Page 119 - The autoimmune hypothesis of narcolepsy and its unexplored clinical features M.S. Schinkelshoek

The fact that direct evidence for the autoimmune hypothesis of NT1 is lacking, led us to believe that pursuing a different approach to identifying the mechanisms responsible for the destruction of the hypocretin-producing neurons is needed. In Chapter 4, we describe our mass cytometry experiments that allow us to compare the immune cell composition in the peripheral blood of NT1 patients with that of healthy HLA-matched controls. This method allows for an in-depth analysis of differences in immune cell composition between both groups. In this way, it is possible to assess the immune system in an unbiased fashion. Our results show several memory CD4+ and CD8+ T cell populations expressing activation markers and regulatory CD4+ T cells indicative of an activated phenotype that are more frequent in NT1 patients with recent disease onset compared with HLA-matched controls. These differences seem to support the autoimmune hypothesis of narcolepsy. However, since differences are mainly found in small populations, they should be regarded with caution and at present can only serve as starting point for identifying novel mechanisms involved in the autoimmune response leading to the destruction of hypocretin-producing neurons. Furthermore, experiments aiming on replicating our findings are very important, since interindividual variability is high and we were only able to replicate a minority of the differences between NT1 patients and healthy controls that were reported previously. Performing experiments on immune cell reactivity to antigens of interest (such as hypocretin, H1N1 or other, still unknown antigens) with the identified NT1-specific immune cell clusters seems a promising strategy, which allows for diminishing the background noise that other immune cells might have caused in experimental research on the autoimmune response leading to NT1 executed until now.
Summary, discussion and future perspectives
• NT1 patients with recent disease onset have increased frequencies of several memory CD4+ and CD8+ T cell populations compared to HLA-matched controls
• Differences in immune cell composition are small between NT1 patients with recent onset compared to those later after onset
• Identified CD4+ and CD8+ T cell populations seem plausible candidates for identifying mechanisms involved in the autoimmune response leading to the destruction of hypocretin-producing neurons
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