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Research Synopsis: 2012
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Selected articles from the medical literature for 2012.
Please note: academic papers and portions thereof are used to illustrate educational concepts. These publications are generally copyright and the reader is asked to be aware of this. Publications are posted for the use of patients and their physicians, please do not redistribute them or use them for other purposes.
DOI: Digital object identifier. This is a new system that permanently identifies an electronic document. Articles displaying a DOI number can be located by entering the number into a locator ("resolver") at http://dx.doi.org Thank you.
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor Fn14 exert pleiotropic effects, including regulation of myogenesis. Sporadic inclusion-body myositis (IBM) is the most common muscle disease of the elderly population and leads to severe disability. IBM mesoangioblasts, different from mesoangioblasts in other inflammatory myopathies, display a myogenic differentiation defect. The objective of the present study was to investigate TWEAK-Fn14 expression in IBM and other inflammatory myopathies and explore whether TWEAK modulation affects myogenesis in IBM mesoangioblasts. TWEAK, Fn14, and NF-KB expression was assessed by immunohistochemistry and Western blot in cell samples from both muscle biopsies and primary cultures. Mesoangioblasts isolated from samples of IBM, dermatomyositis, polymyositis, and control muscles were treated with recombinant human TWEAK, Fn14-Fc chimera, and anti-TWEAK antibody. TWEAK-RNA interference was performed in IBM and dermatomyositis mesoangioblasts. TWEAK levels in culture media were determined by enzyme-linked immunosorbent assay. In IBM muscle, we found increased TWEAK-Fn14 expression. Increased levels of TWEAK were found in differentiation medium from IBM mesoangioblasts. Moreover, TWEAK inhibited myogenic differentiation of mesoangioblasts. Consistent with this evidence, TWEAK inhibition by Fn14-Fc chimera or short interfering RNA induced myogenic differentiation of IBM mesoangioblasts. We provide evidence that TWEAK is a negative regulator of human mesoangioblast differentiation. Dysregulation of the TWEAK-Fn14 axis in IBM muscle may induce progressive muscle atrophy and reduce activation and differentiation of muscle precursor cells.
The results of the present study provide first evidence that TWEAK is a negative regulator of mesoangioblasts differentiation, and furthermore suggest that TWEAK- Fn14 interaction may regulate mesoangioblasts functions. Blocking TWEAK-Fn14 activity, therefore, may restore mesoangioblasts myogenic capacity in the IBM diseased muscle.
Potential relevance for IBM?
Alzheimer's Neurons from Pluripotent Stem Cells: First-Ever Feat Provides New Method to Understand Cause of Disease, Develop DrugsStem-cell-derived neurons, made from patients with Alzheimer's disease, provide a new tool for unraveling the mechanisms underlying the neurodegenerative disease.
Led by researchers at the University of California, San Diego School of Medicine, scientists have, for the first time, created stem cell-derived, in vitro models of sporadic and hereditary Alzheimer's disease (AD), using induced pluripotent stem cells from patients with the much-dreaded neurodegenerative disorder.
"Creating highly purified and functional human Alzheimer's neurons in a dish -- this has never been done before," said senior study author Lawrence Goldstein, PhD, professor in the Department of Cellular and Molecular Medicine, Howard Hughes Medical Institute Investigator and director of the UC San Diego Stem Cell Program. "It's a first step. These aren't perfect models. They're proof of concept. But now we know how to make them. It requires extraordinary care and diligence, really rigorous quality controls to induce consistent behavior, but we can do it."
The feat, published in the January 25 online edition of the journal Nature, represents a new and much-needed method for studying the causes of AD, a progressive dementia that afflicts approximately 5.4 million Americans. More importantly, the living cells provide an unprecedented tool for developing and testing drugs to treat the disorder.
"We're dealing with the human brain. You can't just do a biopsy on living patients," said Goldstein. "Instead, researchers have had to work around, mimicking some aspects of the disease in non-neuronal human cells or using limited animal models. Neither approach is really satisfactory."
Goldstein and colleagues extracted primary fibroblasts from skin tissues taken from two patients with familial AD (a rare, early-onset form of the disease associated with a genetic predisposition), two patients with sporadic AD (the common form whose cause is not known) and two persons with no known neurological problems. They reprogrammed the fibroblasts into induced pluripotent stem cells (iPSCs) that then differentiated into working neurons.
The iPSC-derived neurons from the Alzheimer's patients exhibited normal electrophysiological activity, formed functional synaptic contacts and, critically, displayed tell-tale indicators of AD. Specifically, they possessed higher-than-normal levels of proteins associated with the disorder.
With the in vitro Alzheimer's neurons, scientists can more deeply investigate how AD begins and chart the biochemical processes that eventually destroy brain cells associated with elemental cognitive functions like memory. Currently, AD research depends heavily upon studies of post-mortem tissues, long after the damage has been done.
"The differences between a healthy neuron and an Alzheimer's neuron are subtle," said Goldstein. "It basically comes down to low-level mischief accumulating over a very long time, with catastrophic results."
The researchers have already produced some surprising findings. "In this work, we show that one of the early changes in Alzheimer's neurons thought to be an initiating event in the course of the disease turns out not to be that significant," Goldstein said, adding that they discovered a different early event plays a bigger role.
The scientists also found that neurons derived from one of the two patients with sporadic AD exhibited biochemical changes possibly linked to the disease. The discovery suggests that there may be sub-categories of the disorder and that, in the future, potential therapies might be targeted to specific groups of AD patients.
Though just a beginning, Goldstein emphasized the iPSC-derived Alzheimer's neurons present a huge opportunity in a desperate fight. "At the end of the day, we need to use cells like these to better understand Alzheimer's and find drugs to treat it. We need to do everything we can because the cost of this disease is just too heavy and horrible to contemplate. Without solutions, it will bankrupt us -- emotionally and financially."
Funding for this research came, in part, from the California Institute for Regenerative Medicine, the Weatherstone Foundation, the National Institutes of Health, the Hartwell Foundation, the Lookout Fund and the McDonnell Foundation.
A patent application has been filed on this technology by the University of California, San Diego. For more information, go to: techtransfer.universityofcalifornia.edu/NCD/22199.html
Co-authors are Mason A. Israel and Sol M. Reyna, Howard Hughes Medical Institute and UCSD Department of Cellular and Molecular Medicine and UCSD Biomedical Sciences Graduate Program; Shauna H. Yuan, Howard Hughes Medical Institute and UCSD Department of Cellular and Molecular Medicine and UCSD Department of Neurosciences; Cedric Bardy and Yangling Mu, The Salk Institute for Biological Studies; Cheryl Herrera, Howard Hughes Medical Institute and UCSD Department of Cellular and Molecular Medicine; Michael P. Hefferan, UCSD Department of Anesthesiology; Sebastiaan Van Gorp, Department of Anesthesiology, Maastricht University Medical Center, Netherlands; Kristopher L. Nazor, Department of Chemical Physiology, The Scripps Research Institute; Francesca S. Boscolo and Louise C. Laurent, UCSD Department of Reproductive Medicine; Christian T. Carson, BD Biosciences; Martin Marsala, UCSD Department of Anesthesiology and Institute of Neurobiology, Slovak Academy of Sciences, Slovakia; Fred H. Gage, The Salk Institute of Biological Studies; Anne M. Remes, Department of Clinical Medicine, Neurology and Clinical Research Center, University of Oulu, Finland; and Edward H. Koo, UCSD Department of Neurosciences.
Neurology. 2012 Jan 11. [Epub ahead of print]
CD8+ T-cell immunity in chronic inflammatory demyelinating polyradiculoneuropathy.
Schneider-Hohendorf T, Schwab N, Uçeyler N, Gobel K, Sommer C, Wiendl H.
OBJECTIVE: Chronic inflammatory demyelinating polyradiculopathy (CIDP) is a common, but often misdiagnosed disease of the peripheral nervous system with assumed autoimmune pathogenesis. While current concepts of CIDP postulate a pathogenetic role of B cells and (auto)antibodies, the relevance of CD8 T cells present in the biopsies is still elusive. Thus, we asked whether nervous tissue infiltrating and blood-derived lymphocytes in CIDP are clonally expanded to evaluate the involvement of T cells in the pathogenesis of the disease.
METHODS: We characterized the clonal composition of the T-cell receptor repertoire in sural nerve biopsies (n = 25) and matching peripheral blood (n = 12) of patients with CIDP using PCR-based CDR3 spectratyping and subsequent DNA sequencing. As controls we used inflammatory myopathies (dermatomyositis, inclusion body myositis) and nonpathologic control biopsies. Immunohistochemistry was employed to visualize expanded CD8+ T-cell populations in sural nerve biopsies.
RESULTS: In contrast to controls, T cells in CIDP biopsies showed strong monoclonal and oligoclonal restrictions in their T-cell receptor repertoire. Strikingly, clonal expansions found in the biopsies were reflected in the CD8+ T-cell pool of patients' peripheral blood. Clones overlapping between blood and biopsy could be confirmed by CDR3 sequencing. Finally, the predominance of expanded nerve-infiltrating CD8+ T-cell clones was visualized by immunohistochemistry.
CONCLUSIONS: Together, these data provide strong evidence for an antigen-driven, major histocompatibility complex class I restricted, CD8+ T-cell-mediated attack against peripheral nerve tissue components contributing to the pathogenesis of CIDP.
PMID: 22238416
Mail Bill: btillier@shaw.ca
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