To explore genetic association between human leukocyte antigen (HLA) and neurodegenerative diseases and investigate mechanisms behind the association.
Background
Pathophysiology of Alzheimer’s disease (AD) and Parkinson’s disease (PD) involves accumulation of tau (neurofibrillary tangles) and amyloid-β-rich (Aβ, amyloid plaques) aggregates in AD. Consensus is growing that the adaptive immune system and human leukocyte antigen (HLAs) presentation of tau/Aβ antigens plays a role in AD.
Design/Methods
We analyzed HLA associations in ~176,000 individuals with PD or AD versus controls across ancestry groups. We next screened 448 overlapping tau peptides including the most frequent post translationally modifications (PTM) against multiple HLA subtypes. We further examined tau restricted T cells using tetramer HLAs and performed single-cell RNA sequencing.
Results
A shared genetic association was observed across AD and PD at rs601945 (AD: OR=0.91[0.89; 0.93]; p=1.8x10-22). Hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with DRB1*04:04/DRB1*04:07, intermediary DRB1*04:01/DRB1*04:03 and absent for DRB1*04:05. The same signal was associated with decreased neurofibrillary tangle density postmortem and was more associated with lower tau levels than Aβ42 level changes in the CSF. Further, protective DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, but only when acetylated at K311, a modification central to aggregation. T cells recognizing this epitope were identified and T cell receptor clones were characterized, showing relevance of this immune response in patients with neurodegenerative disorders and suggesting a protective role of HLA DRB1*04.
Conclusion
An HLA-DRB1*04-mediated adaptive immune response, decreases AD risk, offering the possibility of new therapeutic avenues.
