The way to whoop whooping cough
Although the use of vaccines has decreased the incidence of childhood whooping cough, the causative agent, Bordetella pertussis, somehow remains endemic in vaccinated populations where the bacteria causes a coughing illness of variable severity. This poses a threat to children who are too young to be vaccinated, and who often get whooping cough from adult, nonsymptomatic, or mildly symptomatic carriers.
In a paper appearing online on November 17 in advance of print publication of the December issue of the Journal of Clinical Investigation, Eric Harvill and colleagues from Penn State use mouse models to examine sterilizing immunity to B. pertussis. The authors propose that pertussis toxin (PTx), which is expressed by B. pertussis and inhibits specific G protein pathways, delays antibody-mediated clearance of B. pertussis by inhibiting recruitment of neutrophils to the site of infection.
This allows the bacteria to survive and to remain a health risk, even in immunized populations. The authors show that B. pertussis blocked both neutrophil migration and recruitment to the lungs during the first week of infection by a PTx-dependent mechanism. But a PTx mutant of B. pertussis induced neutrophil recruitment and was quickly cleared from the lungs by adoptively transferred antibodies. These results indicate that expression of PTx may be an adaptation strategy used by B. pertussis to permit the bacteria to delay antibody-mediated clearance, allowing repeated infection of immune hosts. These findings may explain the ability of B. pertussis to persist in immune human populations, and suggests that effective vaccination strategies against the bacteria will require an antibody response to PTx.
TITLE: Pertussis toxin inhibits neutrophil recruitment to delay antibody-mediated clearance of Bordetella pertussis
AUTHOR CONTACT:
Eric Harvill
Pennsylvania State University, University Park, PA
Phone: 814-863-8522
Fax: 814-863-6140
E-mail: eth10@psu.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=24609
PHYSIOLOGY
Kicking up kidney failure treatment
Ischemia/reperfusion injury is the most common cause of acute renal failure. Despite advances in supportive treatments such as dialysis, severe acute renal failure remains a major cause of death and has no specific therapies.
In a paper appearing online on November 17 in advance of print publication of the December issue of the Journal of Clinical Investigation, Manoocher Soleimani and colleagues from University of Cincinnati define the early pathways activated by ischemic injury. The authors find that a protein called thrombospondin (TSP-1) can cause severe kidney failure when normal blood flow is disrupted.
TSP-1, known for its ability to prevent angiogenesis and promote death of cancerous cells, is also the molecule with the highest induction level at 3 hours of reperfusion injury in rodent kidneys subjected to ischemia/reperfusion. The predominant sites of expression of TSP-1 are the injured proximal tubules, where TSP-1 colocalizes with activated caspase-3. Cultured kidney cells exposed to TSP-1 also demonstrated signs of programmed cell death-induced damage. Additionally, mice lacking TSP-1 were protected against ischemic injury–induced renal failure and tubular damage. Thus, TSP-1 is a novel mediator of ischemic damage in the kidney and may be a target for drugs that will reduce the risk of kidney failure in humans.
TITLE: Identification of Thrombospondin 1 (TSP-1) as a novel mediator of cell injury in kidney ischemia
AUTHOR CONTACT:
Manoocher Soleimani
University of Cincinnati, Cincinnati, OH
Phone: 513-558-5463
Fax: 513-558-4309
E-mail: manoocher.soleimani@uc.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=25461
PHYSIOLOGY
Sticks and stones may break our bones, but here's what spares them from resorption
In inflammatory osteolysis, bone-resorbing osteoclasts erode periarticular bone and cause joint collapse and potential disfigurement. Large numbers of osteoclasts appear at sites of synovitis, suggesting that products of local inflammation recruit the cells. The cytokine TNF-_ is a key player in bone loss associated with inflammation. TNF-_ exerts its effect by stimulating the production of the osteoclastogenic cytokine RANKL from stromal cells. Although much is known about this pathway, blocking TNF-_ in patients causes problems such as infection. Combination therapy targeting multiple molecules is expected to be more useful.
In a paper appearing online on November 17 in advance of print publication of the December issue of the Journal of Clinical Investigation, Steven Teitelbaum and colleagues from Washington University expose 2 new therapeutic targets for inflammatory skeletal diseases. Both osteoclast precursor cells and bone marrow stromal cells are TNF-_ targets, so the authors examined mice in which these cell types are chimeric for the presence of TNF receptors in order to determine their relative contributions to inflammatory osteoclastogenesis. Both cell types mediate osteoclastogenesis, but stromal cells make the greater contribution. TNF-_ stimulates expression of the stromal cell product M-CSF -- a cytokine responsible for maintaining the survival of osteoclast precursors.
Treating mice with inflammatory arthritis with an antibody against M-CSF receptor eliminated the severe osteoclastogenesis and bone resorption typically seen. M-CSF and its receptor are prospective therapeutic targets for inflammatory bone erosion.
TITLE: M-CSF mediates TNF-induced inflammatory osteolysis
AUTHOR CONTACT:
Steven L. Teitelbaum
Washington University School of Medicine, St. Louis, MO
Phone: 314-454-8463
Fax: 314-454-5505
E-mail: teitelbs@wustl.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=26132
PHYSIOLOGY
Just say NO to clinical blood disorders: How nitric oxide consumption plays a role
Nitric Oxide (NO) is constantly made from the endothelium and regulates many vascular functions. In a paper appearing online on November 17 in advance of print publication of the December issue of the Journal of Clinical Investigation, Mark Gladwin and colleagues from the NHLBI demonstrate a major role for the intact red blood cell in NO homeostasis and show that NO consumption causes the physiologic changes and organ dysfunction that occur during intravascular red blood cell breakdown.
These studies link the presence of excessive hemoglobin with significant NO inhibition, vasomotor instability and impaired organ function. The data provide evidence for the existence of a human syndrome of hemolysis-associated NO dysregulation, which may contribute to disorders such as sickle cell disease, malaria, anemias, and cardiopulmonary bypass.
TITLE: Hemolysis-associated endothelial dysfunction mediated by accelerated NO inactivation by decompartmentalized oxyhemoglobin
AUTHOR CONTACT:
Mark Gladwin
National Heart, Lung, Blood Institute, NIH, Bethesda, MD
Phone: 301-435-2310
Fax: 301-451-7091
E-mail: mgladwin@mail.nih.gov
View the PDF of this article at: https://www.the-jci.org/article.php?id=25040
IMMUNOLOGY
Understanding T cell proliferation to a T
Homeostatic, or spontaneous, proliferation of T cells occurs in many physiological and pathological conditions, including aging and chronic infections. In a paper appearing online on November 17 in advance of print publication of the December issue of the Journal of Clinical Investigation, Juan Lafaille and colleagues from New York University answer the important scientific question: What is the role of regulatory T cells (Treg) in the control of spontaneous T cell proliferation?
The authors use a variety of experimental approaches to show that regulatory T cells do, in fact, control homeostatic proliferation. They show that the intensity of the Treg effect is dependent on the avidity of proliferating T cells for self-ligands. T cells displaying low avidity are almost completely prevented from dividing by Treg; T cells displaying higher avidity divide even in the presence of Treg, but accumulate at lower numbers if Treg are present. This data may explain the discrepancies that currently exist in the literature. Finally, in the presence of Tregs, there is more programmed cell death of target cells.
TITLE: Control of Homeostatic Proliferation by Regulatory T cells
AUTHOR CONTACT:
Juan J. Lafaille
NYU Medical Center, New York, NY
Phone 212-263 1489
Fax: 212-263 5711
E-mail: lafaille@saturn.med.nyu.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=25463
METABOLIC DISEASE
TACE puts a face on insulin resistance and its relation to disease
Insulin resistance underlies type 2 diabetes and coronary artery disease, but the mechanisms underlying its effects have not been entirely worked out. In a paper appearing online on November 17 in advance of print publication of the December issue of the Journal of Clinical Investigation, Massimo Federici and colleagues from the University of Rome report a novel interaction between insulin action and the control of inflammation that could promote diabetes and vascular inflammation.
The authors find that mild insulin resistance due to inactivation of the insulin receptor (IR) combined with a deficiency of TIMP3, a protein involved in inflammation, results in hyperglycemia and vascular inflammation. The authors use different mouse models and genetic approaches to demonstrate that the IR-Timp3 interaction causes a diabetic phenotype. Restoring TIMP3 activity concurrently reduced glucose intolerance and inflammation.
The authors find that the effect of TIMP3 on insulin sensitivity is due to its ability to inhibit the enzyme TACE. TIMP3 deficiency enhances TACE activity leading to increased release of pro-inflammatory TNF-alpha. Blocking TACE improves insulin sensitivity and inflammation. These results show that TIMP3/TACE plays a role in the biological processes underlying diabetes and atherosclerosis suggesting that TACE inhibition could be a target for treatment of such diseases.
TITLE: Timp3 deficiency in insulin receptor haploinsufficient mice promotes glucose intolerance and vascular inflammation via increased TNF-alpha
AUTHOR CONTACT:
Massimo Federici
Universita di Roma, Rome ITALY
Phone: 3906-7259-6535
Fax: 3906-7259-6538
E-mail: federicm@uniroma2.it
View the PDF of this article at: https://www.the-jci.org/article.php?id=26052
Journal
Journal of Clinical Investigation