Graves disease, the most common cause of goiter and hyperthyroidism in the United States, came to national attention in the early 1990s when former United States President and First Lady, George and Barbara Bush, developed the condition. The etiology of Graves disease is multifactorial, and nongenetic factors are thought to play an important role. Sandra McLachlan and researchers at Cedars-Sinai Medical Center in Los Angeles, California now show that it is an unusual structural feature of the thyrotropin receptor (TSHR) that plays a major role in the development of this disease.
Graves disease is the result of the production of autoantibodies to the TSHR located on the surface of thyroid cells. These antibodies bind the TSHR and stimulate it to overproduce thyroid hormones, which results in hyperthyroidism. In the June 16 issue of the Journal of Clinical Investigation, Sandra McLachlan and her team report that studies in a new adenovirus-mediated animal model of Graves disease revealed that cleavage of the TSHR A subunit can induce or amplify the immune response to the TSHR to a greater extent than the intact TSHR molecule.
The data, increase our understanding as to why autoantibodies specifically arise to the TSHR, stimulate the thyroid, and result in Graves hyperthyroidism. However, the mechanisms responsible for TSHR cleavage will require further exploration.
TITLE: The thyrotropin receptor autoantigen in Graves disease is the culprit as well as the victim
AUTHOR CONTACT:
Sandra M. McLachlan
Cedars-Sinai Medical Center, Los Angeles, California, USA.
Phone: 310-423-7680
Fax: 310-423-0221
E-mail: mclachlans@cshs.org
View the PDF of this article at: https://www.the-jci.org/press/17069.pdf
**********************************************
2. Transplantation tolerance: Of mice and men
Little is known about the effect of an individual's immune history on their response to a donated tissue transplant. An important study by researchers at Emory University in Atlanta, Georgia, reveals that individuals harboring virally-induced memory T cells that are cross reactive with donor antigens are resistant to conventional strategies designed to induce transplant tolerance.
Enormous progress has been achieved in the field of transplantation during the past 3 decades, due in large part to the availability of effective immunosuppressive drugs. Such drugs are designed to sufficiently suppress the recipient immune response to the donor tissue without compromising the ability to fight infection. In the 50 years since the first description of tolerance to transplanted tissue in mice, researchers have strived to induce tolerance in human transplant recipients. So why the discrepancy?
In the June 16 issue of the Journal of Clinical Investigation, Christian Larsen and his colleagues demonstrated that a critical distinction between pathogen-free mice used in transplant research and nonhuman primates or human patients is their acquired immune history. The authors demonstrate that a specific threshold of memory cells is necessary to promote rejection and CD8+ central memory cells are principally responsible for mediating rejection. The data reveal that the transplantation field may have underappreciated the barrier that memory to previous viral infections in the recipient serves in the induction of tolerance.
"This study makes a strong argument for the importance of previous antigen exposure in determining the outcome of protocols designed to induce tolerance" says Harvard surgeon David Sachs, Director of the Transplantation Biology Research Center at Massachusetts General Hospital. "The data clearly support the practice of testing for potential cellular as well as humoral sensitization against the donor prior to carrying out such protocols clinically, even in cases for which there has been no known exposure to the donor antigens". Dr. Sachs continues to explore the more general question of why it is more difficult to induce tolerance in large versus small animals in his accompanying commentary. We should expect that differences to prior antigen exposure will be only one of the potential reasons for marked differences that are encountered between mice and primates in attempts to induce tolerance to transplanted tissue. Elucidating the mechanisms of these relationships can only increase the chances of achieving complete tolerance to tissue transplantation in humans.
TITLE: Heterologous immunity provides a potent barrier to transplantation tolerance
AUTHOR CONTACT:
Christian P. Larsen
Emory University, School of Medicine, Atlanta, Georgia, USA.
Phone: 404-727-8466
Fax: 404-727-3660
Email: clarsen@emory.org
View the PDF of this article at: https://www.the-jci.org/press/17477.pdf
ACCOMPANYING COMMENTARY:
Tolerance: Of mice and men
AUTHOR CONTACT:
David H. Sachs
Massachusetts General Hospital, Boston, Massachusetts, USA.
Phone: (617) 726-4065
Fax: (617) 726-4067
Email: sachs@helix.mgh.harvard.edu
View the PDF of this commentary at: https://www.the-jci.org/press/18926.pdf
**********************************************
ONLINE FIRST ARTICLE
Homing of stem cells to the injured kidney averts renal failure
Necrosis of the kidney is responsible for most cases of acute renal failure. A new report demonstrates that following renal injury in the mouse, bone marrow–derived stem cells home to the injured segment of the tubule, differentiate into the cell type specific for that tubular segment, and repair the necrosis. This report challenges the current paradigm for repair of tubular necrosis and suggests that approaches aimed at bone marrow stem cell propagation and delivery to the kidney should be pursued in efforts to treat this disease.
TITLE: Bone marrow stem cells contribute to repair of the ischemically injured renal tubule
AUTHOR CONTACT:
Lloyd Cantley
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone 1: 203-785-7110
Fax 1: 203-785-4904
E-mail: lloyd.cantley@yale.edu
View the PDF of this article at: https://www.the-jci.org/press/17856.pdf
********************************************
Improving the short- and long-term outcomes following stroke
A stroke is the result of an interruption in the blood flow to the brain. Vascular endothelial growth factor (VEGF) promotes the development of new cerebral blood vessels and its potential as a therapeutic agent for stroke is an exciting area of research. A new study in rats now shows that the administration of VEGF 24 hours after stroke reduced tissue death, improved neurological outcome, and enhanced the long-term survival of new neurons and blood vessels in the area of injury.
TITLE: VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia
AUTHOR CONTACT:
David A. Greenberg
Buck Institute for Age Research, Novato, California, USA.
Phone: 415-209-2087
Fax: 415-209-2230
Email: dgreenberg@buckinstitute.org
View the PDF of this article at: https://www.the-jci.org/press/17977.pdf
********************************************
Keeping an eye on insulin
Diabetic retinopathy, the most frequent complication of diabetes and leading cause of vision loss, involves vascular and neural damage in the retina. Insulin and insulin-like growth factor-1 signaling are now shown to contribute to the excessive development of blood vessels in the retina, in part, through the modulation of expression of various vascular mediators.
TITLE: Knockout of insulin and IGF-1 receptors on vascular endothelial cells protects against retinal neovascularization.
AUTHOR CONTACT:
C. Ronald Kahn
Joslin Diabetes Center, Boston, Massachusetts, USA.
Phone: 617-732-2635
Fax: 617-732-2487
E-mail: Ron.Kahn@joslin.harvard.edu
View the PDF of this article at: https://www.the-jci.org/press/17455.pdf
ACCOMPANYING COMMENTARY:
An eye on insulin
AUTHOR CONTACT:
Thomas W. Gardner
Penn State University College of Medicine, Hershey, Pennsylvania, USA.
Phone: 717-531-6711
Fax: 717-531-7667
Email: tgardner@psu.edu
View the PDF of this commentary at: https://www.the-jci.org/press/18927.pdf
********************************************
A role for arginase in asthma
Despite intense ongoing asthma research, the incidence of asthma is on the rise. In a new study, researchers have used microarray analysis to create a profile of all genes with altered expression in the lung tissue of mice with experimentally-induced asthma. Their results revealed high levels of arginase I and arginase II activity, suggesting that arginine metabolism pathways are critical in the pathogenesis of asthma and may provide suitable drug targets for a variety of allergic disorders.
TITLE: Dissection of experimental asthma with DNA microarray analysis identifies arginase in asthma pathogenesis
AUTHOR CONTACT:
Marc E. Rothenberg
Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Phone: 513-636-7210
Fax: 513-636-3310
E-mail: rothenberg@cchmc.org
View the PDF of this article at: https://www.the-jci.org/press/17912.pdf
ACCOMPANYING COMMENTARY:
Arginase: marker, effector, or candidate gene for asthma?
AUTHOR CONTACT:
Donata Vercelli
University of Arizona College of Medicine, Tucson, Arizona, USA.
Phone: 520-626-6387
Fax: 520-626-6970
Email: donata@resp-sci.arizona.edu
View the PDF of this commentary at: https://www.the-jci.org/press/18908.pdf
********************************************
Streptococcal binding to host collagen aids colonization
Acute rheumatic fever is a serious autoimmune sequel of Streptococcus pyogenes infection. During initial infection, the organism targets components of the host extracellular matrix in order to adhere, colonize, and evade host defense mechanisms. A new study reveals that certain strains of S. pyogenes are capable of binding the major extracellular matrix component, collagen type IV. This finding represents a novel colonization mechanism.
TITLE: Rheumatic fever–associated Streptococcus pyogenes isolates aggregate collagen
AUTHOR CONTACT:
Susanne Talay
German Research Centre for Biotechnology, Braunschweig, Germany.
Phone: 49-531-6181-706
Fax: 49-531-6181-708
E-mail: sta@gbf.de
View the PDF of this article at: https://www.the-jci.org/press/17247.pdf
**********************************************
The difference a carbohydrate makes
The abnormal development of the bile ducts inside or outside the liver, of which an early symptom in newborns is jaundice, is known as biliary atresia. Using a reovirus-induced model of this condition in mice, researchers have revealed it is the ability of the virus to specifically bind sialic acid that leads to jaundice and bile duct inflammation. These observations suggest that the carbohydrate-binding specificity of a virus can dramatically alter disease in the host and that infection by sialic acid–binding reovirus strains is a possible contributor to the pathogenesis of neonatal biliary atresia.
TITLE: Utilization of sialic acid as a coreceptor is required for reovirus-induced biliary disease
AUTHOR CONTACT:
Terence Dermody
Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Phone: 615-343-9943
Fax: 615-343-9723
E-mail: terry.dermody@vanderbilt.edu
View the PDF of this article at: https://www.the-jci.org/press/16303.pdf
**********************************************
Nerves sympathetic to angiogenesis
The sympathetic nervous system (SNS) includes the nerves of the heart and blood vessels. A study of the ischemic skeletal muscles of rats has revealed that neuropeptide Y (NPY), a cotransmitter of the SNS, can stimulate the formation of new blood vessels and restore tissue function. This newfound role suggests that the administration of NPY may also be highly effective in the treatment of ischemic tissue symptomatic of, for example, cardiovascular disease.
TITLE: Neuropeptide Y induces ischemic angiogenesis and restores function of ischemic skeletal muscles
AUTHOR CONTACT:
Edward W. Lee
Georgetown University Medical Center, Washington, District of Columbia, USA.
Phone: 202-687-1241
Fax: 202-687-7407
Email: leeew@georgetown.edu
View the PDF of this article at: https://www.the-jci.org/press/16929.pdf
********************************************
ASK1 activation: AIP1 is the key
Activation of ASK1 triggers biological responses such as apoptosis, inflammation, differentiation, and survival in different cell types. The mechanism of this activation is not entirely clear. A new study shows that it is a novel ASK1-interacting protein, AIP1, that triggers this activation.
TITLE: AIP1 mediates TNF-a–induced ASK1 activation by facilitating dissociation _of ASK1 from its inhibitor 14-3-3
AUTHOR CONTACT:
Wang Min
University of Rochester Medical Center, Rochester, New York, USA.
Phone: 716-273-1499
Fax: 716-275-9895
E-mail: wang.min@rochester.edu
View the PDF of this article at: https://www.the-jci.org/press/17790.pdf
ACCOMPANYING COMMENTARY:
AIP1: a new player in TNF signaling
AUTHOR CONTACT:
Gregory Gores
Mayo Clinic, Rochester, Minnesota, USA.
Phone: 507-284-0686
Fax: 507-284-0762
Email: gores.gregory@mayo.edu
View the PDF of this commentary at: https://www.the-jci.org/press/18911.pdf
********************************************
Targeting complement where it counts
TITLE: Complement receptor 2–mediated targeting of complement inhibitors to sites of complement activation
AUTHOR CONTACT:
Stephen Tomlinson
Medical University of South Carolina, Charleston, South Carolina, USA.
Phone: 843-792-1450
Fax: 843-792-0462
E-mail: tomlinss@musc.edu
View the PDF of this article at: https://www.the-jci.org/press/17348.pdf
**********************************************
Enzyme deficiency tips balance towards mutated DNA
TITLE: Site-specific somatic mitochondrial DNA point mutations in patients with thymidine phosphorylase deficiency
AUTHOR CONTACT:
Michio Hirano
Columbia University College of Physicians and Surgeons, New York, New York, USA.
Phone: 212-305-1048
Fax: 212-305-3986
E-mail: mh29@columbia.edu
View the PDF of this article at: https://www.the-jci.org/press/17828.pdf
**********************************************
IL-10 suppresses the immune response in skin
TITLE: Altered cutaneous immune parameters in transgenic mice overexpressing viral IL-10 in the epidermis
AUTHOR CONTACT:
Richard D. Granstein
Cornell Univesity, Weill Medical College, New York, New York, USA.
Phone: 212-746-7274
Fax: 212-746-8656
E-mail: rdgranst@med.cornell.edu
View the PDF of this article at: https://www.the-jci.org/press/15722.pdf
**********************************************
Wire services: All wire service stories must carry the embargo time at the head of each item and may not be sent out more than 24 hours before that time.
Warning: This document and the Journal of Clinical Investigation papers to which it refers, may contain information that is price sensitive with respect to publicly quoted companies. Anyone dealing in securities using information contained within this document or within advance copies of the JCI, may be guilty of insider trading under the US Securities Exchange Act of 1934.
Journal
Journal of Clinical Investigation