AUTOIMMUNE HYPOTHESIS OF NARCOLEPSY TYPE 1.The most important elements in the current hypothesis of narcolepsy type 1 (NT1) pathogenesis include T cells, microglia and antibodies. If autoreactive T cells and antibodies enter the brain, an immune reaction that leads to the destruction of hypocretin neurons in the lateral hypothalamus could be started. The most likely mediators of the loss of hypocretin neurons are cytotoxic CD8+ T cells, which could provide pro-apoptotic signals to the hypocretin neurons, leading to neuronal loss. Although CD4+ T cells can enter the healthy brain, antibodies do not cross the blood–brain barrier under normal circumstances and only cross if the blood–brain barrier is compromised (dashed arrow) by a pathological event. In pathological conditions, autoantibodies can enter the brain, and, by binding to hypocretin neurons or their downstream targets, they could potentially have a role by activating the local microglia.
Defects in the P2Y11 receptor can lead to narcolepsy. In red are shown the amino acids in the P2Y11 protein that we have discovered are mutated in some narcolepsy patients.
Kornum et al. Nature Genetics 2011, Degn et al. Brain 2017.
P2Y11In our quest to understand what causes narcolepsy, we study the immune system of patients. We hypothesise that some of the proteins genetically associated with narcolepsy plays a central role in the disease process, and this is what we study. Importantly our work has shown that defects in the purinergic receptor P2Y11 predisposes to narcolepsy. P2Y11 is a dual Gs-Gq-protein coupled purinergic receptor that is activated by high concentrations of extracellular ATP. The receptor is highly important for the normal function of immune cells, and we are now studying how the narcolepsy associated mutations affects the immune system.
MHC class I subtypes are differentially regulated in neurons.We here show neurons in culture (pink), with MHC class I expression (green). Blue is DAPI staining of the nuclei.