Hypoxia in multiple sclerosis; is it the chicken or the egg?

Over the past 50 years, intense research effort has taught us a great deal about multiple sclerosis. We know that it is the most common neurological disease affecting the young-middle aged, that it affects two to three times more females than males, and that it is characterized as an autoimmune disease, in which autoreactive T lymphocytes cross the blood-brain barrier, resulting in demyelinating lesions. But despite all the knowledge gained, a key question still remains; what is the initial event that triggers the inflammatory demyelinating process? While most research effort to date has focused on the immune system, more recently, another potential candidate has emerged: hypoxia. Specifically, a growing number of studies have described the presence of hypoxia (both 'virtual' and real) at an early stage of demyelinating lesions, and several groups, including our own, have begun to investigate how manipulation of inspired oxygen levels impacts disease progression. In this review we summarize the findings of these hypoxia studies, and in particular, address three main questions: (i) is the hypoxia found in demyelinating lesions 'virtual' or real; (ii) what causes this hypoxia; and (iii) how does manipulation of inspired oxygen impact disease progression?