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Weixi Feng, Yanli Zhang, Peng Sun, Ming Xiao. Acquired immunity and Alzheimer's disease[J]. The Journal of Biomedical Research. doi: 10.7555/JBR.36.20220083
Citation: Weixi Feng, Yanli Zhang, Peng Sun, Ming Xiao. Acquired immunity and Alzheimer's disease[J]. The Journal of Biomedical Research. doi: 10.7555/JBR.36.20220083

Acquired immunity and Alzheimer's disease

doi: 10.7555/JBR.36.20220083
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  • Corresponding author: Weixi Feng, Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing, Jiangsu 211166, China. Tel: ; E-mail: weixif@njmu.edu.cn
  • Received: 2022-04-13
  • Revised: 2022-06-18
  • Accepted: 2022-06-27
  • Published: 2022-07-28
  • Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive cognitive defects. The role of the central immune dominated by microglia in the progression of AD has been extensively investigated. However, little is known about the peripheral immune system in AD pathogenesis. Recently, with the discovery of the meningeal lymphatic vessels and glymphatic system, the roles of acquired immunity in the maintenance of central homeostasis and neurodegenerative diseases have attracted increasing attention. T cells not only regulate the function of neurons, astrocytes, microglia, oligodendrocytes and brain microvascular endothelial cells, but also participate in clearance of β-amyloid (Aβ) plaques. Apart from producing antibodies to bind Aβ peptides, B cells affect Aβ-related cascades via a variety of antibody-independent mechanisms. This review systemically summarizes the recent progress in understanding pathophysiological roles of T cells and B cells in AD.


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  • [1]
    Alzheimer's Association. 2019 Alzheimer's disease facts and figures[J]. Alzheimers Dement, 2019, 15(3): 321–387. doi: 10.1016/j.jalz.2019.01.010
    Long JM, Holtzman DM. Alzheimer disease: an update on pathobiology and treatment strategies[J]. Cell, 2019, 179(2): 312–339. doi: 10.1016/j.cell.2019.09.001
    Tarasoff-Conway JM, Carare RO, Osorio RS, et al. Clearance systems in the brain-implications for Alzheimer disease[J]. Nat Rev Neurol, 2015, 11(8): 457–470. doi: 10.1038/nrneurol.2015.119
    Xie C, Zhuang X, Niu Z, et al. Amelioration of Alzheimer's disease pathology by mitophagy inducers identified via machine learning and a cross-species workflow[J]. Nat Biomed Eng, 2022, 6(1): 76–93. doi: 10.1038/s41551-021-00819-5
    Heneka MT, Carson MJ, El Khoury J, et al. Neuroinflammation in Alzheimer's disease[J]. Lancet Neurol, 2015, 14(4): 388–405. doi: 10.1016/S1474-4422(15)70016-5
    Ransohoff RM. How neuroinflammation contributes to neurodegeneration[J]. Science, 2016, 353(6301): 777–783. doi: 10.1126/science.aag2590
    Fang EF, Hou Y, Palikaras K, et al. Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease[J]. Nat Neurosci, 2019, 22(3): 401–412. doi: 10.1038/s41593-018-0332-9
    Lautrup S, Lou G, Aman Y, et al. Microglial mitophagy mitigates neuroinflammation in Alzheimer's disease[J]. Neurochem Int, 2019, 129: 104469. doi: 10.1016/j.neuint.2019.104469
    Perry VH, Holmes C. Microglial priming in neurodegenerative disease[J]. Nat Rev Neurol, 2014, 10(4): 217–224. doi: 10.1038/nrneurol.2014.38
    Heppner FL, Ransohoff RM, Becher B. Immune attack: the role of inflammation in Alzheimer disease[J]. Nat Rev Neurosci, 2015, 16(6): 358–372. doi: 10.1038/nrn3880
    Heneka MT, Kummer MP, Latz E. Innate immune activation in neurodegenerative disease[J]. Nat Rev Immunol, 2014, 14(7): 463–477. doi: 10.1038/nri3705
    Villegas-Llerena C, Phillips A, Garcia-Reitboeck P, et al. Microglial genes regulating neuroinflammation in the progression of Alzheimer's disease[J]. Curr Opin Neurobiol, 2016, 36: 74–81. doi: 10.1016/j.conb.2015.10.004
    Salter MW, Stevens B. Microglia emerge as central players in brain disease[J]. Nat Med, 2017, 23(9): 1018–1027. doi: 10.1038/nm.4397
    Efthymiou AG, Goate AM. Late onset Alzheimer's disease genetics implicates microglial pathways in disease risk[J]. Mol Neurodegener, 2017, 12(1): 43. doi: 10.1186/s13024-017-0184-x
    Mhatre SD, Tsai CA, Rubin AJ, et al. Microglial malfunction: the third rail in the development of Alzheimer's disease[J]. Trends Neurosci, 2015, 38(10): 621–636. doi: 10.1016/j.tins.2015.08.006
    Keren-Shaul H, Spinrad A, Weiner A, et al. A unique microglia type associated with restricting development of Alzheimer's disease[J]. Cell, 2017, 169(7): 1276–1290.e17. doi: 10.1016/j.cell.2017.05.018
    Zewinger S, Reiser J, Jankowski V, et al. Apolipoprotein C3 induces inflammation and organ damage by alternative inflammasome activation[J]. Nat Immunol, 2020, 21(1): 30–41. doi: 10.1038/s41590-019-0548-1
    Osborn LM, Kamphuis W, Wadman WJ, et al. Astrogliosis: an integral player in the pathogenesis of Alzheimer's disease[J]. Prog Neurobiol, 2016, 144: 121–141. doi: 10.1016/j.pneurobio.2016.01.001
    Bradshaw EM, Chibnik LB, Keenan BT, et al. CD33 Alzheimer's disease locus: altered monocyte function and amyloid biology[J]. Nat Neurosci, 2013, 16(7): 848–850. doi: 10.1038/nn.3435
    Bettens K, Sleegers K, Van Broeckhoven C. Genetic insights in Alzheimer's disease[J]. Lancet Neurol, 2013, 12(1): 92–104. doi: 10.1016/S1474-4422(12)70259-4
    Deming Y, Filipello F, Cignarella F, et al. The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer's disease risk[J]. Sci Transl Med, 2019, 11(505): eaau2291. doi: 10.1126/scitranslmed.aau2291
    Cuyvers E, Sleegers K. Genetic variations underlying Alzheimer's disease: evidence from genome-wide association studies and beyond[J]. Lancet Neurol, 2016, 15(8): 857–868. doi: 10.1016/S1474-4422(16)00127-7
    Yuan P, Condello C, Keene CD, et al. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy[J]. Neuron, 2016, 90(4): 724–739. doi: 10.1016/j.neuron.2016.05.003
    Suárez-Calvet M, Araque Caballero MÁ, Kleinberger G, et al. Early changes in CSF sTREM2 in dominantly inherited Alzheimer's disease occur after amyloid deposition and neuronal injury[J]. Sci Transl Med, 2016, 8(369): 369ra178.
    Hong S, Beja-Glasser VF, Nfonoyim BM, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models[J]. Science, 2016, 352(6286): 712–716. doi: 10.1126/science.aad8373
    Riazi K, Galic MA, Kentner AC, et al. Microglia-dependent alteration of glutamatergic synaptic transmission and plasticity in the hippocampus during peripheral inflammation[J]. J Neurosci, 2015, 35(12): 4942–4952. doi: 10.1523/JNEUROSCI.4485-14.2015
    Zhang J, Malik A, Choi HB, et al. Microglial CR3 activation triggers long-term synaptic depression in the hippocampus via NADPH oxidase[J]. Neuron, 2014, 82(1): 195–207. doi: 10.1016/j.neuron.2014.01.043
    Lau SF, Chen C, Fu W, et al. IL-33-PU. 1 Transcriptome reprogramming drives functional state transition and clearance activity of microglia in alzheimer's disease[J]. Cell Rep, 2020, 31(3): 107530. doi: 10.1016/j.celrep.2020.107530
    Huang K, Marcora E, Pimenova AA, et al. A common haplotype lowers PU. 1 expression in myeloid cells and delays onset of Alzheimer's disease[J]. Nat Neurosci, 2017, 20(8): 1052–1061. doi: 10.1038/nn.4587
    Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β[J]. Sci Transl Med, 2012, 4(147): 147ra111.
    Aspelund A, Antila S, Proulx ST, et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules[J]. J Exp Med, 2015, 212(7): 991–999. doi: 10.1084/jem.20142290
    Mestre H, Hablitz LM, Xavier AL, et al. Aquaporin-4-dependent glymphatic solute transport in the rodent brain[J]. Elife, 2018, 7: e40070. doi: 10.7554/eLife.40070
    Ahn JH, Cho H, Kim JH, et al. Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid[J]. Nature, 2019, 572(7767): 62–66. doi: 10.1038/s41586-019-1419-5
    Louveau A, Smirnov I, Keyes TJ, et al. Structural and functional features of central nervous system lymphatic vessels[J]. Nature, 2015, 523(7560): 337–341. doi: 10.1038/nature14432
    Wang L, Zhang Y, Zhao Y, et al. Deep cervical lymph node ligation aggravates AD-like pathology of APP/PS1 mice[J]. Brain Pathol, 2019, 29(2): 176–192. doi: 10.1111/bpa.12656
    Da Mesquita S, Louveau A, Vaccari A, et al. Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease[J]. Nature, 2018, 560(7717): 185–191. doi: 10.1038/s41586-018-0368-8
    Xu Z, Xiao N, Chen Y, et al. Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Aβ accumulation and memory deficits[J]. Mol Neurodegener, 2015, 10: 58. doi: 10.1186/s13024-015-0056-1
    Peng W, Achariyar TM, Li B, et al. Suppression of glymphatic fluid transport in a mouse model of Alzheimer's disease[J]. Neurobiol Dis, 2016, 93: 215–225. doi: 10.1016/j.nbd.2016.05.015
    Busse M, Michler E, von Hoff F, et al. Alterations in the peripheral immune system in dementia[J]. J Alzheimers Dis, 2017, 58(4): 1303–1313. doi: 10.3233/JAD-161304
    Richartz-Salzburger E, Batra A, Stransky E, et al. Altered lymphocyte distribution in Alzheimer's disease[J]. J Psychiatr Res, 2007, 41(1-2): 174–178. doi: 10.1016/j.jpsychires.2006.01.010
    Pellicanò M, Larbi A, Goldeck D, et al. Immune profiling of Alzheimer patients[J]. J Neuroimmunol, 2012, 242(1-2): 52–59. doi: 10.1016/j.jneuroim.2011.11.005
    Bulati M, Buffa S, Martorana A, et al. Double negative (IgG+IgD-CD27-) B cells are increased in a cohort of moderate-severe Alzheimer's disease patients and show a pro-inflammatory trafficking receptor phenotype[J]. J Alzheimers Dis, 2015, 44(4): 1241–1251. doi: 10.3233/JAD-142412
    Bonotis K, Krikki E, Holeva V, et al. Systemic immune aberrations in Alzheimer's disease patients[J]. J Neuroimmunol, 2008, 193(1-2): 183–187. doi: 10.1016/j.jneuroim.2007.10.020
    Speciale L, Calabrese E, Saresella M, et al. Lymphocyte subset patterns and cytokine production in Alzheimer's disease patients[J]. Neurobiol Aging, 2007, 28(8): 1163–1169. doi: 10.1016/j.neurobiolaging.2006.05.020
    Larbi A, Pawelec G, Witkowski JM, et al. Dramatic shifts in circulating CD4 but not CD8 T cell subsets in mild Alzheimer's disease[J]. J Alzheimers Dis, 2009, 17(1): 91–103. doi: 10.3233/JAD-2009-1015
    Bulati M, Buffa S, Candore G, et al. B cells and immunosenescence: a focus on IgG+IgD-CD27- (DN) B cells in aged humans[J]. Ageing Res Rev, 2011, 10(2): 274–284. doi: 10.1016/j.arr.2010.12.002
    Steele NZR, Carr JS, Bonham LW, et al. Fine-mapping of the human leukocyte antigen locus as a risk factor for Alzheimer disease: a case-control study[J]. PLoS Med, 2017, 14(3): e1002272. doi: 10.1371/journal.pmed.1002272
    Jiang Q, Jin S, Jiang Y, et al. Alzheimer's disease variants with the genome-wide significance are significantly enriched in immune pathways and active in immune cells[J]. Mol Neurobiol, 2017, 54(1): 594–600. doi: 10.1007/s12035-015-9670-8
    Gate D, Saligrama N, Leventhal O, et al. Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease[J]. Nature, 2020, 577(7790): 399–404. doi: 10.1038/s41586-019-1895-7
    Engelhardt B, Ransohoff RM. The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms[J]. Trends Immunol, 2005, 26(9): 485–495. doi: 10.1016/j.it.2005.07.004
    Siffrin V, Brandt AU, Radbruch H, et al. Differential immune cell dynamics in the CNS cause CD4+ T cell compartmentalization[J]. Brain, 2009, 132(Pt 5): 1247–1258.
    Pranzatelli MR, Allison TJ, McGee NR, et al. Cerebrospinal fluid γδ T cell frequency is age-related: a case-control study of 435 children with inflammatory and non-inflammatory neurological disorders[J]. Clin Exp Immunol, 2018, 193(1): 103–112. doi: 10.1111/cei.13122
    Cheng X, He P, Yao H, et al. Occludin deficiency with BACE1 elevation in cerebral amyloid angiopathy[J]. Neurology, 2014, 82(19): 1707–1715. doi: 10.1212/WNL.0000000000000403
    Carrano A, Hoozemans JJM, van der Vies SM, et al. Amyloid Beta induces oxidative stress-mediated blood-brain barrier changes in capillary amyloid angiopathy[J]. Antioxid Redox Signal, 2011, 15(5): 1167–1178. doi: 10.1089/ars.2011.3895
    Liu Y, Guo D, Tian L, et al. Peripheral T cells derived from Alzheimer's disease patients overexpress CXCR2 contributing to its transendothelial migration, which is microglial TNF-α-dependent[J]. Neurobiol Aging, 2010, 31(2): 175–188. doi: 10.1016/j.neurobiolaging.2008.03.024
    Kerfoot SM, Kubes P. Overlapping roles of P-selectin and α4 integrin to recruit leukocytes to the central nervous system in experimental autoimmune encephalomyelitis[J]. J Immunol, 2002, 169(2): 1000–1006. doi: 10.4049/jimmunol.169.2.1000
    Reboldi A, Coisne C, Baumjohann D, et al. C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE[J]. Nat Immunol, 2009, 10(5): 514–523. doi: 10.1038/ni.1716
    Laurent C, Dorothée G, Hunot S, et al. Hippocampal T cell infiltration promotes neuroinflammation and cognitive decline in a mouse model of tauopathy[J]. Brain, 2017, 140(1): 184–200. doi: 10.1093/brain/aww270
    Smolders J, Remmerswaal EBM, Schuurman KG, et al. Characteristics of differentiated CD8+ and CD4+ T cells present in the human brain[J]. Acta Neuropathol, 2013, 126(4): 525–535. doi: 10.1007/s00401-013-1155-0
    Togo T, Akiyama H, Iseki E, et al. Occurrence of T cells in the brain of Alzheimer's disease and other neurological diseases[J]. J Neuroimmunol, 2002, 124(1-2): 83–92. doi: 10.1016/S0165-5728(01)00496-9
    Agrawal S, Anderson P, Durbeej M, et al. Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis[J]. J Exp Med, 2006, 203(4): 1007–1019. doi: 10.1084/jem.20051342
    Song J, Wu C, Korpos E, et al. Focal MMP-2 and MMP-9 activity at the blood-brain barrier promotes chemokine-induced leukocyte migration[J]. Cell Rep, 2015, 10(7): 1040–1054. doi: 10.1016/j.celrep.2015.01.037
    Betsholtz C. Physiology: double function at the blood-brain barrier[J]. Nature, 2014, 509(7501): 432–433. doi: 10.1038/nature13339
    Carrano A, Hoozemans JJM, van der Vies SM, et al. Amyloid Beta induces oxidative stress-mediated blood-brain barrier changes in capillary amyloid angiopathy[J]. Antioxid Redox Signal, 2011, 15(5): 1167–1178. doi: 10.1089/ars.2011.3895
    Kook SY, Seok Hong H, Moon M, et al. Disruption of blood-brain barrier in Alzheimer disease pathogenesis[J]. Tissue Barriers, 2013, 1(2): e23993. doi: 10.4161/tisb.23993
    Stamatovic SM, Martinez-Revollar G, Hu A, et al. Decline in Sirtuin-1 expression and activity plays a critical role in blood-brain barrier permeability in aging[J]. Neurobiol Dis, 2019, 126: 105–116. doi: 10.1016/j.nbd.2018.09.006
    Shechter R, London A, Schwartz M. Orchestrated leukocyte recruitment to immune-privileged sites: absolute barriers versus educational gates[J]. Nat Rev Immunol, 2013, 13(3): 206–218. doi: 10.1038/nri3391
    Engelhardt B, Wolburg-Buchholz K, Wolburg H. Involvement of the choroid plexus in central nervous system inflammation[J]. Microsc Res Tech, 2001, 52(1): 112–129. doi: 10.1002/1097-0029(20010101)52:1<112::AID-JEMT13>3.0.CO;2-5
    Choi JD, Moon Y, Kim HJ, et al. Choroid plexus volume and permeability at brain MRI within the alzheimer disease clinical spectrum[J]. Radiology, 2022, 212400. doi: 10.1148/radiol.212400
    Vargas T, Ugalde C, Spuch C, et al. Aβ accumulation in choroid plexus is associated with mitochondrial-induced apoptosis[J]. Neurobiol Aging, 2010, 31(9): 1569–1581. doi: 10.1016/j.neurobiolaging.2008.08.017
    Brkic M, Balusu S, Van Wonterghem E, et al. Amyloid β oligomers disrupt blood-CSF barrier integrity by activating matrix metalloproteinases[J]. J Neurosci, 2015, 35(37): 12766–12778. doi: 10.1523/JNEUROSCI.0006-15.2015
    Schläger C, Körner H, Krueger M, et al. Effector T-cell trafficking between the leptomeninges and the cerebrospinal fluid[J]. Nature, 2016, 530(7590): 349–353. doi: 10.1038/nature16939
    Roth TL, Nayak D, Atanasijevic T, et al. Transcranial amelioration of inflammation and cell death after brain injury[J]. Nature, 2014, 505(7482): 223–228. doi: 10.1038/nature12808
    Barker CF, Billingham RE. The role of afferent lymphatics in the rejection of skin homografts[J]. J Exp Med, 1968, 128(1): 197–221. doi: 10.1084/jem.128.1.197
    Ransohoff RM, Engelhardt B. The anatomical and cellular basis of immune surveillance in the central nervous system[J]. Nat Rev Immunol, 2012, 12(9): 623–635. doi: 10.1038/nri3265
    Louveau A, Herz J, Alme MN, et al. CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature[J]. Nat Neurosci, 2018, 21(10): 1380–1391. doi: 10.1038/s41593-018-0227-9
    Rogers J, Luber-Narod J, Styren SD, et al. Expression of immune system-associated antigens by cells of the human central nervous system: relationship to the pathology of Alzheimer's disease[J]. Neurobiol Aging, 1988, 9(4): 339–349.
    Sardi F, Fassina L, Venturini L, et al. Alzheimer's disease, autoimmunity and inflammation. The good, the bad and the ugly[J]. Autoimmun Rev, 2011, 11(2): 149–153. doi: 10.1016/j.autrev.2011.09.005
    Monsonego A, Zota V, Karni A, et al. Increased T cell reactivity to amyloid β protein in older humans and patients with Alzheimer disease[J]. J Clin Invest, 2003, 112(3): 415–422. doi: 10.1172/JCI200318104
    Browne TC, McQuillan K, McManus RM, et al. IFN-γ production by amyloid β-specific Th1 cells promotes microglial activation and increases plaque burden in a mouse model of Alzheimer's disease[J]. J Immunol, 2013, 190(5): 2241–2251. doi: 10.4049/jimmunol.1200947
    Fisher Y, Strominger I, Biton S, et al. Th1 polarization of T cells injected into the cerebrospinal fluid induces brain immunosurveillance[J]. J Immunol, 2014, 192(1): 92–102. doi: 10.4049/jimmunol.1301707
    Cao C, Arendash GW, Dickson A, et al. Aβ-specific Th2 cells provide cognitive and pathological benefits to Alzheimer's mice without infiltrating the CNS[J]. Neurobiol Dis, 2009, 34(1): 63–70. doi: 10.1016/j.nbd.2008.12.015
    Asuni AA, Boutajangout A, Scholtzova H, et al. Vaccination of Alzheimer's model mice with Aβ derivative in alum adjuvant reduces Aβ burden without microhemorrhages[J]. Eur J Neurosci, 2006, 24(9): 2530–2542. doi: 10.1111/j.1460-9568.2006.05149.x
    Lambracht-Washington D, Qu B, Fu M, et al. DNA immunization against amyloid beta 42 has high potential as safe therapy for Alzheimer's disease as it diminishes antigen-specific Th1 and Th17 cell proliferation[J]. Cell Mol Neurobiol, 2011, 31(6): 867–874. doi: 10.1007/s10571-011-9680-7
    Fu H, Liu B, Frost JL, et al. Amyloid-β immunotherapy for Alzheimer's disease[J]. CNS Neurol Disord Drug Targets, 2010, 9(2): 197–206. doi: 10.2174/187152710791012017
    Goldeck D, Larbi A, Pellicanó M, et al. Enhanced chemokine receptor expression on leukocytes of patients with Alzheimer's disease[J]. PLoS One, 2013, 8(6): e66664. doi: 10.1371/journal.pone.0066664
    Zhang J, Ke K, Liu Z, et al. Th17 cell-mediated neuroinflammation is involved in neurodegeneration of Aβ1–42-induced Alzheimer's disease model rats[J]. PLoS One, 2013, 8(10): e75786. doi: 10.1371/journal.pone.0075786
    Jones JL, Anderson JM, Phuah CL, et al. Improvement in disability after alemtuzumab treatment of multiple sclerosis is associated with neuroprotective autoimmunity[J]. Brain, 2010, 133(Pt 8): 2232–2247.
    Alves S, Churlaud G, Audrain M, et al. Interleukin-2 improves amyloid pathology, synaptic failure and memory in Alzheimer's disease mice[J]. Brain, 2017, 140(3): 826–842.
    Dansokho C, Ait Ahmed D, Aid S, et al. Regulatory T cells delay disease progression in Alzheimer-like pathology[J]. Brain, 2016, 139(Pt 4): 1237–1251.
    Di Liberto G, Pantelyushin S, Kreutzfeldt M, et al. Neurons under T cell attack coordinate phagocyte-mediated synaptic stripping[J]. Cell, 2018, 175(2): 458–471.e19. doi: 10.1016/j.cell.2018.07.049
    Mattsson N, Andreasson U, Zetterberg H, et al. Association of plasma neurofilament light with neurodegeneration in patients with alzheimer disease[J]. JAMA Neurol, 2017, 74(5): 557–566. doi: 10.1001/jamaneurol.2016.6117
    Preische O, Schultz SA, Apel A, et al. Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease[J]. Nat Med, 2019, 25(2): 277–283. doi: 10.1038/s41591-018-0304-3
    Krishnamoorthy G, Saxena A, Mars LT, et al. Myelin-specific T cells also recognize neuronal autoantigen in a transgenic mouse model of multiple sclerosis[J]. Nat Med, 2009, 15(6): 626–632. doi: 10.1038/nm.1975
    McQuillan K, Lynch MA, Mills KHG. Activation of mixed glia by Aβ-specific Th1 and Th17 cells and its regulation by Th2 cells[J]. Brain Behav Immun, 2010, 24(4): 598–607. doi: 10.1016/j.bbi.2010.01.003
    Takahashi K, Rochford CDP, Neumann H. Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2[J]. J Exp Med, 2005, 201(4): 647–657. doi: 10.1084/jem.20041611
    Gaikwad S, Larionov S, Wang Y, et al. Signal regulatory protein-β1: a microglial modulator of phagocytosis in Alzheimer's disease[J]. Am J Pathol, 2009, 175(6): 2528–2539. doi: 10.2353/ajpath.2009.090147
    Obregon D, Hou H, Bai Y, et al. CD40L disruption enhances Aβ vaccine-mediated reduction of cerebral amyloidosis while minimizing cerebral amyloid angiopathy and inflammation[J]. Neurobiol Dis, 2008, 29(2): 336–353. doi: 10.1016/j.nbd.2007.09.009
    Le Blon D, Guglielmetti C, Hoornaert C, et al. Intracerebral transplantation of interleukin 13-producing mesenchymal stem cells limits microgliosis, oligodendrocyte loss and demyelination in the cuprizone mouse model[J]. J Neuroinflammation, 2016, 13(1): 288. doi: 10.1186/s12974-016-0756-7
    Guarda G, Dostert C, Staehli F, et al. T cells dampen innate immune responses through inhibition of NLRP1 and NLRP3 inflammasomes[J]. Nature, 2009, 460(7252): 269–273. doi: 10.1038/nature08100
    Garg SK, Banerjee R, Kipnis J. Neuroprotective immunity: T cell-derived glutamate endows astrocytes with a neuroprotective phenotype[J]. J Immunol, 2008, 180(6): 3866–3873. doi: 10.4049/jimmunol.180.6.3866
    Beurel E, Harrington LE, Buchser W, et al. Astrocytes modulate the polarization of CD4+ T cells to Th1 cells[J]. PLoS One, 2014, 9(1): e86257. doi: 10.1371/journal.pone.0086257
    Xie L, Choudhury GR, Winters A, et al. Cerebral regulatory T cells restrain microglia/macrophage-mediated inflammatory responses via IL-10[J]. Eur J Immunol, 2015, 45(1): 180–191. doi: 10.1002/eji.201444823
    Dombrowski Y, O'Hagan T, Dittmer M, et al. Regulatory T cells promote myelin regeneration in the central nervous system[J]. Nat Neurosci, 2017, 20(5): 674–680. doi: 10.1038/nn.4528
    Aloisi F, De Simone R, Columba-Cabezas S, et al. Functional maturation of adult mouse resting microglia into an APC is promoted by granulocyte-macrophage colony-stimulating factor and interaction with Th1 cells[J]. J Immunol, 2000, 164(4): 1705–1712. doi: 10.4049/jimmunol.164.4.1705
    Das Sarma J, Ciric B, Marek R, et al. Functional interleukin-17 receptor A is expressed in central nervous system glia and upregulated in experimental autoimmune encephalomyelitis[J]. J Neuroinflammation, 2009, 6: 14. doi: 10.1186/1742-2094-6-14
    Rock RB, Hu S, Deshpande A, et al. Transcriptional response of human microglial cells to interferon-γ[J]. Genes Immun, 2005, 6(8): 712–719. doi: 10.1038/sj.gene.6364246
    Togo T, Akiyama H, Kondo H, et al. Expression of CD40 in the brain of Alzheimer's disease and other neurological diseases[J]. Brain Res, 2000, 885(1): 117–121. doi: 10.1016/S0006-8993(00)02984-X
    Townsend KP, Town T, Mori T, et al. CD40 signaling regulates innate and adaptive activation of microglia in response to amyloid β-peptide[J]. Eur J Immunol, 2005, 35(3): 901–910. doi: 10.1002/eji.200425585
    McManus RM, Mills KHG, Lynch MA. T cells-protective or pathogenic in Alzheimer's disease?[J]. J Neuroimmune Pharmacol, 2015, 10(4): 547–560. doi: 10.1007/s11481-015-9612-2
    Zeinstra E, Wilczak N, De Keyser J. Reactive astrocytes in chronic active lesions of multiple sclerosis express co-stimulatory molecules B7–1 and B7–2[J]. J Neuroimmunol, 2003, 135(1-2): 166–171. doi: 10.1016/S0165-5728(02)00462-9
    Yang J, Kou J, Lalonde R, et al. Intracranial IL-17A overexpression decreases cerebral amyloid angiopathy by upregulation of ABCA1 in an animal model of Alzheimer's disease[J]. Brain Behav Immun, 2017, 65: 262–273. doi: 10.1016/j.bbi.2017.05.012
    Weiss R, Lifshitz V, Frenkel D. TGF-β1 affects endothelial cell interaction with macrophages and T cells leading to the development of cerebrovascular amyloidosis[J]. Brain Behav Immun, 2011, 25(5): 1017–1024. doi: 10.1016/j.bbi.2010.11.012
    Man S, Ma Y, Shang D, et al. Peripheral T cells overexpress MIP-1α to enhance its transendothelial migration in Alzheimer's disease[J]. Neurobiol Aging, 2007, 28(4): 485–496. doi: 10.1016/j.neurobiolaging.2006.02.013
    Pietronigro E, Zenaro E, Bianca VD, et al. Blockade of α4 integrins reduces leukocyte-endothelial interactions in cerebral vessels and improves memory in a mouse model of Alzheimer's disease[J]. Sci Rep, 2019, 9(1): 12055. doi: 10.1038/s41598-019-48538-x
    Hamza TH, Zabetian CP, Tenesa A, et al. Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease[J]. Nat Genet, 2010, 42(9): 781–785. doi: 10.1038/ng.642
    Fuller JP, Stavenhagen JB, Teeling JL. New roles for Fc receptors in neurodegeneration-the impact on Immunotherapy for Alzheimer's Disease[J]. Front Neurosci, 2014, 8: 235.
    Piazza F, Greenberg SM, Savoiardo M, et al. Anti-amyloid β autoantibodies in cerebral amyloid angiopathy-related inflammation: implications for amyloid-modifying therapies[J]. Ann Neurol, 2013, 73(4): 449–458. doi: 10.1002/ana.23857
    Sollvander S, Ekholm-Pettersson F, Brundin RM, et al. Increased number of plasma B cells producing autoantibodies against Aβ42 protofibrils in Alzheimer's disease[J]. J Alzheimers Dis, 2015, 48(1): 63–72. doi: 10.3233/JAD-150236
    Maftei M, Thurm F, Schnack C, et al. Increased levels of antigen-bound β-amyloid autoantibodies in serum and cerebrospinal fluid of Alzheimer's disease patients[J]. PLoS One, 2013, 8(7): e68996. doi: 10.1371/journal.pone.0068996
    Mimouni D, Gdalevich M, Mimouni FB, et al. Does immune serum globulin confer protection against skin diseases?[J]. Int J Dermatol, 2000, 39(8): 628–631. doi: 10.1046/j.1365-4362.2000.00983.x
    Bruhns P, Samuelsson A, Pollard JW, et al. Colony-stimulating factor-1-dependent macrophages are responsible for IVIG protection in antibody-induced autoimmune disease[J]. Immunity, 2003, 18(4): 573–581. doi: 10.1016/S1074-7613(03)00080-3
    Siragam V, Crow AR, Brinc D, et al. Intravenous immunoglobulin ameliorates ITP via activating Fcγ receptors on dendritic cells[J]. Nat Med, 2006, 12(6): 688–692. doi: 10.1038/nm1416
    Marsh SE, Abud EM, Lakatos A, et al. The adaptive immune system restrains Alzheimer's disease pathogenesis by modulating microglial function[J]. Proc Natl Acad Sci USA, 2016, 113(9): E1316–E1325.
    Cribbs DH, Berchtold NC, Perreau V, et al. Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study[J]. J Neuroinflammation, 2012, 9: 179.
    Prüss H, Höltje M, Maier N, et al. IgA NMDA receptor antibodies are markers of synaptic immunity in slow cognitive impairment[J]. Neurology, 2012, 78(22): 1743–1753. doi: 10.1212/WNL.0b013e318258300d
    Martin F, Chan AC. B cell immunobiology in disease: evolving concepts from the clinic[J]. Annu Rev Immunol, 2006, 24: 467–496. doi: 10.1146/annurev.immunol.24.021605.090517
    Lanzavecchia A. Receptor-mediated antigen uptake and its effect on antigen presentation to class II-restricted T lymphocytes[J]. Annu Rev Immunol, 1990, 8: 773–793. doi: 10.1146/annurev.iy.08.040190.004013
    Avalos AM, Ploegh HL. Early BCR events and antigen capture, processing, and loading on MHC class II on B cells[J]. Front Immunol, 2014, 5: 92.
    Sonoda KH, Stein-Streilein J. CD1d on antigen-transporting APC and splenic marginal zone B cells promotes NKT cell-dependent tolerance[J]. Eur J Immunol, 2002, 32(3): 848–857. doi: 10.1002/1521-4141(200203)32:3<848::AID-IMMU848>3.0.CO;2-I
    Tomihara K, Shin T, Hurez VJ, et al. Aging-associated B7-DC+ B cells enhance anti-tumor immunity via Th1 and Th17 induction[J]. Aging Cell, 2012, 11(1): 128–138. doi: 10.1111/j.1474-9726.2011.00764.x
    Xiong L, Xue L, Du R, et al. Single-cell RNA sequencing reveals B cell-related molecular biomarkers for Alzheimer's disease[J]. Exp Mol Med, 2021, 53(12): 1888–1901. doi: 10.1038/s12276-021-00714-8
    Kim K, Wang X, Ragonnaud E, et al. Therapeutic B-cell depletion reverses progression of Alzheimer's disease[J]. Nat Commun, 2021, 12(1): 2185. doi: 10.1038/s41467-021-22479-4
    Weber MS, Prod'Homme T, Patarroyo JC, et al. B-cell activation influences T-cell polarization and outcome of anti-CD20 B-cell depletion in central nervous system autoimmunity[J]. Ann Neurol, 2010, 68(3): 369–383. doi: 10.1002/ana.22081
    Pierson ER, Stromnes IM, Goverman JM. B cells promote induction of experimental autoimmune encephalomyelitis by facilitating reactivation of T cells in the central nervous system[J]. J Immunol, 2014, 192(3): 929–939. doi: 10.4049/jimmunol.1302171
    Desmond DW, Moroney JT, Sano M, et al. Incidence of dementia after ischemic stroke: results of a longitudinal study[J]. Stroke, 2002, 33(9): 2254–2262. doi: 10.1161/01.STR.0000028235.91778.95
    Mena H, Cadavid D, Rushing EJ. Human cerebral infarct: a proposed histopathologic classification based on 137 cases[J]. Acta Neuropathol, 2004, 108(6): 524–530. doi: 10.1007/s00401-004-0918-z
    Rosser EC, Mauri C. Regulatory B cells: origin, phenotype, and function[J]. Immunity, 2015, 42(4): 607–612. doi: 10.1016/j.immuni.2015.04.005
    Olkhanud PB, Damdinsuren B, Bodogai M, et al. Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4+ T cells to T-regulatory cells[J]. Cancer Res, 2011, 71(10): 3505–3515. doi: 10.1158/0008-5472.CAN-10-4316
    Minter MR, Main BS, Brody KM, et al. Soluble amyloid triggers a myeloid differentiation factor 88 and interferon regulatory factor 7 dependent neuronal type-1 interferon response in vitro[J]. J Neuroinflammation, 2015, 12: 71. doi: 10.1186/s12974-015-0263-2
    Bodogai M, Moritoh K, Lee-Chang C, et al. Immunosuppressive and prometastatic functions of myeloid-derived suppressive cells rely upon education from tumor-associated B cells[J]. Cancer Res, 2015, 75(17): 3456–3465. doi: 10.1158/0008-5472.CAN-14-3077
    Sun J, Flach CF, Czerkinsky C, et al. B lymphocytes promote expansion of regulatory T cells in oral tolerance: powerful induction by antigen coupled to cholera toxin B subunit[J]. J Immunol, 2008, 181(12): 8278–8287. doi: 10.4049/jimmunol.181.12.8278
    Shen P, Roch T, Lampropoulou V, et al. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases[J]. Nature, 2014, 507(7492): 366–370. doi: 10.1038/nature12979
    Matsushita T, Yanaba K, Bouaziz JD, et al. Regulatory B cells inhibit EAE initiation in mice while other B cells promote disease progression[J]. J Clin Invest, 2008, 118(10): 3420–3430.
    Collison LW, Chaturvedi V, Henderson AL, et al. IL-35-mediated induction of a potent regulatory T cell population[J]. Nat Immunol, 2010, 11(12): 1093–1101. doi: 10.1038/ni.1952
    Kurnellas MP, Ghosn EEB, Schartner JM, et al. Amyloid fibrils activate B-1a lymphocytes to ameliorate inflammatory brain disease[J]. Proc Natl Acad Sci USA, 2015, 112(49): 15016–15023. doi: 10.1073/pnas.1521206112
    Orgogozo JM, Gilman S, Dartigues JF, et al. Subacute meningoencephalitis in a subset of patients with AD after Aβ42 immunization[J]. Neurology, 2003, 61(1): 46–54. doi: 10.1212/01.WNL.0000073623.84147.A8
    Nicoll JAR, Wilkinson D, Holmes C, et al. Neuropathology of human Alzheimer disease after immunization with amyloid-β peptide: a case report[J]. Nat Med, 2003, 9(4): 448–452. doi: 10.1038/nm840
    Saresella M, Calabrese E, Marventano I, et al. A potential role for the PD1/PD-L1 pathway in the neuroinflammation of Alzheimer's disease[J]. Neurobiol Aging, 2012, 33(3): 624.e11–624.e22. doi: 10.1016/j.neurobiolaging.2011.03.004
    Baruch K, Deczkowska A, Rosenzweig N, et al. PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease[J]. Nat Med, 2016, 22(2): 135–137. doi: 10.1038/nm.4022
    Rosenzweig N, Dvir-Szternfeld R, Tsitsou-Kampeli A, et al. PD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model[J]. Nat Commun, 2019, 10(1): 465. doi: 10.1038/s41467-019-08352-5
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