JCI table of contents: July 24, 2008

EDITOR'S PICK: How cigarette smoke negatively impacts the consequences of viral infections

Jack Elias and colleagues, at Yale University School of Medicine, have performed new studies in mice that provide mechanistic insight into why viral infections have more severe consequences in individuals exposed to cigarette smoke than in those not exposed to cigarette smoke (e.g., influenza-infected smokers have increased mortality when compared with influenza-infected nonsmokers).

In the study, a combination of cigarette smoke and compounds that mimic viral components were found to cause more severe airway damage in a mouse model of the lung disease chronic obstructive pulmonary disease than the compounds that mimic viral components alone. Further, cigarette smoke enhanced the effects of influenza in mice. The effects of the combination of cigarette smoke and the compounds that mimic viral components were associated with an increased immune response in the lung and detailed analysis identified the molecular pathways involved. In an accompanying commentary, Rubin Tuder and Jeong Yun, at the University of Colorado Denver School of Medicine, explain the importance of defining the signaling pathways involved in the cigarette smoke–enhanced effects of viral infection for human disease.

TITLE: Cigarette smoke selectively enhances viral PAMP– and virus-induced pulmonary innate immune and remodeling responses in mice

AUTHOR CONTACT:Jack A. EliasYale University School of Medicine, New Haven, Connecticut, USA.Phone: (203) 785-4119; Fax: (203) 785-6954; E-mail: jack.elias@yale.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32709

ACCOMPANYING COMMENTARYTITLE: It takes two to tango: cigarette smoke partners with viruses to promote emphysema

AUTHOR CONTACT:Rubin M. TuderUniversity of Colorado Denver School of Medicine, Denver, Colorado, USA.Phone: (303) 315-4475: Fax: (303) 315-5632; E-mail: Rubin.Tuder@uchsc.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36536

TRANSPLANTATION: How to identify liver transplant recipients who no longer need drugs

A very small number of individuals who have had a liver transplant are able to stop taking drugs that prevent the immune system from attacking their transplanted liver (immunosuppressants). These people are said to be tolerant of their new liver, and becoming independent of immunosuppressants revolutionizes their life, as long-term use of immunosuppressants has serious side-effects. The problem is, there is no diagnostic test to identify these people. However, Alberto Sánchez-Fueyo and colleagues, at Hospital Clínic Barcelona, Spain, have now made a step toward this goal by identifying several gene signatures that distinguish tolerant liver transplant recipients from those that are not tolerant. Importantly, these gene signatures could be detected by analyzing the peripheral blood and did not require an invasive procedure. Vicki Seyfert-Margolis and Laurence Turka discuss the immense clinical importance of this study in an accompanying commentary.

TITLE: Using transcriptional profiling to develop a diagnostic test of operational tolerance in liver transplant recipients

AUTHOR CONTACT:Alberto Sánchez-FueyoHospital Clínic Barcelona, Barcelona, Spain.Phone: 34-93-2275499; Fax: 34-93-4515522; E-mail: afueyo@clinic.ub.es.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35342

ACCOMPANYING COMMENTARYTITLE: Marking a path to transplant tolerance

AUTHOR CONTACT:Vicki Seyfert-MargolisImmune Tolerance Network, Bethesda, Maryland, USA.Phone: (240) 235-6133; Fax: (240) 235-6198; E-mail: vseyfert@immunetolerance.org.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36552

CARDIOVASCULAR DISEASE: Early warning system: a new way to detect the cause of heart attack

One of the most common causes of heart attacks (also known as myocardial infarctions) and stroke is atherosclerosis, a disease of the major arterial blood vessels. Heart attacks and stroke occur when atherosclerotic plaques in the wall of an artery (which are what gives the disease its alternative name of hardening of the arteries) rupture, clogging up the blood supply to the heart or brain, respectively. A new, noninvasive way to detect the presence of ruptured atherosclerotic plaques has been developed by Kitty Cleutjens and colleagues, at the University of Maastricht, The Netherlands.

Specifically, it was shown that the blood of individuals with ruptured atherosclerotic plaques (as evidenced by hospitalization for an acute heart attack) contained antibodies reactive against two newly identified peptides, E1 and E12. The presence of these antibodies was detected extremely early after the onset of symptoms of a heart attack and so the authors hope that this approach might one day be used to improve early detection of ruptured atherosclerotic plaques such that individuals can get more timely treatment. However, as they note, further studies on additional patients are needed before this work can be translated into the clinic, and this sentiment is echoed, in an accompanying commentary, by Robert Gerszten and colleagues, at Massachusetts General Hospital, Charlestown.

TITLE: Noninvasive diagnosis of ruptured peripheral atherosclerotic lesions and myocardial infarction by antibody profiling

AUTHOR CONTACT:Kitty B.J.M. CleutjensUniversity of Maastricht, Maastricht, The Netherlands.Phone: 31-43-3874629; Fax: 31-43-3876613; E-mail: kitty.cleutjens@path.unimaas.nl.

View the PDF of this article at: https://www.the-jci.org/article.php?id=32767

ACCOMPANYING COMMENTARYTITLE: Novel antibody markers of unstable atherosclerotic lesions

AUTHOR CONTACT:Robert E. GersztenMassachusetts General Hospital, Charlestown, Massachusetts, USA.Phone: (617) 724-8322; Fax: (617) 726-5651; E-mail: rgerszten@partners.org.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36270

HEMATOLOGY: Solving problems with platelets

Individuals with very few platelets (the blood cells that regulate blood clot formation) are said to suffer from thrombocytopenia. There are many causes of thrombocytopenia, including increased destruction of platelets. New data, generated by two independent groups, have provided clinically relevant insight into two forms of thrombocytopenia caused by increased platelet destruction — immune thrombocytopenic purpura (ITP) and fetomaternal alloimmune thrombocytopenia (FMAIT). The importance of these studies for the development of new therapeutics is discussed in an accompany commentary by Bethan Psaila and James Bussel, at Weill Cornell Medical College of Cornell University, New York.

In the first study, Masataka Kuwana and colleagues, at Keio University School of Medicine, Japan, set out to understand why platelet numbers return to nearly normal levels in about 50% of individuals with ITP who are also infected with the bacterium Helicobacter pylori after they have been treated with antibiotics to clear their H. pylori infection. It was found that immune cells known as monocytes (which are involved in the destruction of platelets through their ability to take up and degrade antibody coated platelets via activating Fc receptors) exhibited characteristics of activated cells before the H. pylori infection was eradicated. This included high levels of activating Fc-gamma receptors and low levels of an inhibitory Fc-gamma receptor. Upon H. pylori eradication levels of the activating Fc-gamma receptors decreased and levels of the inhibitory receptor increased. The authors therefore conclude that H. pylori eradication dampens the activation status of monocytes such that their Fc-gamma repertoire favors uptake and destruction of platelets and that this is reversed upon H. pylori eradication.

In the second study, Cedric Ghevaert and colleagues, at NHS Blood and Transplant, United Kingdom, developed an approach to manipulate the interaction between antibody coated platelets and activating Fc-gamma receptors to decrease monocyte uptake and destruction of platelets. In FMAIT, mothers generate antibodies that bind to a molecule (HPA-1a) on the platelets of their fetus such that they are taken up by monocytes and destroyed. The authors developed a molecule that binds HPA-1a in place of the mother's antibodies when analyzed in vitro. Further in vitro and mouse studies indicated that this molecule dramatically decreased platelet destruction, leading to the suggestion that this approach be evaluated in human clinical studies.

TITLE: Helicobacter pylori eradication shifts monocyte Fc-gamma receptor balance toward inhibitory Fc-gamma-RIIB in immune thrombocytopenic purpura patients

AUTHOR CONTACT:Masataka KuwanaKeio University School of Medicine, Tokyo, Japan.Phone: 81-3-3350-3567; Fax: 81-3-3350-3567; E-mail: kuwanam@sc.itc.keio.ac.jp.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34496

RELATED MANUSCRIPTTITLE: Developing recombinant HPA-1a–specific antibodies with abrogated Fc-gamma receptor binding for the treatment of fetomaternal alloimmune thrombocytopenia

AUTHOR CONTACT:Cedric GhevaertNHS Blood and Transplant, Cambridge, United Kingdom.Phone: 44-7712-179785; Fax: 44-1223-548136; E-mail: cedric.ghevaert@nhsbt.nhs.uk.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34708

ACCOMPANYING COMMENTARYTITLE: Fc receptors in immune thrombocytopenias: a target for immunomodulation?

AUTHOR CONTACT:James B. BusselWeill Cornell Medical College of Cornell University, New York, New York, USA.Phone: (212) 746-3400; Fax: (212) 746-8609; E-mail: jbussel@med.cornell.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36451

OPHTHALMOLOGY: How to PROM(1)ote vision

Age-related macular degeneration is the leading cause of central vision loss in Americans over the age of 65. Inherited forms of macular degeneration are far less common, but, as noted in a commentary by Mark Kleinman and Jayakrishna Ambati, at the University of Kentucky, Lexington, defining the genes mutated in individuals with these forms of the disease has led to numerous discoveries regarding the molecular bases of vision. This has again proven true in work performed by a team of researchers, at the University of Utah, Salt Lake City, and the University of California, at Los Angeles, that has determined why a genetic mutation that leads to the generation of a mutant form of the protein PROM1 causes macular degeneration.

In the study, the same mutant form of PROM1 was identified in individuals with three different forms of inherited macular degeneration. When mice were engineered to express this mutant form of human PROM1 it was observed that cells in the eye crucial for vision (rod photoreceptors) underwent progressive degeneration. Further, the part of the rod photoreceptors known as the outer segment, which is made of a series of discrete membranous disks and is the light-sensing part of the cell, was greatly overgrown and misoriented. These data indicate that PROM1 seems to direct the organization of rod photoreceptor outer segment disks, providing important insight into the mechanisms underlying vision.

TITLE: Mutant prominin 1 found in patients with macular degeneration disrupts photoreceptor disk morphogenesis in mice

AUTHOR CONTACT:Zhenglin YangUniversity of California, at San Diego, San Diego, California, USA.Phone: (858) 246-0040; Fax: (858) 534-8293; E-mail: zliny@yahoo.com.

Kang ZhangUniversity of California, at San Diego, San Diego, California, USA.Phone: (858) 246-0040; Fax: (858) 534-8293; E-mail: kangzhang@ucsd.edu.

David S. WilliamsUniversity of California, at Los Angeles, Los Angeles, California, USA.Phone: (310) 825-9546; Fax: (310) 825-9546; E-mail: dswilliams@ucla.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=35891

ACCOMPANYING COMMENTARYTITLE: Fifty years later: the disk goes to the prom

AUTHOR CONTACT:Jayakrishna AmbatiUniversity of Kentucky, Lexington, Kentucky, USA.Phone: (859) 323-0686; Fax: (859) 323-1122; E-mail: jamba2@email.uky.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36515

METABOLISM: Improving the efficacy of enzyme replacement therapies

Mucopolysaccharidoses (MPSs) are a family of genetic diseases caused by deficiency in any one of a number of proteins known as enzymes. The tissues of individuals with MPSs accumulate high levels of molecules known as GAGs, ultimately resulting in premature death. Certain tissues are resistant to administration of the deficient enzyme (enzyme replacement therapy [ERT]), possibly due, in part, to the body's immune response to the replaced enzyme. In a new study, a team of researchers, at the University of California, Los Angeles, the University of Tennessee, Knoxville, and BioMarin Pharmaceutical Inc., Novato, used dogs with a disease similar to MPS I to demonstrate that treatments that make the immune system tolerate the replaced enzyme (i.e., make the immune system think that the replaced enzyme is a normal part of the body that should not be attacked) improves the effectiveness of ERT.

Dogs with a disease similar to MPS I that had not been "tolerized" to the missing enzyme developed antibodies against the replacement enzyme and showed a less favorable response to ERT than the tolerized dogs, where ERT reduced GAG accumulation. The authors conclude that inducing immune tolerance to replacement enzymes could improve the success of ERT for MPS I as well as other MPSs in humans. In an accompanying commentary, Katherine Ponder of Washington University School of Medicine, St. Louis, agrees with this conclusion and further suggests that similar immune tolerance or immunosuppressive treatments are likely to become standard practice for treating individuals with MPSs or related disorders.

TITLE: Immune tolerance improves the efficacy of enzyme replacement therapy in canine mucopolysaccharidosis I

AUTHOR CONTACT:Emil D. KakkisBioMarin Pharmaceutical Inc., Novato, California, USA.Phone: (415) 506-6700; Fax: (415) 382-7889; E-mail: ekakkis@bmrn.com.

View the PDF of this article at: https://www.the-jci.org/article.php?id=34676

ACCOMPANYING COMMENTARYTITLE: Immune response hinders therapy for lysosomal storage diseases

AUTHOR CONTACT:Katherine P. PonderWashington University School of Medicine, St. Louis, Missouri, USA.Phone: (314) 362-5188; Fax: (314) 362-8813; Email: KPONDER@DOM.WUSTL.EDU.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36521

METABOLIC DISEASE: The protein FSP27 helps bulk up white fat

White fat cells (adipocytes) contain a large droplet of fat-soluble molecules (lipids) that acts as an energy store that can be built up or used as necessary, to balance energy intake and expenditure. Obesity, which occurs when an individual's energy intake is greater than their expenditure, is associated with complications such as type 2 diabetes, and it is hoped that understanding the mechanism(s) by which these lipid droplets form and are maintained might provide clues about how obesity leads to such severe consequences. And now, Masato Kasuga and his colleagues, at Kobe University Graduate School of Medicine, Japan, have revealed a link between lipid accumulation in white adipocytes, energy balance, and a characteristic of type 2 diabetes, resistance to the effects of the hormone insulin.

In the study, the protein FSP27 was found to be localized to lipid droplets in mouse white adipocytes and to enhance the formation of white adipocytes from precursor cells. Mice deficient in FSP27 were protected from obesity and insulin resistance, and had an increased metabolic rate (i.e., they burnt more energy). FSP27 depletion in cultured mouse white adipocytes resulted in the breakdown of lipids, whereas FSP27 overexpression promoted lipid droplet formation. The authors therefore conclude that FSP27 promotes the formation of lipid droplets in white adipocytes and thereby has a crucial role in trying to control the energy imbalance that arises in obesity. The importance of these data and the next steps forward are discussed in an accompanying commentary, by Vishwajeet Puri and Michael Czech, at the University of Massachusetts Medical School, Worcester.

TITLE: FSP27 contributes to efficient energy storage in murine white adipocytes by promoting the formation of unilocular lipid droplets

AUTHOR CONTACT:Masato KasugaKobe University Graduate School of Medicine, Kobe, JapanPhone: 81-78-382-5860; Fax: 81-78-382-2084; E-mail: kasuga@med.kobe-u.ac.jp

View the PDF of this article at: https://www.the-jci.org/article.php?id=34090

ACCOMPANYING COMMENTARYTITLE: Lipid droplets: FSP27 knockout enhances their sizzle

AUTHOR CONTACT:Michael P. CzechUniversity of Massachusetts Medical School, Worcester, Massachusetts, USA.Phone: (508) 856-2254; Fax: (508) 856-1617; Email: michael.czech@umassmed.edu.

View the PDF of this article at: https://www.the-jci.org/article.php?id=36554

Source: Journal of Clinical Investigation