Page 57 - The autoimmune hypothesis of narcolepsy and its unexplored clinical features M.S. Schinkelshoek
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Discussion
HLA-DQ6-H1N1-HA peptide-specific CD4+ T cell responses were readily detected in both NT1 patients and healthy controls, with a higher proportion in the NT1 group. We did not detect HLA-DQ6-Hcrt peptide-specific T cell responses. Our experiments do not support the hypothesis that these Hcrt peptides are implicated in cross-reactivity leading to Hcrt-producing neuronal destruction and, thereby, to NT1.
The HLA-DQ6-H1N1-HA peptide-specific TCCs did show some, but no extensive clustering of T cell receptor sequences in NT1 patients. Larger studies would be required to determine if the H1N1-specific TCR repertoire in NT1 patients differs from controls.
Our findings add to those of others in the field who did show antibody-mediated reactivity to H1N1-HA in NT1 patients. Several groups found H1N1-HA specific antibodies in NT1 patients (Lind et al., 2017, Lind et al., 2014), but H1N1-HA specific T cells have not been described. The lack of reactivity to Hcrt peptides was reported in studies focusing on autoantibodies (Black et al., 2005) and CD4+ T cells (Ramberger et al., 2017, Kornum et al., 2017a). HLA-DR-restricted Hcrt-specific T cell responses have recently been described (Latorre et al., 2018), but that study does not explain the strong link with HLA- DQ6. Interestingly, one other study (Ramberger et al., 2017) reported reactivity to Hcrt-peptide pools in a small minority of NT1 patients, although the peptides used differed from the ones in the current study.
Moreover, in our current study we focused on H1N1-HA and Hcrt peptides that display sequence homology, which does not rule out that other H1N1 peptides are involved. Another possibility is that the key differences between the peptides, a histidine residue at position 59 and 90 of the Hcrt56-68 and Hcrt87-99 peptides, respectively, as compared with an alanine residue in the corresponding position in the H1N1-HA275-287 peptide, may prevent cross-reactive responses. We therefore also tested substitution variants of the Hcrt-peptides in which the histidine residues were replaced by an alanine, but we observed no cross- reactivity to these peptides as well, making it unlikely that posttranslational modification of Hcrt-peptides underlies cross-reactivity (results not shown). In future studies we will therefore be testing T cell responses to peptide pools representing the H1N1 proteome and preprohypocretin.
H1N1 reactivity in CD4+ T cells
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