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Le Guen Y, Luo G, Ambati A, Damotte V, Jansen I, Yu E, Nicolas A, de Rojas I, Peixoto Leal T, Miyashita A, Bellenguez C, Lian MM, Parveen K, Morizono T, Park H, Grenier-Boley B, Naito T, Küçükali F, Talyansky SD, Yogeshwar SM, Sempere V, Satake W, Alvarez V, Arosio B, Belloy ME, Benussi L, Boland A, Borroni B, Bullido MJ, Caffarra P, Clarimon J, Daniele A, Darling D, Debette S, Deleuze JF, Dichgans M, Dufouil C, During E, Düzel E, Galimberti D, Garcia-Ribas G, García-Alberca JM, García-González P, Giedraitis V, Goldhardt O, Graff C, Grünblatt E, Hanon O, Hausner L, Heilmann-Heimbach S, Holstege H, Hort J, Jung YJ, Jürgen D, Kern S, Kuulasmaa T, Ling L, Masullo C, Mecocci P, Mehrabian S, de Mendonça A, Boada M, Mir P, Moebus S, Moreno F, Nacmias B, Gael G, Nordestgaard BG, Papenberg G, Papma J, Parnetti L, Pasquier F, Pastor P, Peters O, Pijnenburg YAL, Piñol-Ripoll G, Popp J, Molina Porcel L, Puerta R, Pérez-Tur J, Rainero I, Ramakers I, Real LM, Riedel-Heller S, Rodriguez-Rodriguez E, Royo JL, Rujescu D, S. Protective association of HLA-DRB1*04 subtypes in neurodegenerative diseases implicates acetylated Tau PHF6 sequences. medRxiv. Dec 30, 2021. medRxiv.
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Weizmann Institute of Science
In this study, the authors attribute an important protective role to self-reactive T cells and speculate that the T cell facilitates early clearance of toxic aggregated tau seeds, either by recruiting β cells and generating an antibody response targeting the same epitope recognized by the T cells, or simply by activating T cell clearance of such early aggregates. Although the antigenic specificity and the mechanism proposed by the authors require further study, the overall observations support the notion that neurodegenerative disease could benefit from adaptive immune response, and thus from immunotherapy.
This discovery is extremely exciting, and is in line with the narrative introduced more than two decades ago that adaptive immunity plays an important role in recovery from damage to the CNS (Moalem et al., 1999), a phenomenon that we termed “Protective Autoimmunity.” At that time, together with Prof. J. Kipnis, back then a Ph.D. student, we demonstrated that the ability to mount a protective immune response to CNS damage in mice is genetically controlled by the MHC-II loci (Kipnis et al., 2001). These observations, together with numerous additional studies over the last two decades, introduced the role of systemic adaptive immunity in coping with Alzheimer’s disease (AD), and have led to the suggestion of immunotherapy for the treatment of neurodegenerative diseases (Schwartz, 2017).
References:
Moalem G, Leibowitz-Amit R, Yoles E, Mor F, Cohen IR, Schwartz M. Autoimmune T cells protect neurons from secondary degeneration after central nervous system axotomy. Nat Med. 1999 Jan;5(1):49-55. PubMed.
Kipnis J, Yoles E, Schori H, Hauben E, Shaked I, Schwartz M. Neuronal survival after CNS insult is determined by a genetically encoded autoimmune response. J Neurosci. 2001 Jul 1;21(13):4564-71. PubMed.
Schwartz M. Can immunotherapy treat neurodegeneration?. Science. 2017 Jul 21;357(6348):254-255. PubMed.
View all comments by Michal SchwartzUniversity Hospital Erlangen
The genetics of the human leukocyte antigen (HLA) system is very complex and fascinating, and a genetic association with the HLA locus is indicative of an involvement of the adaptive immune system. In this elegant and exciting study, the authors re-analyzed existing genome-wide association studies (GWAS) from an impressive number of participants with Parkinson’s and Alzheimer’s diseases and controls, focusing on fine mapping of the HLA locus. By this approach, a protective association of the HLA-DRB1*04 subtype with PD and AD was identified and was biologically strengthened by HLA-DRB1*04 associating with fewer neurofibrillary tangles in postmortem brains and lower tau levels in the cerebrospinal fluid (CSF).
The exciting result of preferential binding of the acetylated K311 tau PHF6 peptide, which is prone to aggregate, by the protective HLA-DRB1*04 subtypes potentiates the idea that an adaptive immune response against aggregated tau might be beneficial and protective against neurodegenerative diseases.
The results of this study have several important implications for deepening our understanding of neurodegenerative mechanisms in tauopathies. I would like to highlight two conceptual aspects: On one hand, the results emphasize a crucial involvement of the adaptive immune response in the pathology of human neurodegenerative diseases; and on the other, this study adds to the concept of protective autoimmunity proposed by Michal Schwartz. While initially the idea of protective autoimmunity was that autoimmune T lymphocytes play a beneficial role in repair of the central nervous system (CNS) after injury, this study expands the potential benefits of an autoimmune reaction against CNS self-antigens to protection against neurodegeneration.
These conceptually novel findings might revolutionize our knowledge and the development of therapeutics in the field of neurodegenerative disorders. As proposed by the authors, possibilities include either immunizing DRB1*04-carrying individuals with the acetyl-K311 PHF6 epitope, or targeting the acetyl-K311 PHF6 tau epitope with chimeric antigen receptor (CAR) T cells.
The presence of tau-specific T cells in healthy individuals was reported previously, and was quite surprising. Considering the data in this manuscript, and the fact that pronounced post-translational modifications might increase tau's immunogenicity, the auto-reactivity of T cells to tau may represent a protective mechanism aiming to control tau aggregation and the appearance of neurofibrillary tangles, thereby preventing neurodegeneration onset and/or progression.
This, in turn, points toward a beneficial autoimmune response, in contrast to the classical view of autoimmune reaction as pathological. In order to remain beneficial, an autoimmune response needs tight control, which might be provided by regulatory cytokines and T cells. In this respect, it would be very interesting to determine which effector T cell populations are activated by the DRB1*04-acetylated-K311 PHF6 peptide presentation, and what is the differentiation capacity of acetyl-K311 PHF6-reacting T cells. In line with this, a comparison of effector T cell profiles in the peripheral blood of AD patients with and without DRB1*04 subtypes could shed light on the balance of pro- and anti-inflammatory (anti-tau) responses and their correlation to the HLA class II subtypes. An open question is, do HLA-DRB1*04 individuals have a less severe or more slowly progressing AD?
Interestingly, despite the protective association of HLA-DRB1*04 with PD and Lewy pathology reported in this study, no preferential binding of DRB1*04 subtypes to PTM-positive α-synuclein peptides was observed. Does this suggest a central role of tau as an auto-epitope(s) for protective autoimmune response that hamper proteinopathy in different neurodegenerative diseases?
View all comments by Iryna ProtsMake a Comment
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