Multiple inducers and novel roles of autoantibodies against the obligatory NMDAR subunit NR1: a translational study from chronic life stress to brain injury.
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
06 2021
06 2021
Historique:
received:
05
11
2019
accepted:
23
01
2020
revised:
13
01
2020
pubmed:
25
2
2020
medline:
12
10
2021
entrez:
25
2
2020
Statut:
ppublish
Résumé
Circulating autoantibodies (AB) of different immunoglobulin classes (IgM, IgA, and IgG), directed against the obligatory N-methyl-D-aspartate-receptor subunit NR1 (NMDAR1-AB), belong to the mammalian autoimmune repertoire, and appear with age-dependently high seroprevalence across health and disease. Upon access to the brain, they can exert NMDAR-antagonistic/ketamine-like actions. Still unanswered key questions, addressed here, are conditions of NMDAR1-AB formation/boosting, intraindividual persistence/course in serum over time, and (patho)physiological significance of NMDAR1-AB in modulating neuropsychiatric phenotypes. We demonstrate in a translational fashion from mouse to human that (1) serum NMDAR1-AB fluctuate upon long-term observation, independent of blood-brain barrier (BBB) perturbation; (2) a standardized small brain lesion in juvenile mice leads to increased NMDAR1-AB seroprevalence (IgM + IgG), together with enhanced Ig-class diversity; (3) CTLA4 (immune-checkpoint) genotypes, previously found associated with autoimmune disease, predispose to serum NMDAR1-AB in humans; (4) finally, pursuing our prior findings of an early increase in NMDAR1-AB seroprevalence in human migrants, which implicated chronic life stress as inducer, we independently replicate these results with prospectively recruited refugee minors. Most importantly, we here provide the first experimental evidence in mice of chronic life stress promoting serum NMDAR1-AB (IgA). Strikingly, stress-induced depressive-like behavior in mice and depression/anxiety in humans are reduced in NMDAR1-AB carriers with compromised BBB where NMDAR1-AB can readily reach the brain. To conclude, NMDAR1-AB may have a role as endogenous NMDAR antagonists, formed or boosted under various circumstances, ranging from genetic predisposition to, e.g., tumors, infection, brain injury, and stress, altogether increasing over lifetime, and exerting a spectrum of possible effects, also including beneficial functions.
Identifiants
pubmed: 32089545
doi: 10.1038/s41380-020-0672-1
pii: 10.1038/s41380-020-0672-1
pmc: PMC8440197
doi:
Substances chimiques
Autoantibodies
0
Receptors, N-Methyl-D-Aspartate
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2471-2482Informations de copyright
© 2020. The Author(s).
Références
Li F, Tsien JZ. Memory and the NMDA receptors. N Engl J Med. 2009;361:302–3.
pubmed: 19605837
pmcid: 3703758
doi: 10.1056/NEJMcibr0902052
Dzamba D, Honsa P, Anderova M. NMDA receptors in glial cells: pending questions. Curr Neuropharmacol. 2013;11:250–62.
pubmed: 24179462
pmcid: 3648778
doi: 10.2174/1570159X11311030002
Lau CG, Zukin RS. NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders. Nat Rev Neurosci. 2007;8:413–26.
pubmed: 17514195
doi: 10.1038/nrn2153
Reijerkerk A, Kooij G, van der Pol SM, Leyen T, Lakeman K, van Het Hof B, et al. The NR1 subunit of NMDA receptor regulates monocyte transmigration through the brain endothelial cell barrier. J Neurochem. 2010;113:447–53.
pubmed: 20085611
doi: 10.1111/j.1471-4159.2010.06598.x
Saab AS, Tzvetavona ID, Trevisiol A, Baltan S, Dibaj P, Kusch K, et al. Oligodendroglial NMDA receptors regulate glucose import and axonal energy metabolism. Neuron. 2016;91:119–32.
pubmed: 27292539
doi: 10.1016/j.neuron.2016.05.016
pmcid: 9084537
Du J, Li XH, Li YJ. Glutamate in peripheral organs: biology and pharmacology. Eur J Pharm. 2016;784:42–8.
doi: 10.1016/j.ejphar.2016.05.009
Dalmau J, Tuzun E, Wu HY, Masjuan J, Rossi JE, Voloschin A, et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol. 2007;61:25–36.
pubmed: 17262855
pmcid: 2430743
doi: 10.1002/ana.21050
Dalmau J, Gleichman AJ, Hughes EG, Rossi JE, Peng X, Lai M, et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7:1091–8.
pubmed: 18851928
pmcid: 2607118
doi: 10.1016/S1474-4422(08)70224-2
Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 2011;10:63–74.
pubmed: 21163445
pmcid: 3158385
doi: 10.1016/S1474-4422(10)70253-2
Titulaer MJ, McCracken L, Gabilondo I, Armangué T, Glaser C, Iizuka T, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol. 2013;12:157–65.
pubmed: 23290630
pmcid: 3563251
doi: 10.1016/S1474-4422(12)70310-1
Hughes EG, Peng X, Gleichman AJ, Lai M, Zhou L, Tsou R, et al. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J Neurosci. 2010;30:5866–75.
pubmed: 20427647
pmcid: 2868315
doi: 10.1523/JNEUROSCI.0167-10.2010
Choe CU, Karamatskos E, Schattling B, Leypoldt F, Liuzzi G, Gerloff C, et al. A clinical and neurobiological case of IgM NMDA receptor antibody associated encephalitis mimicking bipolar disorder. Psychiatry Res. 2013;208:194–6.
pubmed: 23246244
doi: 10.1016/j.psychres.2012.09.035
Prüss H, Finke C, Holtje M, Hofmann J, Klingbeil C, Probst C, et al. N-methyl-D-aspartate receptor antibodies in herpes simplex encephalitis. Ann Neurol. 2012;72:902–11.
pubmed: 23280840
pmcid: 3725636
doi: 10.1002/ana.23689
Prüss H, Holtje M, Maier N, Gomez A, Buchert R, Harms L, et al. IgA NMDA receptor antibodies are markers of synaptic immunity in slow cognitive impairment. Neurology. 2012;78:1743–53.
pubmed: 22539565
pmcid: 3359581
doi: 10.1212/WNL.0b013e318258300d
Steiner J, Walter M, Glanz W, Sarnyai Z, Bernstein HG, Vielhaber S, et al. Increased prevalence of diverse N-methyl-D-aspartate glutamate receptor antibodies in patients with an initial diagnosis of schizophrenia: specific relevance of IgG NR1a antibodies for distinction from N-methyl-D-aspartate glutamate receptor encephalitis. JAMA Psychiatry. 2013;70:271–8.
pubmed: 23344076
doi: 10.1001/2013.jamapsychiatry.86
Zerche M, Weissenborn K, Ott C, Dere E, Asif AR, Worthmann H, et al. Preexisting serum autoantibodies against the NMDAR subunit NR1 modulate evolution of lesion size in acute ischemic stroke. Stroke. 2015;46:1180–6.
pubmed: 25765725
doi: 10.1161/STROKEAHA.114.008323
Hammer C, Stepniak B, Schneider A, Papiol S, Tantra M, Begemann M, et al. Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood-brain barrier integrity. Mol Psychiatry. 2014;19:1143–9.
pubmed: 23999527
doi: 10.1038/mp.2013.110
Castillo-Gomez E, Oliveira B, Tapken D, Bertrand S, Klein-Schmidt C, Pan H, et al. All naturally occurring autoantibodies against the NMDA receptor subunit NR1 have pathogenic potential irrespective of epitope and immunoglobulin class. Mol Psychiatry. 2017;22:1776–84.
pubmed: 27502473
doi: 10.1038/mp.2016.125
Hammer C, Zerche M, Schneider A, Begemann M, Nave KA, Ehrenreich H. Apolipoprotein E4 carrier status plus circulating anti-NMDAR1 autoantibodies: association with schizoaffective disorder. Mol Psychiatry. 2014;19:1054–6.
pubmed: 24888362
pmcid: 4195337
doi: 10.1038/mp.2014.52
Pan H, Oliveira B, Saher G, Dere E, Tapken D, Mitjans M, et al. Uncoupling the widespread occurrence of anti-NMDAR1 autoantibodies from neuropsychiatric disease in a novel autoimmune model. Mol Psychiatry. 2019;24:1489–501.
doi: 10.1038/s41380-017-0011-3
pubmed: 29426955
Castillo-Gomez E, Kastner A, Steiner J, Schneider A, Hettling B, Poggi G, et al. The brain as immunoprecipitator of serum autoantibodies against N-Methyl-D-aspartate receptor subunit NR1. Ann Neurol. 2016;79:144–51.
pubmed: 26505629
doi: 10.1002/ana.24545
Dahm L, Ott C, Steiner J, Stepniak B, Teegen B, Saschenbrecker S, et al. Seroprevalence of autoantibodies against brain antigens in health and disease. Ann Neurol. 2014;76:82–94.
doi: 10.1002/ana.24189
pubmed: 24853231
Steiner J, Teegen B, Schiltz K, Bernstein HG, Stoecker W, Bogerts B. Prevalence of N-methyl-D-aspartate receptor autoantibodies in the peripheral blood: healthy control samples revisited. JAMA Psychiatry. 2014;71:838–9.
pubmed: 24871043
doi: 10.1001/jamapsychiatry.2014.469
Begemann M, Grube S, Papiol S, Malzahn D, Krampe H, Ribbe K, et al. Modification of cognitive performance in schizophrenia by complexin 2 gene polymorphisms. Arch Gen Psychiatry. 2010;67:879–88.
pubmed: 20819981
doi: 10.1001/archgenpsychiatry.2010.107
Ribbe K, Friedrichs H, Begemann M, Grube S, Papiol S, Kastner A, et al. The cross-sectional GRAS sample: a comprehensive phenotypical data collection of schizophrenic patients. BMC Psychiatry. 2010;10:91.
pubmed: 21067598
pmcid: 3002316
doi: 10.1186/1471-244X-10-91
Stepniak B, Kastner A, Poggi G, Mitjans M, Begemann M, Hartmann A, et al. Accumulated common variants in the broader fragile X gene family modulate autistic phenotypes. EMBO Mol Med. 2015;7:1565–79.
pubmed: 26612855
pmcid: 4693501
doi: 10.15252/emmm.201505696
Franke GH, Heemann U, Kohnle M, Luetkes P, Maehner N, Reimer J. Quality of life in patients before and after kidney transplantation. Psychol Health. 2000;14:1037–49.
pubmed: 22175260
doi: 10.1080/08870440008407365
Wandinger KP, Saschenbrecker S, Stoecker W, Dalmau J. Anti-NMDA-receptor encephalitis: a severe, multistage, treatable disorder presenting with psychosis. J Neuroimmunol. 2011;231:86–91.
pubmed: 20951441
doi: 10.1016/j.jneuroim.2010.09.012
Sirén AL, Radyushkin K, Boretius S, Kammer D, Riechers CC, Natt O, et al. Global brain atrophy after unilateral parietal lesion and its prevention by erythropoietin. Brain. 2006;129:480–9.
pubmed: 16339796
doi: 10.1093/brain/awh703
Cryan JF, Mombereau C, Vassout A. The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice. Neurosci Biobehav Rev. 2005;29:571–625.
pubmed: 15890404
doi: 10.1016/j.neubiorev.2005.03.009
Li Q, Li D, Zhang X, Wan Q, Zhang W, Zheng M, et al. E3 Ligase VHL promotes group 2 innate lymphoid cell maturation and function via glycolysis inhibition and induction of interleukin-33 receptor. Immunity. 2018;48:258–70.
pubmed: 29452935
pmcid: 5828523
doi: 10.1016/j.immuni.2017.12.013
Chang CC, Chow CC, Tellier LC, Vattikuti S, Purcell SM, Lee JJ. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience. 2015;4:7.
pubmed: 25722852
pmcid: 4342193
doi: 10.1186/s13742-015-0047-8
Dorshkind K, Montecino-Rodriguez E, Signer RA. The ageing immune system: is it ever too old to become young again? Nat Rev Immunol. 2009;9:57–62.
pubmed: 19104499
doi: 10.1038/nri2471
Nikolich-Zugich J. The twilight of immunity: emerging concepts in aging of the immune system. Nat Immunol. 2018;19:10–9.
pubmed: 29242543
doi: 10.1038/s41590-017-0006-x
Atabani SF, Thio CL, Divanovic S, Trompette A, Belkaid Y, Thomas DL, et al. Association of CTLA4 polymorphism with regulatory T cell frequency. Eur J Immunol. 2005;35:2157–62.
pubmed: 15940668
doi: 10.1002/eji.200526168
Birlea SA, Laberge GS, Procopciuc LM, Fain PR, Spritz RA. CTLA4 and generalized vitiligo: two genetic association studies and a meta-analysis of published data. Pigment Cell Melanoma Res. 2009;22:230–4.
pubmed: 19175525
pmcid: 2745263
doi: 10.1111/j.1755-148X.2009.00543.x
Blomhoff A, Lie BA, Myhre AG, Kemp EH, Weetman AP, Akselsen HE, et al. Polymorphisms in the cytotoxic T lymphocyte antigen-4 gene region confer susceptibility to Addison’s disease. J Clin Endocrinol Metab. 2004;89:3474–6.
pubmed: 15240634
doi: 10.1210/jc.2003-031854
Howson JM, Dunger DB, Nutland S, Stevens H, Wicker LS, Todd JA. A type 1 diabetes subgroup with a female bias is characterised by failure in tolerance to thyroid peroxidase at an early age and a strong association with the cytotoxic T-lymphocyte-associated antigen-4 gene. Diabetologia. 2007;50:741–6.
pubmed: 17334650
pmcid: 2387192
doi: 10.1007/s00125-007-0603-6
Maier LM, Anderson DE, De Jager PL, Wicker LS, Hafler DA. Allelic variant in CTLA4 alters T cell phosphorylation patterns. Proc Natl Acad Sci USA. 2007;104:18607–12.
pubmed: 18000051
pmcid: 2141824
doi: 10.1073/pnas.0706409104
Torres B, Aguilar F, Franco E, Sanchez E, Sanchez-Roman J, Jimenez Alonso J, et al. Association of the CT60 marker of the CTLA4 gene with systemic lupus erythematosus. Arthritis Rheum. 2004;50:2211–5.
pubmed: 15248219
doi: 10.1002/art.20347
Ueda H, Howson JM, Esposito L, Heward J, Snook H, Chamberlain G, et al. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature. 2003;423:506–11.
pubmed: 12724780
doi: 10.1038/nature01621
Walker EJ, Hirschfield GM, Xu C, Lu Y, Liu X, Lu Y, et al. CTLA4/ICOS gene variants and haplotypes are associated with rheumatoid arthritis and primary biliary cirrhosis in the Canadian population. Arthritis Rheum. 2009;60:931–7.
pubmed: 19333938
doi: 10.1002/art.24412
Bartels F, Stronisch T, Farmer K, Rentzsch K, Kiecker F, Finke C. Neuronal autoantibodies associated with cognitive impairment in melanoma patients. Ann Oncol. 2019;30:823–9.
pubmed: 30840061
pmcid: 6551450
doi: 10.1093/annonc/mdz083
de Moel EC, Rozeman EA, Kapiteijn EH, Verdegaal EME, Grummels A, Bakker JA, et al. Autoantibody development under treatment with immune-checkpoint inhibitors. Cancer Immunol Res. 2019;7:6–11.
pubmed: 30425107
doi: 10.1158/2326-6066.CIR-18-0245
Lühder F, Hoglund P, Allison JP, Benoist C, Mathis D. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) regulates the unfolding of autoimmune diabetes. J Exp Med. 1998;187:427–32.
pubmed: 9449722
pmcid: 2212113
doi: 10.1084/jem.187.3.427
June CH, Warshauer JT, Bluestone JA. Is autoimmunity the Achilles’ heel of cancer immunotherapy? Nat Med. 2017;23:540–7.
pubmed: 28475571
doi: 10.1038/nm.4321
Walunas TL, Lenschow DJ, Bakker CY, Linsley PS, Freeman GJ, Green JM, et al. CTLA-4 can function as a negative regulator of T cell activation. Immunity. 1994;1:405–13.
pubmed: 7882171
doi: 10.1016/1074-7613(94)90071-X
Martinez RC, Carvalho-Netto EF, Amaral VC, Nunes-de-Souza RL, Canteras NS. Investigation of the hypothalamic defensive system in the mouse. Behav Brain Res. 2008;192:185–90.
pubmed: 18468701
doi: 10.1016/j.bbr.2008.03.042
Diamond B, Huerta PT, Mina-Osorio P, Kowal C, Volpe BT. Losing your nerves? Maybe it’s the antibodies. Nat Rev Immunol. 2009;9:449–56.
pubmed: 19424277
pmcid: 2783680
doi: 10.1038/nri2529
Ferreira MF, Castanheira L, Sebastiao AM, Telles-Correia D. Depression assessment in clinical trials and pre-clinical tests: a critical review. Curr Top Med Chem. 2018;18:1677–703.
pubmed: 30430942
doi: 10.2174/1568026618666181115095920
Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, et al. Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature. 2012;485:512–6.
pubmed: 22622580
pmcid: 4047116
doi: 10.1038/nature11087
Halliday MR, Pomara N, Sagare AP, Mack WJ, Frangione B, Zlokovic BV. Relationship between cyclophilin a levels and matrix metalloproteinase 9 activity in cerebrospinal fluid of cognitively normal apolipoprotein e4 carriers and blood-brain barrier breakdown. JAMA Neurol. 2013;70:1198–1200.
pubmed: 24030206
pmcid: 4047029
doi: 10.1001/jamaneurol.2013.3841
Zlokovic BV. Cerebrovascular effects of apolipoprotein E: implications for Alzheimer disease. JAMA Neurol. 2013;70:440–4.
pubmed: 23400708
pmcid: 4414030
doi: 10.1001/jamaneurol.2013.2152
Endesfelder D, Zu Castell W, Bonifacio E, Rewers M, Hagopian WA, She JX, et al. Time-resolved autoantibody profiling facilitates stratification of preclinical type 1 diabetes in children. Diabetes. 2019;68:119–30.
pubmed: 30305370
doi: 10.2337/db18-0594
Bechter K. Mild encephalitis underlying psychiatric disorder—a reconsideration and hypothesis exemplified on Borna disease. Neurol Psychiat Br. 2001;9:55–70.
Salvi S, Holgate ST. Could the airway epithelium play an important role in mucosal immunoglobulin A production? Clin Exp Allergy. 1999;29:1597–605.
pubmed: 10594535
doi: 10.1046/j.1365-2222.1999.00644.x
Tezuka H, Ohteki T. Regulation of IgA production by intestinal dendritic cells and related cells. Front Immunol. 2019;10:1891.
pubmed: 31456802
pmcid: 6700333
doi: 10.3389/fimmu.2019.01891
Zanos P, Moaddel R, Morris PJ, Riggs LM, Highland JN, Georgiou P, et al. Ketamine and Ketamine Metabolite Pharmacology: insights into therapeutic mechanisms. Pharm Rev. 2018;70:621–60.
pubmed: 29945898
pmcid: 6020109
doi: 10.1124/pr.117.015198
Peltoniemi MA, Hagelberg NM, Olkkola KT, Saari TI. Ketamine: a review of clinical pharmacokinetics and pharmacodynamics in anesthesia and pain therapy. Clin Pharmacokinet. 2016;55:1059–77.
pubmed: 27028535
doi: 10.1007/s40262-016-0383-6
Aleksandrova LR, Phillips AG, Wang YT. Antidepressant effects of ketamine and the roles of AMPA glutamate receptors and other mechanisms beyond NMDA receptor antagonism. J Psychiatry Neurosci. 2017;42:222–9.
pubmed: 28234212
pmcid: 5487269
doi: 10.1503/jpn.160175
Molero P, Ramos-Quiroga JA, Martin-Santos R, Calvo-Sanchez E, Gutierrez-Rojas L, Meana JJ. Antidepressant efficacy and tolerability of ketamine and esketamine: a critical review. CNS Drugs. 2018;32:411–20.
pubmed: 29736744
doi: 10.1007/s40263-018-0519-3
Moda-Sava RN, Murdock MH, Parekh PK, Fetcho RN, Huang BS, Huynh TN, et al. Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science. 2019;364:pii:eaat8078.
Beyeler A. Do antidepressants restore lost synapses? Science. 2019;364:129–30.
pubmed: 30975877