Autoimmunity in narcolepsy

Abstract

Purpose of review: Summarize the recent findings in narcolepsy focusing on the environmental and genetic risk factors in disease development.

Recent findings: Both genetic and epidemiological evidence point towards an autoimmune mechanism in the destruction of orexin/hypocretin neurons. Recent studies suggest both humoral and cellular immune responses in the disease development.

Summary: Narcolepsy is a severe sleep disorder, in which neurons producing orexin/hypocretin in the hypothalamus are destroyed. The core symptoms of narcolepsy are debilitating, extreme sleepiness, cataplexy, and abnormalities in the structure of sleep. Both genetic and epidemiological evidence point towards an autoimmune mechanism in the destruction of orexin/hypocretin neurons. Importantly, the highest environmental risk is seen with influenza-A infection and immunization. However, how the cells are destroyed is currently unknown. In this review we summarize the disease symptoms, and focus on the immunological findings in narcolepsy. We also discuss the environmental and genetic risk factors as well as propose a model for disease development.

Figure 1

Vaccination coverage in Europe shows higher percentage of vaccination in Northern Europe.

Figure 2

Possible immune mechanisms inducing narcolepsy via molecular mimicry and/or epitope spreading. Molecular mimicry. CD4 T cell-mediated activation: after being processed by an antigen presenting cell, H1N1 influenza peptides are presented associated to MHC class II molecule (HLA-DQB1*06:02) to CD4+ T cell, that in turn, through cytokine secretion, activate B cells and/or CD8+ T cell that are cross reactive with hypocretin-producing neurons. CD8+ T cell response: after being processed by an antigen presenting cell, H1N1 influenza peptides are presented associated to MHC class I molecule to CD8+ T cell, that in turn will attack hypocretin-producing neurons by cross-reactivity. B cell response: After being activated with H1N1 Influenza, B cells will secrete H1N1-specific antibodies that are cross-reactive with hypocretin-producing neurons. Epitope spreading: after immune response against H1N1 Influenza virus caused tissue damages (macrophages), some self peptides are released and treated by APC as antigens, meaning they are presented to CD4+ T cells that in turn initiate an immune response against self antigens.