Figure 1.

An autoimmune hypothesis of HLA DQB1*0602-linked narcolepsy with cataplexy. (A) Normal numbers of Hcrt cells are found in the non-narcoleptic human hypothalamus. Scale bar: 50 μm. (B) An individual is exposed to infectious agents and toxins through the respiratory and gastrointestinal tracts, and through direct contact with other tissues. (C) Top panel: bacteria, other pathogens and toxins are engulfed by phagocytic cells and broken down inside acidified endosomes. Bottom panel: viruses, other pathogens and toxins are bound by antibodies on B cells, endocytosed and digested in endosomes. (D) Vesicles containing newly synthesized HLA DQB1*0602 class II molecules pass through endosomes and bind peptide fragments. These MHC class II:antigen complexes are inserted into cell membranes on professional antigen-presenting cells, including macrophages, microglia, dendritic cells and B cells. (E) Top panel: a B cell presenting antigen via HLA DQB1*0602 class II molecules becomes activated by a helper T cell recognizing the MHC class II:antigen complex. The B cell proliferates, and large quantities of antibodies are produced. Bottom panel: a CD4⁺ helper T cell, or possibly a cytotoxic T lymphocyte, becomes activated. (F) When the HLA DQB1*0602 class II:antigen complex closely resembles an epitope on Hcrt cells, these cells might be killed. Autoreactive cytotoxic T lymphocytes might kill cells. Antibody binding might also result in the killing of Hcrt cells by natural killer (NK) cells or complement-mediated lysis. (G) Few Hcrt cells remain in the narcoleptic human brain. Scale bar: 50 μm. Abbreviations: APC, antigen-presenting cell; B, B cell; CTL, cytotoxic T lymphocyte; Hcrt, hypocretin; MHC, major histocompatibility complex; NK, natural killer cell; T, T cell; T_H2, type 2 helper T cell.