Investigation of the HLA locus in autopsy-confirmed progressive supranuclear palsy
Why this work is in the frame
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Bibliographic record
Abstract
Progressive supranuclear palsy (PSP) is a neurodegenerative disease showing pathological tau accumulation in subcortical neurons and glial cells. The human leukocyte antigen ( HLA ) locus on chromosome 6 is a polymorphic region with complex linkage patterns that has been implicated in several autoimmune and neurological disorders. The HLA locus has not been systematically examined in PSP. It is unclear whether tau and HLA can interact to induce an autoimmune disease mechanism. We evaluated an autopsy confirmed PSP cohort ( n = 44) and compared allele/haplotype frequencies to those of the reference group of a local deceased Canadian donor pool. We performed HLA-Tau peptide binding prediction and modelling of HLA Class II – Tau Peptide interactions. Odds ratio was 2.94 (95 % CI 1.01 to 8.55; p = 0.047) for DQB1 *06:01 allele, and 2.59 (95 % CI 1.39 to 4.83; p = 0.0025) for the narcolepsy-associated haplotype ( DRB1 *15:01- DQB1 *06:02). One patient with 4-repeat tau PSP-type pathology was a carrier of the IgLON5-associated haplotype ( DRB1 *10:01- DQB1 *05:01). HLA-Tau peptide binding prediction and modelling of HLA Class II – Tau Peptide interactions revealed strong-binding tau peptides but not the PSP-protofilament fold for alleles DQA1* 01:02-DQB1* 06:02 and DQA1* 01:03-DQB1* 06:01. Our study suggests that epitopes within the tau peptide may bind to HLA alleles that are found in a subset of PSP patients supporting the notion of an autoimmune pathophysiological component. These findings have implications for subtyping and stratifying patients for therapies, including those targeting immune modulation. • Progressive supranuclear palsy (PSP) is a neurodegenerative tauopathy. • The human leukocyte antigen ( HLA ) has been implicated in neurological disorders. • Evaluation of autopsy confirmed PSP cases revealed rare HLA haplotypes and alleles. • Modelling showed epitopes within the tau peptide that may bind to these HLA alleles. • We propose that PSP may have an autoimmune pathophysiological component.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 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) | 0.000 | 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 it