Autoimmunity to hypocretin and molecular mimicry to flu antigens in Type 1 narcolepsy
Bibliographic record
Abstract
Abstract Type 1 narcolepsy (T1N) is caused by hypocretin (HCRT) neuronal loss. Association with the Human Leukocyte Antigen (HLA)-DQB1*06:02/DQA1*01:02 (98% vs 25%) heterodimer (DQ0602), T cell receptor (TCR) and other immune loci suggest autoimmunity but autoantigen(s) are unknown. Onset is seasonal and associated with influenza A, notably pandemic 2009 H1N1 (pH1N1). An extensive unbiased DQ0602 binding peptide screen was performed encompassing peptides derived from Pandemrix ® X-179-A pH1N1 influenza-A vaccine, a known T1N trigger, other H1N1 strains, and potential human autoantigens HCRT and RFX4, identifying 109 binders. The presence of cognate tetramer-peptide specific CD4 + T cells was studied in 35 narcolepsy cases and 22 DQ0602 controls after expansion of antigen-specific cells in Peripheral Blood Monocytes Cell (PBMC) cultures. Higher reactivity to influenza epitopes pHA 273-287 (pH1N1 specific) and PR8 (H1N1 pre 2009)-specific NP 17-31 were observed in T1N. Extensive reactivity to C-amidated but not native version of HCRT 54-66 and HCRT 86-97 , which are two highly homologous peptides (HCRT NH2 ) was observed with higher frequencies of specific T cells in T1N. TCRα/β CDR3 sequences found in pHA 273-287, NP 17-31 and HCRT NH2 tetramer positive CD4 + cells were also retrieved in single INFγ-secreting CD4 + sorted cells stimulated with Pandemrix ® , confirming immunodominance and functional significance in DQ0602-mediated responses and molecular mimicry. TCRα/β CDR3 motifs of HCRT 54-66 and HCRT 86-97 tetramers were extensively shared. Particularly notable was sharing across subjects of an CDR3α, CAVETDSWGKLQF (in association with various CDR3β that used TRAJ24, a chain modulated by Single Nucleotide Polymorphism (SNPs) rs1154155 and rs1483979 associated with T1N. Sharing of CDR3β CASSQETQGRNYGYTF (in association with various CDR3α was also observed with HCRT NH2 and pHA 273-287 -tetramers across subjects. This segment uses TRBV4-2, a segment modulated by narcolepsy-associated SNP rs1008599. Higher HCRT NH2 positive CD4 + T cell numbers in T1N together with sharing of J24 CAVETDSWGKLQF in HCRT NH2 autoimmune responses, indicates causal DQ0602-mediated CD4 + autoreactivity to HCRT in T1N. Our results provide evidence for autoimmunity and molecular mimicry with flu antigens modulated by genetic components in the pathophysiology of T1N.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".