Fig. 3: Postulated potential disease mechanisms in autoimmune narcolepsy.

(1) Peripheral response: Influenza virions or vaccine protein debris are ingested by DCs facilitated by CD207; flu proteins are processed by cathepsins CTSH and CTSC for presentation by HLA molecules to specific TCRα-bearing CD4+ cells, initiating an immunological synapse and responses to influenza. Presentation by DC is modulated by IFNAR1 in the context of influenza infection and the type 1 INF response. Cross presentation of influenza antigens processed via the MHC class I pathway in concert with TNFSF4 in DCs is necessary to activate CD8+ cells that mature into cytotoxic lymphocytes (CTLs), initiating cell killing of viron infected cells. Activated Th1 CD4+ cells produce cytokines such as IFNγ and IL-2, which augment cytotoxic activity of CTLs via perforin (PRF1). SIRPG on activated T cells may also promote cell-to-cell adhesion and proliferation in this response. (2) CNS autoimmunity: Activated and primed specific CD4+ cells migrate to the CNS, where they interact with microglia and resident DCs via DQ0602 bound to an influenza-mimic autoimmune-epitope (derived from hypocretin cells), initiating a secondary memory response. Hypocretin cell proteins are processed by cathepsins CTSH and CTSC for presentation by DQ0602 to specific TCRα-bearing CD4+ cells, initiating an immunological synapse and autoimmune response. Chain usage for TRAJ24-2, TRAJ28 and TRBV4-2 is associated with NT1 risk and may be crucial for autoantigen recognition. Further, cross presentation by resident DCs and microglial cells activates specific CD8+ cells via MHC class I binding of another HCRT neuron-derived peptide. These primed cytotoxic CD8+ cells then kill HCRT neurons after recognizing MHC class I (such as A*11:01, associated with NT1 independently of DQ0602) bound, cognate HCRT neuron-derived peptide, may be derived from RFX4 or LHX9, on hypocretin neurons. SIRPG1 on DCs, microglia or activated T cells may also promote cell-to-cell adhesion and proliferation in this response.