Anthrax, a disease previously primarily relevant to the livestock-management community recently became a wordwide bioterrorism concern. However, human anthrax infection is primarily a result of direct or indirect contact with infected animals or exposure to contaminated animal products.
Bacillus anthracis, the causative agent of anthrax, is believed to induce disease and death in humans in an endotoxic shock–like manner.
A comprehensive study of the effects of anthrax lethal toxin in mice by Stephen Leppla and colleagues at the National Institutes of Health demonstrated that toxin-induced death does not result from septic shock mediated by cytokine release as previously thought, but via hypoxia-induced liver failure.
The study strongly suggests that the therapies developed for the treatment of cytokine-mediated septic shock will not be appropriate for the treatment of anthrax.
In an accompanying commentary, Alice Prince from Columbia University College of Physicians and Surgeons in New York states that "this analysis of the pathological effects of the B. anthracis lethal toxin should help focus future studies of optimal therapy for patients exposed to this organism.
These results make clear that anthrax patients exhibit a unique pathophysiology and should not be considered to have generic shock analogous to Gram-negative sepsis". Prince continues "exactly how the lethal factor produces such profound tissue hypoxia, what metabolic processes are affected in the liver and elsewhere, and how these effects may be blocked will require further studies".
TITLE: Bacillus anthracis lethal toxin induces TNF-alpha–independent hypoxia-mediated toxicity in mice
AUTHOR CONTACT:
Stephen Leppla
National Institutes of Health, Bethesda, Maryland, USA
Phone: 301-594-2865
Fax: 301-480-0326
E-mail: Leppla@nih.gov
View the PDF of this article at: https://www.the-jci.org/press/17991.pdf
ACCOMPANYING COMMENTARY:
The host response to anthrax lethal toxin: unexpected observations
AUTHOR CONTACT:
Alice S. Prince
Columbia University College of Physicians and Surgeons, New York, New York, USA
Phone: 212-305-4193
Fax: 212-305-2284
E-mail: asp7@columbia.edu
View the PDF of this commentary at: https://www.the-jci.org/press/19581.pdf
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Safely achieving tolerance to stem cell transplantation
Dale Greiner and colleagues at the University of Massachusetts have developed a protocol for achieving stem cell transplantation that is not limited by significant patient side-effects and may not necessarily require that donor blood, bone marrow or whole organs are a "match" with the recipient –- characteristics that make these new procedures highly attractive for development and use in clinical human transplantation.
Hematopoietic stem cells (HSCs) are parent cells in the bone marrow that give rise to blood cells. Allogeneic stem cell transplantation has great potential in the treatment of malignancy, genetic disorders, and in solid organ transplantation.
However, the radiation or high doses of chemotherapy commonly used in the treatment of blood cancers to destroy abnormal HSCs--a process called myeloablation-- is very toxic.
Furthermore, even following this form of conditioning, many patients develop graft-versus-host disease (GVHD), where the host immune system launches an attack against the newly transplanted HSCs.
In order to avoid both lethal conditioning and GVHD, new HSC transplant strategies are in development. Greiner et al. have adapted a costimulatory blockade–based protocol developed for solid organ transplantation for use in stem cell transplantation. The authors combined donor-specific transfusion and anti-CD154 monoclonal antibody administration to achieve functional donor and recipient HSC populations within the donor without the need for myeloablation or stimulating the induction of GVHD.
TITLE: Hematopoietic chimerism and central tolerance created by peripheral-tolerance induction without myeloablative conditioning
AUTHOR CONTACT:
Dale L. Greiner
University of Massachusetts Medical School, Worcester, Massachusetts, USA
Phone: 508-856-3800
Fax: 508-856-4093
E-mail: dale.greiner@umassmed.edu
View the PDF of this article at: https://www.the-jci.org/press/18599.pdf
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Scientists explain why Crohn disease is localized to specific regions of the gut
Markus Neurath and fellow researchers at the University of Mainz, Germany, have characterized the interaction between intestinal bacteria and dendritic cells (DCs) that may provide an explanation for the clinical symptoms of Crohn disease that only occur in specific regions of the gut.
The authors used transgenic mice to investigate the expression of the p40 subunit of IL-12 and IL-23. The authors demonstrate that p40 is expressed by a newly identified subset of DCs at greater levels in the lower part of the small intestine when compared to the proximal part of the small intestine or the colon. Neurath and colleagues demonstrate that p40 production is dependent on the intestinal bacteria as germ-free animals do not exhibit elevated p40 expression in the small intestine. The data reveal important functional differences between the mucosal immune systems of the small and large bowel in healthy mice and suggest that the high numbers of bacteria in the terminal ileum activate p40 expression. The authors suggest that this pattern of p40 expression may explain the predisposition of the terminal ileum to develop chronic inflammation responses via IL-23 and may therefore provide a molecular reason for the preferential clinical manifestation of Crohn disease in this region of the gut.
In an accompanying commentary, Holm Uhlig and Fiona Powrie from the University of Oxford discuss how intestinal DCs sense bacteria in the gut. They also comment that the IL-12 p40 promoter transgenic mice produced by Neurath and coworkers "will be an excellent tool to study the interaction between particular bacteria and the host immune system and how this influences the localization of the immune response".
TITLE: Constitutive p40 promoter activation and IL-23 production in the terminal ileum mediated by dendritic cells
AUTHOR CONTACT:
Markus F. Neurath
University of Mainz, Mainz, Germany
Phone: 49-6131-172374
Fax: 49-6131-175508
E-mail: neurath@1-med.klinik.uni-mainz.de
View the PDF of this article at: https://www.the-jci.org/press/17464.pdf
ACCOMPANYING COMMENTARY:
Dendritic cells and the intestinal bacterial flora: a role for localized mucosal immune responses
AUTHOR CONTACT:
Fiona Powrie
Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
Phone: 44-1865-285494
Fax: 44-1865-275591
E-mail: https://www.the-jci.org/press/19545.pdf
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Channeling solutions for hypertension
Luis Santana and colleagues at the University of Washington have revealed that decreased expression of the b subunit of the calcium-activated potassium channel in vascular cells is critical for maintaining vascular tone and blood pressure.
Hypertension is silent killer and affects more than 40 million Americans, approximately a third of whom are not aware of the condition, resulting in an increased risk of heart attack, stroke, and kidney disease. Unfortunately, the root causes of progressive hypertension remain elusive.
Increases in smooth muscle tone of major arteries causes the narrowing of arteries, which leads to chronic increases in blood pressure. Recent studies have suggested that calcium channels and calcium-activated potassium channels (BK channels), which facilitate the passage of calcium and potassium ions in and out of vascular myocytes, play a major role in relaxing arterial smooth muscle. The BK channel is comprised of an alpha and beta subunit. Calcium release within the myocyte activates the BK channel and the beta subunit is crucial in regulating the sensitivity of this channel to calcium ions.
Santana and colleagues examined the role of this critical subunit in hypertension. The authors found that in rats chronically infused with the substrate angiotensin II, at levels sufficient to raise blood pressure, expression of the beta1, but not the alpha, subunit was markedly decreased, which prevented the transmission of signals that cause vessel relaxation. The exact mechanism underlying the effect of angiotensin II binding on beta1 subunit expression remains unclear.
In an accompanying commentary, Michael Kotlikoff from Cornell University and Ian Hall from the University of Nottingham discuss potential mechanisms that could result in this disruption to b1 subunit expression and other target genes that may be involved in the progressive induction of hypertension.
TITLE: Modulation of the molecular composition of large conductance Ca2+ activated K+ channels in vascular smooth muscle during hypertension
AUTHOR CONTACT:
Luis F. Santana, University of Washington Seattle, Washington, USA
Phone: 206-543-0986
Fax: 206-685-0619
E-mail: santana@u.washington.edu
View the PDF of this article at: https://www.the-jci.org/press/18684.pdf
ACCOMPANYING COMMENTARY:
Hypertension: beta testing
AUTHOR CONTACT:
Michael Kotlikoff
College of Veterinary Medicine, Cornell University, Ithaca, New York, USA
Phone: 607-253-3336
Fax: 607-253-3317
E-mail: mik7@cornell.edu
View the PDF of this commentary at: https://www.the-jci.org/press/19580.pdf
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Meningitis beats up the blood-brain barrier
Meningitis occurs when pathogens in the blood cross the tightly sealed blood-brain barrier (BBB). Kelly Doran and colleagues from the University of California, San Diego, have closely examined the initial response of cells that comprise the BBB to group B Streptococcus (GBS) – the bacterium that causes meningitis in humans. Using microarray technology the authors showed that GBS infection induced a highly specific and coordinate set of genes known to orchestrate neutrophil recruitment and activation, thereby clearing the infection and enhancing survival. Doran and colleagues demonstrate that this striking immune reaction is induced in specific response to the potent b-hemolysin/cytolysin toxin release by this organism. The results will help our understanding of how the BBB responds to infectious diseases and may point to a therapeutic target.
TITLE: Group B streptococcal beta-hemolysin/cytolysin activates neutrophil signaling pathways in brain endothelium and contributes to development of meningitis
AUTHOR CONTACT:
Kelly Doran
University of California, San Diego School of Medicine, La Jolla, California, USA
Phone: 858-534-7477
Fax: 858-534-7411
E-mail: kdoran@ucsd.edu
View the PDF of this article at: https://www.the-jci.org/press/17335.pdf
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Unsuspected protein plays a role in inflammatory bowel disease
Richard Blumberg and fellow researchers at Brigham and Women's Hospital and Harvard Medical School have shown that heat shock protein 110 (Hsp110) contributes to the regulation of CD1d expression and subsequent intestinal inflammation in inflammatory bowel disease (IBD).
Intestinal epithelial cells (IECs) serve as the cellular barrier between the antigenic environment of the gut – consisting of dietary antigens, viruses, bacteria, and fungi – and the mucosal immune system. Many of the complex interactions that maintain these two environments may go awry, resulting in the chronic, T lymphocyte–mediated mucosal injury that characterizes inflammatory bowel diseases.
Many studies have implicated CD1d, a non-classical MHC class I–like molecule prominently expressed on intestinal epithelial cells, in the regulation of intestinal intraepithelial lymphocyte activity. Blumberg et al. examined whether CD1d expression could be regulated by intestinal luminal contents using colon-derived tissue culture cell lines. Alone, these cells express only low levels of CD1d, however when cultured in the presence of intestinal luminal contents, CD1d expression was significantly increased. The authors carried out the same experiment with the luminal contents of germ-free mice to rule out microbial-related CD1d stimulation. Analyses of purified luminal contents revealed that Hsp110 was a major protein component of the extract and addition of purified recombinant Hsp110 to colon-derived cells recapitulated the effects of the luminal contents by inducing increased CD1d expression. The authors also report that Hsp110 is abundantly expressed in IECs, suggesting that Hsp110 may undergo regulated release from epithelia, where it would provide a signal for CD1d regulation.
In an accompanying commentary, Christopher Nicchitta from Duke University, North Carolina, discusses some potential sites of gut Hsp110 and mechanisms of Hsp110 release.
TITLE: Intestinal heat shock protein 110 regulates expression of CD1d on intestinal epithelial cells
AUTHOR CONTACT:
Richard S. Blumberg
Brigham And Woman's Hospital, Boston, Massachusetts, USA
Phone: 617-732-6912
Fax: 617-264-5185
Email: rblumberg@partners.org
View the PDF of this article at: https://www.the-jci.org/press/17241.pdf
ACCOMPANYING COMMENTARY:
Come forth CD1d: Hsp110 in the regulation of intestinal epithelial CD1d expression
AUTHOR CONTACT:
Chris Nicchitta
Duke University Medical Center, Durham, North Carolina, USA
Phone: 919-684-8948
Fax: 919-684-5481
E-mail: c.nicchitta@cellbio.duke.edu
View the PDF of this commentary at: https://www.the-jci.org/press/19614.pdf
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Chronic workplace condition reveals independent T cell group
The differentiation of naive T cells into memory T cells is a crucial step in the evolution of an immune response. Optimal activation requires 2 steps: (i) T cell receptor binding to the foreign antigen; and (ii) engagement of the CD28 molecule on the T cell with it's ligands on the antigen presenting cell – a process known as costimulation. In contrast with naïve T cells, memory T cells can be activated after engagement of the T cell receptor, without CD28-mediated costimulation. Andrew Fontenot and colleagues at the University of Colorado Health Sciences Center studied the role of CD28 costimulation in patients with chronic beryllium disease (CBD). These individuals suffer from granulomatous inflammation of the lung resulting from continued exposure to beryllium in the workplace. The authors found that although the majority of T cells in peripheral blood from patients with CBD are CD28+, a large fraction of the CD4+ T cells that accumulate in the lung are CD28-. Despite the absence of CD28 costimulation, these cells are able to mount an immune response. However, upon comparison with CD28+ cells they have a reduced ability to proliferate and are more susceptible to cell death upon exposure to foreign antigen. The data support a model in which central memory CD4 cells maintain dependence on CD28 stimulation while cells accumulating in the periphery in response to chronic engagement with beryllium become progressively functionally independent of CD28, and then lose CD28 expression. This is associated with a decline in the ability of these cells to survive and proliferate. The study lends great insight into the maintenance of memory cells and their persistence at the site of chronic inflammatory disease.
TITLE: CD28 costimulation independence of target organ versus circulating memory antigen-specific CD4+ T cells
AUTHOR CONTACT:
Andrew P. Fontenot
University of Colorado Health Sciences Center, Denver, Colorado, USA
Phone: 303-315-7601
Fax: 303-315-7642
E-mail: andrew.fontenot@uchsc.edu
View the PDF of this article at: https://www.the-jci.org/press/18317.pdf
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Diabetic disruption of endothelial function
Tetrahydrobiopterin (BH4) is a suspected mediator of reduced endothelial NO synthase activity, which results in endothelial dysfunction characteristic of diabetes. The underlying regulatory mechanism, however, remains incompletely defined. Keith M. Channon and colleagues from John Radcliffe Hospital in Oxford, United Kingdom describe the generation of a novel transgenic mouse with endothelium-specific overexpression of guanosine triphosphate–cyclohydrolase I (GTPCH), the rate-limiting enzyme in BH4 synthesis. The authors found that loss of endothelial BH4 in diabetes results from biopterin oxidation, rather than an alteration in biopterin synthesis. Comparison of healthy and diabetic mice revealed that overexpression of GTPCH increases endothelial BH4 synthesis and preserves NO-mediated endothelial function. The data indicate that endothelial BH4 is an important regulator of dysfunctional eNOS regulation in diabetes and represents a rational therapeutic target in the restoration of NO-mediated endothelial function in this and other vascular disease states.
TITLE: Tetrahydrobiopterin-dependent preservation of nitric oxide–mediated endothelial function in diabetes by targeted transgenic GTP–cyclohydrolase I overexpression
AUTHOR CONTACT:
Keith Channon
John Radcliffe Hospital, Oxford, United Kingdom
Phone : 44-1865-851085
Fax : 44-1865-222077
E-mail: keith.channon@cardiov.ox.ac.uk
View the PDF of this article at: https://www.the-jci.org/press/17786.pdf
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Will the real phosphatonin please stand up
A novel circulation phosphaturic hormone is postulated to regulate systemic phosphate homeostasis. Two new studies reveal proteins with phosphaturic activity that may be implicated in achieving this baance.
A study by Paolo Bioanco and colleagues at the Università "La Sapienza", Rome, revealed that expression of the phosphaturic factor FGF-23 is increased in bone and blood in hypophosphatemic subjects with hereditary fibrous bone dysplasia associated with McCune Albright syndrome (MAS). The authors also demonstrate that FGF-23 is produced by normal and fibrous dysplasia osteoprogenitors and bone-forming cells. FGF-23 levels appeared to correlate with disease burden and support the notion that FGF-23 production pays an important role in the renal-phosphate wasting syndrome associated with MAS and fibrous dysplasia of bone.
In a second independent study in the same issue of the Journal of Clinical Investigation, Rajiv Kumar and colleagues at the Mayo Clinic in Rochester, Minnesota, report that secreted frizzled-related protein-4 (sFRP-4), a factor produced by tumors derived from subjects with tumor-induced osteomalacia (TIO, another syndrome associated with excessive renal phosphate excretion), also has phosphaturic activity.
In an accompanying commentary on both articles, L. Darryl Quarles from Duke University Medical Center in North Carolina discusses the interactions involved in the coordination of bone mineralization and phosphate handling by the kidney. It remains to be established whether FGF-23 and sFRP-4 represent two distinct phosphatonins or are somehow integrated in a novel phosphate-regulating bone-kidney axis. Quarles suggest that "a bone-kidney hormonal axis would provide a mechanism for the skeleton to communicate with the kidney to coordinate the mineralization of extracellular matrix with the renal handling of phosphate".
TITLE: FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting
AUTHOR CONTACT:
Paolo Bianco
Dipartmento di medicina Sperimentale e Patologia, Università "La Sapienza", Rome, Italy
Phone: 39-06-444-1049
Fax: 39-06-494-0896
E-mail:
p.bianco@flashnet.it
View the PDF of this article at: https://www.the-jci.org/press/18399.pdf
ASSOCIATED ARTICLE: TITLE: Secreted frizzled-related protein 4 is a potent tumor-derived phosphaturic agent
AUTHOR CONTACT:
Rajiv Kumar
Mayo Clinic and Foundation, Rochester, Minnesota, USA
Phone: 507-284-0020
Fax: 507-266-4710
E-mail: rkumar@mayo.edu
View the PDF of this article at: https://www.the-jci.org/press/18563.pdf
COMMENTARY ACCOMPANYING BOTH ARTICLES:
Evidence for a bone-kidney axis regulating phosphate homeostasis
AUTHOR CONTACT:
L. Darryl Quarles
Duke University Medical Center, Durham, North Carolina, USA
Phone: 919-660-6853
Fax: 919-684-4476
E-mail: quarl001@mc.duke.edu
View the PDF of this commentary at: https://www.the-jci.org/press/19687.pdf
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Lymphotoxin comes out of the LIGHT in multiple sclerosis
There is a long-standing conflict regarding the role of the lymphotoxin (LT) pathway in multiple sclerosis (MS). By using different animal models, Jen Gommerman and colleagues from Biogen Inc., in Cambridge, Massachusetts, demonstrate a clear role for this pathway in MS. The authors used a fusion protein decoy, which blocks the LT pathway in vivo without evoking the developmental defects inherent in LT-deficient mice. Inhibition of the LT pathway prevented disease in two models of MS. Disease attenuation was due to inhibition of LT and not the related ligand LIGHT. These results suggest that the LT pathway and its ability to maintain lymphoid microenvironments are critical for sustaining late-phase T cell responses in MS. Inhibition of this pathway may be a promising strategy for the treatment of MS as well as other autoimmune diseases.
TITLE: A role for surface lymphotoxin in experimental autoimmune encephalomyelitis independent of LIGHT
AUTHOR CONTACT:
Jennifer Gommerman
University of Toronto, Toronto, Ontario, Canada
Phone: 416-978-6959
Fax: 416-978-1938
E-mail: jen.gommerman@utoronto.ca
View the PDF of this article at: https://www.the-jci.org/press/18648.pdf
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Steady your nerves, steady your bowels
A study by Matti Airaksinen and colleagues at the University of Helsinki in Finland has provided insight into intestinal obstruction associated with Hirschsprung disease, often suffered by individuals with Down Syndrome. The obstruction is caused by the absence of nerves in a section of intestine, which limits intestinal motility.
Formation of parasympathetic and enteric neurons requires glial cell line–derived neurotrophic factor (GDNF) signaling via GDNF family receptor alpha2 (GFRalpha2). The authors examined the factors that could contribute to growth retardation in GFRA2–/– mice. GFRA knockout mice had fewer intrapancreatic neurons, severely impaired cholinergic innervation of exocrine tissue, and little vagally-mediated stimulation of pancreatic secretion. Knockout mice had retarded growth that could be partially overcome with wet-mash feeding. These results suggest that the growth retardation of the Gfra2–/– mice is largely due to impaired salivary and pancreatic secretion and intestinal dysmotility.
TITLE: Alimentary tract innervation deficits and dysfunction in mice lacking GDNF family receptor alpha2
AUTHOR CONTACT:
Matti Airaksinen
Institute of Biotechnology, University of Helsinki, Helsinki, Finland
Phone: 3589-191-59397
Fax: 3589-191-59560
E-mail: mairaksi@operoni.helsinki.fi
View the PDF of this article at: https://www.the-jci.org/press/17995.pdf
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Troponin T controls energetic affairs of the heart
It has long been noted that while patients with familial hypertrophic cardiomyopathy due to cardiac troponin T (cTnT) mutations often suffer sudden cardiac death, they do not develop significant ventricular hypertrophy (ventricle enlargement), suggesting that a distinct cellular mechanism apart from alterations in myocardial contractility is responsible. A new study by Jil Tardiff and colleagues at the Albert Einstein College of Medicine in New York has revealed that a single missense mutation in cTnT causes a striking disruption to energy metabolism, and cardiomyopathy.
In an accompanying commentary, Ketty Schwartz and Jean-Jacques Mercadier from INSERM in Paris discuss how troponin T regulates cardiac contraction and the functional consequences of this mutation.
TITLE: Decreased energetics in murine hearts bearing the R92Q mutation in cardiac troponin T
AUTHOR CONTACT:
Jil C. Tardiff
Albert Einstein College of Medicine, Bronx, New York, USA
Phone: 718-430-8914
Fax: 718-430-8989
E-mail: tardiff@aecom.yu.edu
View the PDF of this article at: https://www.the-jci.org/press/15967.pdf
ACCOMPANYING COMMENTARY:
Cardiac troponin T and familial hypertrophic cardiomyopathy: an energetic affair
AUTHOR CONTACT:
Ketty Schwartz
INSERM U582, Institut Fédératif de Recherches 14, Paris, France
Phone: 33-1-42-16-57-05
Fax: 33-1-42-46-57-00
E-mail: k.schwartz@myologie.chups.jussieu.fr
View the PDF of this commentary at: https://www.the-jci.org/press/19632.pdf
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Follicular development in the ovary is driven by angiogenesis
Follicles in the ovary require new blood vessel growth in order to develop. The newly formed ovarian blood vessels secure an increasing supply of gonadotropins, growth factors, oxygen, and steroid precursors to the growing follicle. Blockage of angiogenesis can inhibit follicle development partly by blocking hormonal feedback loops between the ovary and the pituitary gland. Ralf Zimmermann and colleagues from Columbia University in New York studied the intraovarian role of VEGFR- 2 activity on follicular development by using a model in which the pituitary gland is absent, the prepuberally hypophysectomized mouse. Hypophysectomy prevents advanced follicle growth and maturation, but follicle development to the preovulatory stage could be stimulated with gonadotropins. The exogenous gonadotropins were unable to drive follicle development to the preovulatory stage in the presence of anti–VEGFR-2 antibodies. These results show that the intraovarian VEGF/VEGFR-2 pathway is critical for gonadotropin-dependent angiogenesis and follicular development.
TITLE: Vascular endothelial growth factor receptor 2–mediated angiogenesis is essential for gonadotropin-dependent follicle development
AUTHOR CONTACT:
Ralf C. Zimmerman
Columbia University College of Physicians and Surgeons, New York, New York, USA
Phone: 212-305-8693
Fax: 212-305-3869
E-mail: rcz3@columbia.edu
View the PDF of this article at: https://www.the-jci.org/press/18740.pdf
Journal
Journal of Clinical Investigation