Pathological Heterogeneity in Multiple Sclerosis

Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system in which oligodendrocytes and myelin are targeted and destroyed by the body’s immune system. Chemical elements such as iron, sulfur, and phosphorous are crucial in the synthesis and maintenance of myelin, and their imbalances have been linked to demyelination and neurodegeneration. Early MS is heterogeneous with respect to its neuropathological features suggesting that the target of injury and the mechanisms of demyelination are different in different patient subgroups, also called immunopatterns. Using a multidisciplinary approach that combines synchrotron X-ray fluorescence imaging (XFI), histology and immunohistochemistry, I firstly investigated the heterogeneity of iron content and distribution in immunopattern II and III MS, to determine whether iron can be used as a marker to differentiate immunopatterns. XFI showed that iron was significantly increased in immunopattern II lesions (p=0.003) and predominantly stored as ferritin within myelin-laden macrophages. These observations suggest that there is a profound iron heterogeneity in early active MS lesions and I propose that iron dysregulation plays an important role in the pathogenesis of MS lesions. An estimate of iron load may be quantifiable by My findings have potentially important clinical implications because iron may be used as a magnetic resonance imaging biomarker, allowing possibly routine early immunopattern recognition in the clinical setting and advancing treatment approaches specific to the pathology. The human brain is highly susceptible to oxidative damage due to its high concentrations of lipids and unsaturated fatty acids. Iron has been proposed to promote MS tissue injury through generation of toxic reactive oxygen species which damage carbohydrates, lipids, proteins, and DNA. Using XFI and Fourier-transform infrared imaging, I found that biopsied early MS lesions displayed increased oxidized lipids and aggregated proteins, and lower of iron, sulfur, phosphorus and phosphate. The oxidative damage in early MS does is not driven by iron accumulation, and this argues against the use of iron chelators in the treatment of early MS. Future studies will have to determine if the differential iron distribution between immunopatterns II and III MS is the result of different macrophage polarization in the two lesion patterns and/or is the expression of the iron’s role in complement cleavage and activation characteristic of immunopattern II MS lesions