The immune system recognizes and neutralizes or destroys toxins and foreign pathogens that have gained access to the body. Autoimmune diseases result when the system attacks the body's own tissues instead. One of the most common examples is multiple sclerosis (MS).
MS is a serious condition in which nerve-cell projections, or axons, in the brain and the spinal cord are destroyed as a result of misdirected inflammatory reactions. It is often characterized by an unpredictable course, with periods of remission being interrupted by episodes of relapse. A team of researchers led by LMU Munich Professor Martin Kerschensteiner of the Medical Center of the University of Munich and Professor Thomas Misgeld from the Technical University of Munich has now been able to explain how the damage is inflicted.
Their results reveal that the inflammatory reaction can induce a previously unknown type of axonal degeneration, which they call "focal axonal degeneration" (FAD). In an animal model of MS, this process is reversible if it is recognized and treated early, so the researchers believe that it could serve as a potential target for therapeutic intervention. "Development of an effective treatment will be a long-term project," cautions Kerschensteiner. "As yet, we only have a superficial understanding of the underlying molecular mechanisms and, of course, finding effective therapies will require time-consuming screens and extensive trials of drug candidates." (Nature Medicine online, 27 March 2011)
Multiple sclerosis is a common and, in many cases seriously disabling, autoimmune disease that can lead to the disturbance or loss of sensory function, voluntary movement, vision and bladder control. Commonly, it is thought that the primary target of MS is the myelin sheath, an insulating membrane that enwraps axons, and increases the speed of signal transmission. However, damage to nerve fibers is also a central process, as whether autoimmune pathology ultimately leads to permanent disability depends largely on how many nerve fibers are damaged over the course of time.
The team led by Kerschensteiner and Misgeld set out to define precisely how the damage to the nerve axons occurs. As Misgeld explains, "We used an animal model in which a subset of axons is genetically marked with a fluorescent protein, allowing us to observe them directly by fluorescence microscopy." After inoculation with myelin, these mice begin to show MS-like symptoms. But the researchers found that many axons showing early signs of damage were still surrounded by an intact myelin sheath, suggesting that loss of myelin is not a prerequisite for axonal damage.
Instead a previously unrecognized mechanism, termed focal axonal degeneration (FAD), is responsible for the primary damage. FAD can damage axons that are still wrapped in their protective myelin sheath. This process could also help explain some of the spontaneous remissions of symptoms that are characteristic of MS. "In its early stages, axonal damage is spontaneously reversible," says Kerschensteiner. "This finding gives us a better understanding of the disease, but it may also point to a new route to therapy, as processes that are in principle reversible should be more susceptible to treatment."
However, one must remember that it takes years to transform novel findings in basic research into effective therapies. First the process that leads to disease symptoms must be elucidated in molecular detail. In the case of MS it has already been suggested that reactive oxygen and nitrogen radicals play a significant role in facilitating the destruction of axons. These aggressive chemicals are produced by immune cells, and they disrupt and may ultimately destroy the mitochondria. Mitochondria are the cell's powerhouses, because they synthesize ATP, the universal energy source needed for the build-up and maintenance of cell structure and function.
"In our animal model, at least, we can neutralize these radicals and this allows acutely damaged axons to recover," says Kerschensteiner. The results of further studies on human tissues, carried out in collaboration with specialists based at the Universities of Göttingen and Geneva, are encouraging. The characteristic signs of the newly discovered process of degeneration can also be identified in brain tissue from patients with MS, suggesting that the basic principle of treatment used in the mouse model might also be effective in humans.
Even if this turns out to be the case, it would not mean that a new therapy would soon be at hand. The chemical agents used in the mouse experiments are not specific enough and not tolerated well enough to be of clinical use. "Before appropriate therapeutic strategies can be developed, we need to clarify exactly how the damage arises at the molecular level," says Kerschensteiner. "We also want to investigate whether similar mechanisms play a role in later chronic stages of multiple sclerosis ." (göd)
The work received generous support from the Deutsche Forschungsgemeinschaft (DFG), in the context of Sonderforschungsbereich 571 (Autoimmune disease: From symptoms via mechanism to therapy) and the Emmy Noether Program. The Hertie Foundation and the Alexander von Humboldt Foundation also contributed significantly to financing the project. The study was performed within the framework of the Center for Integrated Protein Science Munich (CIPSM) – a Cluster of Excellence – and the Multiple Sclerosis Competence Network set up by the Federal Ministry for Research and Technology.
Publication:"A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis",
Nature Medicine online, 27 March, 6 p.m. London time / 1 p.m. US Eastern time doi: 10.1038/nm.2324
Contact:Prof. Thomas Misgeld
Prof. Martin Kerschensteiner | EurekAlert!
First line of defence against influenza further decoded
21.02.2018 | Helmholtz-Zentrum für Infektionsforschung
Helping in spite of risk: Ants perform risk-averse sanitary care of infectious nest mates
21.02.2018 | Institute of Science and Technology Austria
For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.
In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...
Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale
Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...
For photographers and scientists, lenses are lifesavers. They reflect and refract light, making possible the imaging systems that drive discovery through the microscope and preserve history through cameras.
But today's glass-based lenses are bulky and resist miniaturization. Next-generation technologies, such as ultrathin cameras or tiny microscopes, require...
Scientists from the University of Zurich have succeeded for the first time in tracking individual stem cells and their neuronal progeny over months within the intact adult brain. This study sheds light on how new neurons are produced throughout life.
The generation of new nerve cells was once thought to taper off at the end of embryonic development. However, recent research has shown that the adult brain...
Theoretical physicists propose to use negative interference to control heat flow in quantum devices. Study published in Physical Review Letters
Quantum computer parts are sensitive and need to be cooled to very low temperatures. Their tiny size makes them particularly susceptible to a temperature...
15.02.2018 | Event News
13.02.2018 | Event News
12.02.2018 | Event News
21.02.2018 | Life Sciences
21.02.2018 | Power and Electrical Engineering
21.02.2018 | Trade Fair News