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. 2023 Sep 5;120(36):e2302720120.
doi: 10.1073/pnas.2302720120. Epub 2023 Aug 29.

Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Yann Le Guen #  1   2 , Guo Luo #  3 , Aditya Ambati #  3 , Vincent Damotte #  4 , Iris Jansen  5   6 , Eric Yu  7   8   9 , Aude Nicolas  4 , Itziar de Rojas  10   11 , Thiago Peixoto Leal  12 , Akinori Miyashita  13 , Céline Bellenguez  4 , Michelle Mulan Lian  14   15 , Kayenat Parveen  16   17 , Takashi Morizono  18 , Hyeonseul Park  19 , Benjamin Grenier-Boley  4 , Tatsuhiko Naito  20   21 , Fahri K��çükali  22   23   24 , Seth D Talyansky  1 , Selina Maria Yogeshwar  3   25   26 , Vicente Sempere  3 , Wataru Satake  21 , Victoria Alvarez  27   28 , Beatrice Arosio  29 , Michael E Belloy  1 , Luisa Benussi  30 , Anne Boland  31 , Barbara Borroni  32 , María J Bullido  11   33   34 , Paolo Caffarra  35 , Jordi Clarimon  11   36 , Antonio Daniele  37   38 , Daniel Darling  3 , Stéphanie Debette  39   40 , Jean-François Deleuze  31 , Martin Dichgans  41   42   43 , Carole Dufouil  44   45 , Emmanuel During  3 , Emrah Düzel  46   47 , Daniela Galimberti  48   49 , Guillermo Garcia-Ribas  50 , José María García-Alberca  11   51 , Pablo García-González  10 , Vilmantas Giedraitis  52   53 , Oliver Goldhardt  54 , Caroline Graff  55 , Edna Grünblatt  56   57   58 , Olivier Hanon  59 , Lucrezia Hausner  60 , Stefanie Heilmann-Heimbach  61 , Henne Holstege  5   62 , Jakub Hort  63   64 , Yoo Jin Jung  65 , Deckert Jürgen  66 , Silke Kern  67   68 , Teemu Kuulasmaa  69 , Kun Ho Lee  70   71   72   73   74 , Ling Lin  3 , Carlo Masullo  75 , Patrizia Mecocci  76 , Shima Mehrabian  77 , Alexandre de Mendonça  78 , Mercè Boada  10   11 , Pablo Mir  11   79 , Susanne Moebus  80 , Fermin Moreno  11   81   82 , Benedetta Nacmias  83   84 , Gael Nicolas  85 , Shumpei Niida  18 , Børge G Nordestgaard  86   87 , Goran Papenberg  88 , Janne Papma  89 , Lucilla Parnetti  90 , Florence Pasquier  91 , Pau Pastor  92   93 , Oliver Peters  94   95 , Yolande A L Pijnenburg  5 , Gerard Piñol-Ripoll  96   97 , Julius Popp  98   99   100 , Laura Molina Porcel  101   102 , Raquel Puerta  10 , Jordi Pérez-Tur  11   103   104 , Innocenzo Rainero  105 , Inez Ramakers  106 , Luis M Real  107   108 , Steffi Riedel-Heller  109 , Eloy Rodriguez-Rodriguez  11   110 , Owen A Ross  111   112 , Luis Jose Royo  113 , Dan Rujescu  114 , Nikolaos Scarmeas  115   116 , Philip Scheltens  5 , Norbert Scherbaum  117 , Anja Schneider  118   119 , Davide Seripa  120 , Ingmar Skoog  67   121 , Vincenzo Solfrizzi  122 , Gianfranco Spalletta  123   124 , Alessio Squassina  125 , John van Swieten  126 , Raquel Sánchez-Valle  127 , Eng-King Tan  128   129 , Thomas Tegos  130 , Charlotte Teunissen  131 , Jesper Qvist Thomassen  132 , Lucio Tremolizzo  133 , Martin Vyhnalek  62   63 , Frans Verhey  134 , Margda Waern  135   136 , Jens Wiltfang  137   138   139 , Jing Zhang  3 ; EADB; GR@ACE study group; DEGESCO consortium; DemGene; EADI; GERAD; Asian Parkinson’s Disease Genetics consortium; Henrik Zetterberg  140   141   142   143   144 , Kaj Blennow  140   141 , Zihuai He  1 , Julie Williams  145   146 , Philippe Amouyel  4 , Frank Jessen  118   147   148 , Patrick G Kehoe  149 , Ole A Andreassen  150   151 , Cornelia Van Duin  152   153 , Magda Tsolaki  130 , Pascual Sánchez-Juan  11   154 , Ruth Frikke-Schmidt  87   132 , Kristel Sleegers  22   23   24 , Tatsushi Toda  21 , Anna Zettergren  135 , Martin Ingelsson  52   53   155   156 , Yukinori Okada  20   157   158   159 , Giacomina Rossi  160 , Mikko Hiltunen  69 , Jungsoo Gim  19   71   72 , Kouichi Ozaki  18   161 , Rebecca Sims  162 , Jia Nee Foo  14   15 , Wiesje van der Flier  5 , Takeshi Ikeuchi  13 , Alfredo Ramirez  16   17   118   148   163 , Ignacio Mata  12 , Agustín Ruiz  10   11 , Ziv Gan-Or  7   8   9 , Jean-Charles Lambert #  4 , Michael D Greicius #  1 , Emmanuel Mignot #  3
Affiliations

Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Yann Le Guen et al. Proc Natl Acad Sci U S A. .

Abstract

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

Keywords: Alzheimer’s dementia; HLA; Parkinson’s disease; autoimmunity; neurodegeneration.

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Conflict of interest statement

A patent application was filed by G.L. and E.M. on this discovery. Y.L.G. and reviewer F.C. shared the same institution.

Figures

Fig. 1.
Fig. 1.
Colocalization of the HLA locus signal in AD, PD, and ALS. PP4: posterior probability of colocalization.
Fig. 2.
Fig. 2.
Haplotypes harboring key HLA-DRB1*04 subtypes and/or HLA-DQB1*03:02. Effect sizes highlighted in red were nominally significant (P < 0.05).
Fig. 3.
Fig. 3.
The pro-aggregation PHF6 region of tau binds HLA-DRB1*04 subtypes only when acetylated at K311. Fifteen-mer peptides (800 µM) encompassing the entirety of all tau isoforms (schematized in panel A), overlapping across 11 residues, were screened for HLA-DRB1*04:01, HLA-DRB1*04:04 and HLA-DRB1*04:05 binding (Methods), with and without common PTMs as reported by Wesseling et al. (32). Four regions (labeled in purple, red, blue, orange, panel B) containing strong HLA-DRB1*04 binders (log displacement <1 to 1.4, below 25% of baseline control) were further tested at various concentrations (panel C), showing three promising regions where binding was stronger with HLA-DRB1*04:04/ HLA-DRB1*04:01, intermediary with HLA-DRB1*04:03 and absent or weak with HLA-DRB1*04:05 and HLA-DRB1*04:06, a pattern similar to GWAS risk (Table 1). Among these candidate regions, PHF6 306VQIVY(acetylK)PVDLSK317 is the only one that strongly binds HLA-DRB1*04:01, HLA-DRB1*04:03, and HLA-DRB1*04:04 and only when posttranslationally modified at K311. This segment is well known to seed tau aggregation, and this process is increased in the presence of acetylK311. Outcompeting a biotinylated epitope (known binder) 75% and 50% is considered as strong binding (SB) and weak binding (WB), respectively. Predicted binding cores are highlighted correspondingly.
Fig. 4.
Fig. 4.
Immune clearance of Acetylated PHF6 tau sequences may reduce neurodegeneration in AD and PD. Pathological tau seeds, soluble tau fragments, or misfolded tau present in the extracellular space are taken up and phagocytosed by activated microglia where it is processed. In addition to autophagy, resulting tau peptide fragments, notably acetylated lysine (K-ac) 311 PHF6 are bound to HLA-DRB1*04:01 or HLA-DRB1*04:04 and the resulting HLA-peptide complexes presented by microglial cells (or other antigen presenting cells) to CD4+ T helper cells. CD4+ T cells trigger beneficial downstream immune responses perhaps involving CD8+ T and antibody producing B cells. These responses limit propagation of misfolded tau and reduce neuropathology, also explaining reduced CSF tau in HLA-DRB1*04 individuals.
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