Functional immunogenetics of multiple sclerosis

Abstract

In addition to the inflammatory component of MS, neurodegeneration is another important hallmark of the disease. Compared to the immunological component of MS, relatively little is known about the underlying mechanisms of neurodegeneration. Only a few MS risk genes have a presumed function within the CNS and thereby these genes are promising candidates for further study to increase our understanding of neurodegeneration. In chapter 6, we investigated the kinesin kif21b. Kinesins are important proteins involved in the transport of organelles and proteins within cells. These molecules are very important for the survival and function of neurons, since large distances need to be covered. We found that cortical kif21b expression was increased in Alzheimer’s patients (AD, a classical neurodegenerative disease) younger than 62 years compared with MS patients and non-demented controls (NDC). In the white matter, kif21b expression was significantly increased in MS patients compared with NDC. Increasing levels of cortical kif21b were observed in areas with more severe neuropathology in both MS and AD and enhanced kif21b expression was associated with a shorter disease duration. Additionally, accelerated progression to sustained disability (EDSS 6) in MS was found in patients with abundant kif21b expression. Lastly, kif21b protein was expressed in neurons as expected. Interestingly, kif21b protein was also found in astrocytes. Upon astrocyte activation, kif21b expression increased. This may explain the observed differences between the patients groups, as reactive astrocytosis is mainly found in young Alzheimer’s patients and in the white matter of MS patients.

Currently, for the minority of MS-associated SNP functional immunogenetic studies have been performed. The majority of studies found functional alterations associated with the SNP. For the remaining SNP, it will be important to perform functional studies to increase our knowledge regarding the (immune)pathogenic mechanism underlying MS, to integrate these studies into clinical trials in order to indentify reliable biomarkers. This will facilitate the development of new more targeted drugs to efficiently treat MS patients and minimising the side effects caused by currently more general immunomodulatory drugs.