical College, Cornell University, New York, New York, USA.
Phone: (212) 774-2187; Fax: (212) 717-1192; E-mail: girardig@hss.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=36089
ACCOMPANYING COMMENTARY TITLE: Tracing the molecular pathogenesis of antiphospholipid syndrome
AUTHOR CONTACT:
Hartmut Weiler
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, Wisconsin, USA.
Phone: (414) 937-3813; Fax: (414) 937-6284; E-mail: hartmut.weiler@bcw.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=37243
EDITOR'S PICK: New vaccine element could generate better protection from avian influenza
Current vaccines for influenza provide protection against specific seasonal influenza A strains and their close relatives, but not against more distant seasonal influenza A viruses and new avian influenza A viruses, such as H5N1, which still poses a real global health concern. However, a team of researchers led by Tao Dong and Andrew McMichael, at Oxford University, United Kingdom, has now generated data that suggest adding a new component to vaccines for influenza might enable them to confer protection against a broad range of avian and seasonal influenza A viruses. In an accompanying commentary, Peter Doherty and Anne Kelso discuss in more detail how the data generated in this paper might be translated into a new and improved vaccine.
In the study, subsets of immune cells known as memory CD4+ and memory CD8+ T cells from individuals from the United Kingdom and Viet Nam were found to respond to fragments of proteins from both a seasonal influenza A strain and a strain of H5N1. Nearly all people tested had cells that cross-reacted between the seasonal influenza A strain and H5N1. The authors therefore suggest that adding fragments of influenza proteins to current vaccines for influenza might boost memory CD4+ and memory CD8+ T cell responses towards both seasonal and avian influenza viruses, providing broad protection.
TITLE: Memory T cells established by seasonal influenza A infection cross-react with avian influenza A (H5N1) in healthy individuals
AUTHOR CONTACT:
Tao Dong
Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
Phone: 44-1865-222336; Fax: 44-1865-222600; E-mail: tao.dong@imm.ox.ac.uk.
Andrew McMichael
Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
Phone: 44-1865-222336; Fax: 44-1865-222600; E-mail: andrew.mcmichael@ndm.ox.ac.uk.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32460
ACCOMPANYING COMMENTARY TITLE: Toward a broadly protective influenza vaccine
AUTHOR CONTACT:
Peter C. Doherty
St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Phone: (901) 495-3470; Fax: (901) 495-3107; E-mail: peter.doherty@stjude.org or pcd@unimelb.edu.au.
View the PDF of this article at: https://www.the-jci.org/article.php?id=37232
AUTOIMMUNITY: Killers of pancreatic beta-cells identified in type I diabetics
Type 1 diabetes occurs when the immune system attacks and destroys the beta-cells in the pancreas, the cells that produce the hormone insulin. Although much is known about the mechanisms by which beta-cells are killed in mouse models of type 1 diabetes, little is known about how beta-cells are killed in humans with the disease. However, Mark Peakman and colleagues, at King's College London, United Kingdom, have now identified both immune cells capable of killing beta-cells in the pancreas and a mechanism by which killing is accelerated in the later stages of the development of clinical diabetes.
In the study, immune cells known as CD8+ T cells that recognized fragments of the precursor form of insulin (preproinsulin) were found in the blood of patients with type 1 diabetes. Furthermore, these preproinsulin fragments were detected on the surface of human beta-cells in a form that enabled the CD8+ T cells from the blood of patients with type 1 diabetes to recognize them and kill the beta cells. Importantly, if the human beta-cells were exposed to high concentrations of glucose (which is what happens in individuals as type 1 diabetes progresses, because the decrease in insulin production as beta-cells are killed causes the amount of glucose in the blood to increase) then the amount of these preproinsulin fragments on the surface of the remaining beta-cells increased, as did CD8+ T cell killing. These data indicate that CD8+ T cells that can kill beta-cells are present in individuals with type 1 diabetes and identify a self-propelling loop likely to result in increasing beta-cell death as the disease progresses. The authors and, in an accompanying commentary, Jeffrey Frelinger, from the University of North Carolina, Chapel Hill, therefore suggest that targeting CD8+ T cells that recognize preproinsulin fragments as soon after an individual is diagnosed with type 1 diabetes as possible would be beneficial.
TITLE: CTLs are targeted to kill beta-cells in patients with type 1 diabetes through recognition of a glucose-regulated preproinsulin epitope
AUTHOR CONTACT:
Mark Peakman
King's College London, London, United Kingdom.
Phone: 44-207-188-0148; Fax: 44-207-188-3385; E-mail: mark.peakman@kcl.ac.uk.
View the PDF of this article at: https://www.the-jci.org/article.php?id=35449
ACCOMPANYING COMMENTARY TITLE: Novel epitope begets a novel pathway in type 1 diabetes progression
AUTHOR CONTACT:
Jeffrey A. Frelinger
University of North Carolina, Chapel Hill, North Carolina, USA.
Phone: (919) 966-2599; Fax: (919) 962-8103; E-mail: jfrelin@med.unc.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=37125
AUTOIMMUNITY: Brain protein expressed in the liver protects mice from multiple sclerosis–like disease
Autoimmune diseases occur when the immune system attacks and destroys cells of the body. It has been suggested that developing approaches to generate immune cells known as Tregs, which are able to dampen the destructive autoimmune response, might be of therapeutic benefit to individuals with autoimmune disease. Consistent with this, Johannes Herkel and colleagues, at the University Medical Centre Hamburg-Eppendorf, Germany, have now shown that mice are protected from disease in a model of multiple sclerosis if they express in their liver a brain protein targeted by immune cells that cause multiple sclerosis–like disease. Furthermore, protection was mediated by Tregs, which developed from naïve T cells. The authors therefore suggest that directing proteins that are targeted by destructive autoimmune responses to the liver might be a new approach to treating and preventing autoimmune disease. In an accompanying commentary, Brad Hoffman and Roland Herzog, at the University of Florida, Gainesville, discuss these therapeutic potentials as well as their limitations.
TITLE: Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs
AUTHOR CONTACT:
Johannes Herkel
University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
Phone: 49-40-428039736; Fax: 49-40-428038014; E-mail: jherkel@uke-uni-hamburg.de.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32132
ACCOMPANYING COMMENTARY TITLE: Coaxing the liver into preventing autoimmune disease in the brain
AUTHOR CONTACT:
Roland W. Herzog
University of Florida, Gainesville, Florida, USA.
Phone: (352) 273-8113; Fax: (352) 273-8342; E-mail: rherzog@ufl.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=37079
AUTOIMMUNITY: B cells have distinct roles at different stages of a multiple sclerosis–like disease
A recent clinical trial indicated that depletion of a subset of immune cells known as B cells using the drug rituximab has some benefit in individuals with the inflammatory disease multiple sclerosis. However, B cell depletion has been shown to worsen or trigger other inflammatory diseases, such as ulcerative colitis and psoriasis. As the most effective use of a B cell depleting drug requires knowledge of the role of B cells in disease processes, Thomas Tedder and colleagues, at Duke University Medical Center, Durham, set out to investigate the role of B cells at different stages of a mouse disease known as EAE, which is used to model multiple sclerosis.
In the study, rituximab-mediated B cell depletion before the induction of EAE markedly exacerbated the severity of the disease. By contrast, rituximab-mediated B cell depletion during EAE disease progression diminished the severity of the disease. Further analysis indicated that these opposing effects occurred because B cell depletion before disease onset eliminated a rare subset of regulatory B cells that were effective at dampening disease severity during early EAE disease initiation but were ineffective during disease progression. In addition, B cell depletion during EAE disease progression eliminated B cells essential for the disease process. These data indicate that B cells have different roles at different stages of EAE. As discussed by the authors and, in an accompanying commentary, Tomohiro Kurosaki, at RIKEN Research Center for Allergy and Immunology, Japan, this has important implications for developing effective approaches to using B cell depleting drugs such as rituximab.
TITLE: Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression
AUTHOR CONTACT:
Thomas F. Tedder
Duke University Medical Center, Durham, North Carolina, USA.
Phone: (919) 684-3578; Fax: (919) 684-8982; E-mail: thomas.tedder@duke.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=36030
ACCOMPANYING COMMENTARY TITLE: Paradox of B cell–targeted therapies
AUTHOR CONTACT:
Tomohiro Kurosaki
RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa, Japan.
Phone: 81-45-503-7019; Fax: 81-45-503-7018; E-mail: kurosaki@rcai.riken.jp.
View the PDF of this article at: https://www.the-jci.org/article.php?id=37099
GASTROENTEROLOGY: A thorny issue: Hedgehog signaling involved in bile duct damage
Chronic injury to the small bile ducts in the liver can lead to scarring, fibrosis, cirrhosis, and ultimately liver failure. New data, generated by Anna Mae Diehl and colleagues, at Duke University Medical Center, Durham, using rodent models of biliary fibrosis as well as human and rodent cells, has provide new insight into the molecular pathways involved in the development of the condition. In an accompanying commentary, Linda Greenbaum, at the University of Pennsylvania School of Medicine, Philadelphia, discusses the importance of this work in furthering our understanding of a health problem that can have such deleterious consequences.
In the study, it was found that some adult bile ductular cells (which are known as cholangiocytes) in liver sections from patients with chronic biliary injury were undergoing a process known as EMT, which has been suggested to have a role in chronic biliary injury. Furthermore, this process only occurred in cells that exhibited high levels of signaling through the hedgehog (Hh) pathway. Similarly, in a rat model of biliary fibrosis only cholangiocytes exhibiting high levels of Hh signaling activity were undergoing EMT. Reversing biliary injury in the rats reduced Hh signaling activity, EMT, and biliary fibrosis. Additional analysis in vitro and in mice provided more evidence that molecules that stimulate Hh signaling promote EMT and contribute to the development of biliary fibrosis when bile ducts are obstructed and subjected to constant injury.
TITLE: Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans
AUTHOR CONTACT:
Anna Mae Diehl
Duke University Medical Center, Durham, North Carolina, USA.
Phone: (919) 684-4173; Fax: (919) 684-4183; E-mail: annamae.diehl@duke.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=35875
ACCOMPANYING COMMENTARY TITLE: Hedgehog signaling in biliary fibrosis
AUTHOR CONTACT:
Linda E. Greenbaum
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: (215) 573-1868; Fax: (215) 573-2024; E-mail: greenbal@mail.med.upenn.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=37189
DERMATOLOGY: To heal or scar: a key role for the protein GSK-3beta
Although the two GSK-3 proteins GSK-3alpha and GSK-3beta are thought to be involved in the processes that occur after wounding, healing and scarring, the precise role of these proteins has not been determined. Now, Andrew Leask and colleagues, at the University of Western Ontario, London, have identified a mechanism by which GSK-3beta controls the progression of wound healing and scarring in mice.
In the study, mice lacking GSK-3beta only in cells known as fibroblasts (cells that have a crucial role in wound closure) were found to exhibit faster wound closure and increased scarring. This was associated with increased levels of the protein ET-1, due to increased production by the GSK-3beta–deficient fibroblasts. Antagonizing ET-1 restored the speed of wound closure to normal and dramatically diminished scarring. The authors therefore suggest that modulating the GSK-3beta pathway or ET-1 might be translated for the treatment of nonhealing or chronic skin wounds and of excessive scarring.
TITLE: GSK-3beta in mouse fibroblasts controls wound healing and fibrosis through an endothelin-1–dependent mechanism
AUTHOR CONTACT:
Andrew Leask
University of Western Ontario, London, Ontario, Canada.
Phone: (519) 661-2111 ext. 81002; Fax: (519) 850-2459; E-mail: Andrew.leask@schulich.uwo.ca.
View the PDF of this article at: https://www.the-jci.org/article.php?id=35381
Journal
Journal of Clinical Investigation