March 5, 2004
Amit Bar-Or, M.D.
A recent article in the prestigious scientific journal Neuron described a new enzyme that may play an important role in the pathogenesis of multiple sclerosis. MS is viewed as a chronic condition in which the immune system inappropriately attacks components of the central nervous system. This leads to damage to myelin (the insulation that covers neurons as a sheath and helps the nerves to transmit signals more quickly), as well as to the neural pathways. However, it has long been appreciated that the involvement of the immune system is not the whole story. For example, the fact that in MS, injury by the dysregulated immune system is restricted to the central nervous system (CNS), and does not involve other body organs, has suggested that there may be something particular to the CNS that makes it susceptible. It is also known that patients with MS, particularly in the progressive phases, can have ongoing damage with loss of myelin and neural axons, even with little or no immune cell involvement – again suggesting that something within the CNS itself may provide an important contribution to propagating the injury over time.
Since myelin injury is so prominent in MS, investigators have wondered whether there may be particular components of myelin that can contribute to the damage, either directly or by stimulating more aggressive immune responses. For example, a component of normal myelin that is usually hidden in the normal myelin folds, might become exposed, or abnormally modified, as part of the immune mediated injury. Perhaps this abnormally regulated molecule could then participate in additional aspects of CNS injury?
Research by Sam David’s laboratory at McGill University, may have identified such a molecule. The researchers found that an enzyme, phospholipase A2 (cPLA2), is highly increased in the CNS of animals with an MS-like illness, experimental autoimmune encephalomyelitis (EAE). In an elegant series of studies, they discovered that the increased levels of this enzyme result in the generation of two additional molecules that could contribute to different aspects of the CNS injury. One of these metabolites has prominent pro-inflammatory characteristics, and could therefore contribute to the damaging inflammatory responses in the CNS. The other metabolite has the capacity to induce myelin breakdown directly, causing demyelination as well as the release of immune related molecules (chemokines and cytokines) that would further precipitate immune responses. Thus, the abnormal upregulation of cPLA2 in EAE could result in these metabolites that both induce direct damage and precipitate further inflammation and injury to myelin. With this in mind, the authors proceeded to treat animals that had EAE, with a chemical inhibitor that would specifically block cPLA2 and thereby limit the formation of its toxic metabolites. Indeed, this blockade of cPLA2 resulted in significant reductions in EAE induction and in the occurrence of relapses in these animals. Based on these findings, cPLA2 is identified as an enzyme that plays a central role in the onset and progress of this EAE model.
One of the most interesting features of this discovery relates to the metabolite of cPLA2 that can directly (without additional immune mediators) lead to myelin degradation. It is possible that this represents one of the “missing links” that could explain how myelin damage actually starts, and/or how it can continue even in settings where immune responses are no longer as prominent. In this regard, it is interesting to note how advances in our basic understanding of the structure of myelin can complement the story. Recently, Ohler and colleagues used EAE animals to carefully consider the structure of myelin and how it changes during the process of demyelination. They make the point that as the myelin is injured, it changes in ways that could make it further susceptible for further injury and degradation. Using three complementary techniques, the authors explain how early immune mediated injury can induce changes in the lipid composition of the myelin that, in turn, result in myelin that is more fluid, less adherent, and overall more fragile.
Together, these studies point to the molecular composition of myelin as an important consideration in the MS injury process. The discovery by Dr. David and his group identifies the cPLA2 enzyme as a potential target for the development of drugs to treat MS. Upcoming research will strive to develop inhibitors of this enzyme that could then be tested in clinical trials of MS to see whether the proper balance of safety and efficacy can be reached with this promising new strategy.
1. Athena Kalyvas and Samuel David. Cytosolic Phospholipase A2 Plays a Key Role in the Pathogenesis of Multiple Sclerosis-like Disease. Neuron, Vol 41, 323-335, 2004.
2. Ohler B. Graf K. Bragg R. Lemons T. Coe R. Genain C. Israelachvili
J. Husted C. Role of lipid interactions in autoimmune Demyelination. Biochimica
et Biophysica Acta. 1688(1):10-7, 2004.
Copyright © 2004, Veritas Medicine