Dysregulation of Systemic Immunity in Aging and Dementia
Jenny Lutshumba, Barbara S Nikolajczyk, Adam D Bachstetter, Jenny Lutshumba, Barbara S Nikolajczyk, Adam D Bachstetter
Abstract
Neuroinflammation and the tissue-resident innate immune cells, the microglia, respond and contribute to neurodegenerative pathology. Although microglia have been the focus of work linking neuroinflammation and associated dementias like Alzheimer's Disease, the inflammatory milieu of brain is a conglomerate of cross-talk amongst microglia, systemic immune cells and soluble mediators like cytokines. Age-related changes in the inflammatory profile at the levels of both the brain and periphery are largely orchestrated by immune system cells. Strong evidence indicates that both innate and adaptive immune cells, the latter including T cells and B cells, contribute to chronic neuroinflammation and thus dementia. Neurodegenerative hallmarks coupled with more traditional immune system stimuli like infection or injury likely combine to trigger and maintain persistent microglial and thus brain inflammation. This review summarizes age-related changes in immune cell function, with special emphasis on lymphocytes as a source of inflammation, and discusses how such changes may potentiate both systemic and central nervous system inflammation to culminate in dementia. We recap the understudied area of AD-associated changes in systemic lymphocytes in greater detail to provide a unifying perspective of inflammation-fueled dementia, with an eye toward evidence of two-way communication between the brain parenchyma and blood immune cells. We focused our review on human subjects studies, adding key data from animal models as relevant.
Keywords: CD4; CD8; T cells; Th17; Treg; monocytes; neuroimmunology; neuroinflammation.
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Copyright © 2021 Lutshumba, Nikolajczyk and Bachstetter.
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References
- Abbott A. (2020). Are infections seeding some cases of Alzheimer’s disease? Nature 587 22–25. 10.1038/d41586-020-03084-9
- Abner E. L., Kryscio R. J., Schmitt F. A., Fardo D. W., Moga D. C., Ighodaro E. T., et al. (2017). Outcomes after diagnosis of mild cognitive impairment in a large autopsy series. Ann. Neurol. 81 549–559. 10.1002/ana.24903
- Agrawal A., Agrawal S., Gupta S. (2017). Role of dendritic cells in inflammation and loss of tolerance in the elderly. Front. Immunol. 8:896. 10.3389/fimmu.2017.00896
- Agrawal S., Abud E. M., Snigdha S., Agrawal A. (2018). IgM response against amyloid-beta in aging: a potential peripheral protective mechanism. Alzheimers Res. Ther. 10:81.
- Allnutt M. A., Johnson K., Bennett D. A., Connor S. M., Troncoso J. C., Pletnikova O., et al. (2020). Human Herpesvirus 6 detection in Alzheimer’s disease cases and controls across multiple cohorts. Neuron 105 1027–1035.e2.
- Alpert A., Pickman Y., Leipold M., Rosenberg-Hasson Y., Ji X., Gaujoux R., et al. (2019). A clinically meaningful metric of immune age derived from high-dimensional longitudinal monitoring. Nat. Med. 25 487–495. 10.1038/s41591-019-0381-y
- Andrews S. J., Fulton-Howard B., Goate A. (2020). Interpretation of risk loci from genome-wide association studies of Alzheimer’s disease. Lancet Neurol. 19 326–335. 10.1016/s1474-4422(19)30435-1
- Antonaci S., Garofalo A. R., Chicco C., Polignano A. V., Pugliese P., Misefari A., et al. (1990). Senile dementia, Alzheimer type: a distinct entity in the immunosenescence? J. Clin. Lab. Anal. 4 16–21. 10.1002/jcla.1860040106
- Araga S., Kagimoto H., Funamoto K., Takahashi K. (1991). Reduced natural killer cell activity in patients with dementia of the Alzheimer type. Acta Neurol. Scand. 84 259–263. 10.1111/j.1600-0404.1991.tb04948.x
- Bachstetter A. D., Van Eldik L. J., Schmitt F. A., Neltner J. H., Ighodaro E. T., Webster S. J., et al. (2015). Disease-related microglia heterogeneity in the hippocampus of Alzheimer’s disease, dementia with Lewy bodies, and hippocampal sclerosis of aging. Acta Neuropathol. Commun. 3:32.
- Baruch K., Deczkowska A., Rosenzweig N., Tsitsou-Kampeli A., Sharif A. M., Matcovitch-Natan O., et al. (2016). PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer’s disease. Nat. Med. 22 135–137. 10.1038/nm.4022
- Baruch K., Rosenzweig N., Kertser A., Deczkowska A., Sharif A. M., Spinrad A., et al. (2015). Breaking immune tolerance by targeting Foxp3(+) regulatory T cells mitigates Alzheimer’s disease pathology. Nat. Commun. 6:7967.
- Baulch J. E., Acharya M. M., Agrawal S., Apodaca L. A., Monteiro C., Agrawal A. (2020). Immune and inflammatory determinants underlying Alzheimer’s disease pathology. J. Neuroimmune Pharmacol. 15 852–862. 10.1007/s11481-020-09908-9
- Berent-Maoz B., Montecino-Rodriguez E., Dorshkind K. (2012). Genetic regulation of thymocyte progenitor aging. Semin. Immunol. 24 303–308. 10.1016/j.smim.2012.04.006
- Bharath L. P., Agrawal M., Mccambridge G., Nicholas D. A., Hasturk H., Liu J., et al. (2020). Metformin enhances autophagy and normalizes mitochondrial function to alleviate aging-associated inflammation. Cell Metab. 32 44–55.e6.
- Blevins B. L., Vinters H. V., Love S., Wilcock D. M., Grinberg L. T., Schneider J. A., et al. (2020). Brain arteriolosclerosis. Acta Neuropathol. 141 1–24.
- Bonotis K., Krikki E., Holeva V., Aggouridaki C., Costa V., Baloyannis S. (2008). Systemic immune aberrations in Alzheimer’s disease patients. J. Neuroimmunol. 193 183–187. 10.1016/j.jneuroim.2007.10.020
- Born J., Uthgenannt D., Dodt C., Nunninghoff D., Ringvolt E., Wagner T., et al. (1995). Cytokine production and lymphocyte subpopulations in aged humans. An assessment during nocturnal sleep. Mech. Ageing Dev. 84 113–126. 10.1016/0047-6374(95)01638-4
- Bulati M., Buffa S., Martorana A., Candore G., Lio D., Caruso C., et al. (2014). Trafficking phenotype and production of granzyme B by double negative B cells (IgG(+)IgD(-)CD27(-)) in the elderly. Exp. Gerontol. 54 123–129. 10.1016/j.exger.2013.12.011
- Bulati M., Buffa S., Martorana A., Gervasi F., Camarda C., Azzarello D. M., et al. (2015). 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. Alzheimers Dis. 44 1241–1251. 10.3233/jad-142412
- Busse M., Michler E., Von Hoff F., Dobrowolny H., Hartig R., Frodl T., et al. (2017). Alterations in the peripheral immune system in dementia. J. Alzheimers Dis. 58 1303–1313. 10.3233/jad-161304
- Candore G., Di Lorenzo G., Mansueto P., Melluso M., Frada G., Li Vecchi M., et al. (1997). Prevalence of organ-specific and non organ-specific autoantibodies in healthy centenarians. Mech. Ageing Dev. 94 183–190. 10.1016/s0047-6374(96)01845-3
- Cao W., Zheng H. (2018). Peripheral immune system in aging and Alzheimer’s disease. Mol. Neurodegener. 13:51.
- Chalasani G., Rothstein D. (2014). Non-antibody mediated roles of B cells in allograft survival. Curr. Transplant. Rep. 1 155–165. 10.1007/s40472-014-0020-y
- Chatta G. S., Andrews R. G., Rodger E., Schrag M., Hammond W. P., Dale D. C. (1993). Hematopoietic progenitors and aging: alterations in granulocytic precursors and responsiveness to recombinant human G-CSF, GM-CSF, and IL-3. J. Gerontol. 48 M207–M212.
- Chiorazzi N., Ferrarini M. (2003). B cell chronic lymphocytic leukemia: lessons learned from studies of the B cell antigen receptor. Annu. Rev. Immunol. 21 841–894.
- Colonna-Romano G., Bulati M., Aquino A., Pellicano M., Vitello S., Lio D., et al. (2009). A double-negative (IgD-CD27-) B cell population is increased in the peripheral blood of elderly people. Mech. Ageing Dev. 130 681–690. 10.1016/j.mad.2009.08.003
- Cros J., Cagnard N., Woollard K., Patey N., Zhang S. Y., Senechal B., et al. (2010). Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. Immunity 33 375–386. 10.1016/j.immuni.2010.08.012
- Cruz Hernandez J. C., Bracko O., Kersbergen C. J., Muse V., Haft-Javaherian M., Berg M., et al. (2019). Neutrophil adhesion in brain capillaries reduces cortical blood flow and impairs memory function in Alzheimer’s disease mouse models. Nat. Neurosci. 22 413–420. 10.1038/s41593-018-0329-4
- Defrance T., Taillardet M., Genestier L. (2011). T cell-independent B cell memory. Curr. Opin. Immunol. 23 330–336. 10.1016/j.coi.2011.03.004
- Della Bella S., Bierti L., Presicce P., Arienti R., Valenti M., Saresella M., et al. (2007). Peripheral blood dendritic cells and monocytes are differently regulated in the elderly. Clin. Immunol. 122 220–228. 10.1016/j.clim.2006.09.012
- den Braber I., Mugwagwa T., Vrisekoop N., Westera L., Mogling R., De Boer A. B., et al. (2012). Maintenance of peripheral naive T cells is sustained by thymus output in mice but not humans. Immunity 36 288–297. 10.1016/j.immuni.2012.02.006
- Dezfulian M. (2018). A new Alzheimer’s disease cell model using B cells to induce beta amyloid plaque formation and increase TNF alpha expression. Int. Immunopharmacol. 59 106–112. 10.1016/j.intimp.2018.04.012
- Drayman N., Patel P., Vistain L., Tay S. (2019). HSV-1 single-cell analysis reveals the activation of anti-viral and developmental programs in distinct sub-populations. eLife 8:e46339.
- Dykstra B., Olthof S., Schreuder J., Ritsema M., De Haan G. (2011). Clonal analysis reveals multiple functional defects of aged murine hematopoietic stem cells. J. Exp. Med. 208 2691–2703. 10.1084/jem.20111490
- Dysken M. W., Minichiello M. D., Hill J. L., Skare S., Little J. T., Molchan S. E., et al. (1992). Distribution of peripheral lymphocytes in Alzheimer patients and controls. J. Psychiatr. Res. 26 213–218. 10.1016/0022-3956(92)90024-i
- Engelhardt B., Vajkoczy P., Weller R. O. (2017). The movers and shapers in immune privilege of the CNS. Nat. Immunol. 18 123–131. 10.1038/ni.3666
- Erickson M. A., Wilson M. L., Banks W. A. (2020). In vitro modeling of blood-brain barrier and interface functions in neuroimmune communication. Fluids Barriers CNS 17:26.
- Faraco G., Brea D., Garcia-Bonilla L., Wang G., Racchumi G., Chang H., et al. (2018). Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response. Nat. Neurosci. 21 240–249. 10.1038/s41593-017-0059-z
- Fest J., Ruiter R., Ikram M. A., Voortman T., Van Eijck C. H. J., Stricker B. H. (2018). Reference values for white blood-cell-based inflammatory markers in the Rotterdam Study: a population-based prospective cohort study. Sci. Rep. 8:10566.
- Galea I., Bechmann I., Perry V. H. (2007). What is immune privilege (not)? Trends Immunol. 28 12–18. 10.1016/j.it.2006.11.004
- Gate D., Saligrama N., Leventhal O., Yang A. C., Unger M. S., Middeldorp J., et al. (2020). Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature 577 399–404. 10.1038/s41586-019-1895-7
- Giubilei F., Antonini G., Montesperelli C., Sepe-Monti M., Cannoni S., Pichi A., et al. (2003). T cell response to amyloid-beta and to mitochondrial antigens in Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 16 35–38.
- Godbout J. P., Moreau M., Lestage J., Chen J., Sparkman N. L., O’connor J., et al. (2008). Aging exacerbates depressive-like behavior in mice in response to activation of the peripheral innate immune system. Neuropsychopharmacology 33 2341–2351. 10.1038/sj.npp.1301649
- Greenhalgh A. D., David S., Bennett F. C. (2020). Immune cell regulation of glia during CNS injury and disease. Nat. Rev. Neurosci. 21 139–152. 10.1038/s41583-020-0263-9
- Griffin W. S., Stanley L. C., Ling C., White L., Macleod V., Perrot L. J., et al. (1989). Brain interleukin 1 and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc. Natl. Acad. Sci. U.S.A. 86 7611–7615. 10.1073/pnas.86.19.7611
- Guilliams M., Mildner A., Yona S. (2018). Developmental and functional heterogeneity of monocytes. Immunity 49 595–613. 10.1016/j.immuni.2018.10.005
- Hart B. L. (1988). Biological basis of the behavior of sick animals. Neurosci. Biobehav. Rev. 12 123–137. 10.1016/s0149-7634(88)80004-6
- Hazenberg M. D., Otto S. A., Cohen Stuart J. W., Verschuren M. C., Borleffs J. C., Boucher C. A., et al. (2000). Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T cell population in HIV-1 infection. Nat. Med. 6 1036–1042. 10.1038/79549
- Hearps A. C., Martin G. E., Angelovich T. A., Cheng W. J., Maisa A., Landay A. L., et al. (2012). Aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function. Aging Cell 11 867–875. 10.1111/j.1474-9726.2012.00851.x
- Herz J., Filiano A. J., Smith A., Yogev N., Kipnis J. (2017). Myeloid cells in the central nervous system. Immunity 46 943–956. 10.1016/j.immuni.2017.06.007
- High K. P., Akbar A. N., Nikolich-Zugich J. (2012). Translational research in immune senescence: assessing the relevance of current models. Semin. Immunol. 24 373–382. 10.1016/j.smim.2012.04.007
- Holmes C., Cunningham C., Zotova E., Woolford J., Dean C., Kerr S., et al. (2009). Systemic inflammation and disease progression in Alzheimer disease. Neurology 73 768–774. 10.1212/wnl.0b013e3181b6bb95
- Hu B., Yang X. R., Xu Y., Sun Y. F., Sun C., Guo W., et al. (2014). Systemic immune-inflammation index predicts prognosis of patients after curative resection for hepatocellular carcinoma. Clin. Cancer Res. 20 6212–6222. 10.1158/1078-0432.ccr-14-0442
- Hu G. R., Walls R. S., Creasey H., Mccusker E., Broe G. A. (1995). Peripheral blood lymphocyte subset distribution and function in patients with Alzheimer’s disease and other dementias. Aust. N.Z. J. Med. 25 212–217. 10.1111/j.1445-5994.1995.tb01525.x
- Iadecola C. (2017). The neurovascular unit coming of age: a journey through neurovascular coupling in health and disease. Neuron 96 17–42. 10.1016/j.neuron.2017.07.030
- Ighodaro E. T., Abner E. L., Fardo D. W., Lin A. L., Katsumata Y., Schmitt F. A., et al. (2017). Risk factors and global cognitive status related to brain arteriolosclerosis in elderly individuals. J. Cereb. Blood Flow Metab. 37 201–216. 10.1177/0271678x15621574
- Ikeda T., Yamamoto K., Takahashi K., Yamada M. (1991). Immune system-associated antigens on the surface of peripheral blood lymphocytes in patients with Alzheimer’s disease. Acta Psychiatr. Scand. 83 444–448. 10.1111/j.1600-0447.1991.tb05573.x
- Ikram M. A., Brusselle G. G. O., Murad S. D., Van Duijn C. M., Franco O. H., Goedegebure A., et al. (2017). The Rotterdam Study: 2018 update on objectives, design and main results. Eur. J. Epidemiol. 32 807–850. 10.1007/s10654-017-0321-4
- Ip B., Cilfone N. A., Belkina A. C., Defuria J., Jagannathan-Bogdan M., Zhu M., et al. (2016). Th17 cytokines differentiate obesity from obesity-associated type 2 diabetes and promote TNFalpha production. Obesity 24 102–112. 10.1002/oby.21243
- Jellinger K. A. (2020). Pathobiological subtypes of Alzheimer disease. Dement. Geriatr. Cogn. Disord. 49 321–333. 10.1159/000508625
- Jevtic S., Sengar A. S., Salter M. W., Mclaurin J. (2017). The role of the immune system in Alzheimer disease: etiology and treatment. Ageing Res. Rev. 40 84–94. 10.1016/j.arr.2017.08.005
- Kalelioglu T., Yuruyen M., Gultekin G., Yavuzer H., Ozturk Y., Kurt M., et al. (2017). Neutrophil and platelet to lymphocyte ratios in people with subjective, mild cognitive impairment and early Alzheimer’s disease. Psychogeriatrics 17 506–508. 10.1111/psyg.12260
- Karanth S., Nelson P. T., Katsumata Y., Kryscio R. J., Schmitt F. A., Fardo D. W., et al. (2020). Prevalence and clinical phenotype of quadruple misfolded proteins in older adults. JAMA Neurol. 77 1299–1307. 10.1001/jamaneurol.2020.1741
- Kong F. K., Chen C. L. H., Six A., Hockett R. D., Cooper M. D. (1999). T cell receptor gene deletion circles identify recent thymic emigrants in the peripheral T cell pool. Proc. Natl. Acad. Sci. U.S.A. 96 1536–1540. 10.1073/pnas.96.4.1536
- Kovacs G. G. (2015). Neuropathology of tauopathies: principles and practice. Neuropathol. Appl. Neurobiol. 41 3–23. 10.1111/nan.12208
- Kovacs G. G. (2020). Astroglia and Tau: new perspectives. Front. Aging Neurosci. 12:96. 10.3389/fnagi.2020.00096
- Kunkle B. W., Grenier-Boley B., Sims R., Bis J. C., Damotte V., Naj A. C., et al. (2019). Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates A beta, tau, immunity and lipid processing. Nat. Genet. 51 414–430.
- Kuyumcu M. E., Yesil Y., Ozturk Z. A., Kizilarslanoglu C., Etgul S., Halil M., et al. (2012). The evaluation of neutrophil-lymphocyte ratio in Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 34 69–74.
- Le Page A., Garneau H., Dupuis G., Frost E. H., Larbi A., Witkowski J. M., et al. (2017). Differential Phenotypes of Myeloid-Derived suppressor and T regulatory cells and cytokine levels in Amnestic Mild cognitive impairment subjects compared to Mild Alzheimer Diseased Patients. Front. Immunol. 8:783. 10.3389/fimmu.2017.00783
- Leffell M. S., Lumsden L., Steiger W. A. (1985). An analysis of T lymphocyte subpopulations in patients with Alzheimer’s disease. J. Am. Geriatr. Soc. 33 4–8. 10.1111/j.1532-5415.1985.tb02851.x
- Licastro F., Savorani G., Sarti G., Salsi A., Cavazzuti F., Zanichelli L., et al. (1990). Zinc and thymic hormone-dependent immunity in normal ageing and in patients with senile dementia of the Alzheimer type. J. Neuroimmunol. 27 201–208. 10.1016/0165-5728(90)90070-4
- Liu X., Nemeth D. P., Mckim D. B., Zhu L., Disabato D. J., Berdysz O., et al. (2019). Cell-type-specific interleukin 1 receptor 1 signaling in the brain regulates distinct neuroimmune activities. immunity 50 317–333.e6.
- Liu X., Quan N. (2018). Microglia and CNS Interleukin-1: beyond immunological concepts. Front. Neurol. 9:8. 10.3389/fneur.2018.00008
- Lombardi V. R., Garcia M., Rey L., Cacabelos R. (1999). Characterization of cytokine production, screening of lymphocyte subset patterns and in vitro apoptosis in healthy and Alzheimer’s Disease (AD) individuals. J. Neuroimmunol. 97 163–171. 10.1016/s0165-5728(99)00046-6
- Lord J. M., Butcher S., Killampali V., Lascelles D., Salmon M. (2001). Neutrophil ageing and immunesenescence. Mech. Ageing Dev. 122 1521–1535. 10.1016/s0047-6374(01)00285-8
- Lueg G., Gross C. C., Lohmann H., Johnen A., Kemmling A., Deppe M., et al. (2015). Clinical relevance of specific T-cell activation in the blood and cerebrospinal fluid of patients with mild Alzheimer’s disease. Neurobiol. Aging 36 81–89. 10.1016/j.neurobiolaging.2014.08.008
- Madore C., Yin Z., Leibowitz J., Butovsky O. (2020). Microglia, lifestyle stress, and neurodegeneration. Immunity 52 222–240. 10.1016/j.immuni.2019.12.003
- Marsh S. E., Abud E. M., Lakatos A., Karimzadeh A., Yeung S. T., Davtyan H., et al. (2016). The adaptive immune system restrains Alzheimer’s disease pathogenesis by modulating microglial function. Proc. Natl. Acad. Sci. U.S.A. 113 E1316–E1325.
- Mayne K., White J. A., Mcmurran C. E., Rivera F. J., De La Fuente A. G. (2020). Aging and neurodegenerative disease: Is the Adaptive immune system a friend or foe? Front. Aging Neurosci. 12:572090. 10.3389/fnagi.2020.572090
- McKee A. C. (2020). The neuropathology of chronic traumatic encephalopathy: the status of the literature. Semin. Neurol. 40 359–369. 10.1055/s-0040-1713632
- Miller A. E., Neighbour P. A., Katzman R., Aronson M., Lipkowitz R. (1981). Immunological studies in senile dementia of the Alzheimer type: evidence for enhanced suppressor cell activity. Ann. Neurol. 10 506–510. 10.1002/ana.410100603
- Montgomery R. R., Shaw A. C. (2015). Paradoxical changes in innate immunity in aging: recent progress and new directions. J. Leukoc. Biol. 98 937–943. 10.1189/jlb.5mr0315-104r
- Montine T. J., Phelps C. H., Beach T. G., Bigio E. H., Cairns N. J., Dickson D. W., et al. (2012). National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease: a practical approach. Acta Neuropathol. 123 1–11.
- Murray J. M., Kaufmann G. R., Hodgkin P. D., Lewin S. R., Kelleher A. D., Davenport M. P., et al. (2003). Naive T cells are maintained by thymic output in early ages but by proliferation without phenotypic change after age twenty. Immunol. Cell Biol. 81 487–495. 10.1046/j.1440-1711.2003.01191.x
- Naylor K., Li G., Vallejo A. N., Lee W. W., Koetz K., Bryl E., et al. (2005). The influence of age on T cell generation and TCR diversity. J. Immunol. 174 7446–7452. 10.4049/jimmunol.174.11.7446
- Nelson P. T., Dickson D. W., Trojanowski J. Q., Jack C. R., Boyle P. A., Arfanakis K., et al. (2019). Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report. Brain 142 1503–1527.
- Nelson P. T., Head E., Schmitt F. A., Davis P. R., Neltner J. H., Jicha G. A., et al. (2011). Alzheimer’s disease is not “brain aging”: neuropathological, genetic, and epidemiological human studies. Acta Neuropathol. 121 571–587. 10.1007/s00401-011-0826-y
- Neltner J. H., Abner E. L., Jicha G. A., Schmitt F. A., Patel E., Poon L. W., et al. (2016). Brain pathologies in extreme old age. Neurobiol. Aging 37 1–11.
- Neuner S. M., Tcw J., Goate A. M. (2020). Genetic architecture of Alzheimer’s disease. Neurobiol. Dis. 143:104976.
- Nevo U., Kipnis J., Golding I., Shaked I., Neumann A., Akselrod S., et al. (2003). Autoimmunity as a special case of immunity: removing threats from within. Trends Mol. Med. 9 88–93. 10.1016/s1471-4914(03)00024-8
- Nikolich-Zugich J. (2008). Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nat. Rev. Immunol. 8 512–522. 10.1038/nri2318
- Nikolich-Zugich J. (2014). Aging of the T cell compartment in mice and humans: from no naive expectations to foggy memories. J. Immunol. 193 2622–2629. 10.4049/jimmunol.1401174
- Nikolich-Zugich J. (2018). The twilight of immunity: emerging concepts in aging of the immune system. Nat. Immunol. 19 10–19. 10.1038/s41590-017-0006-x
- Nomellini V., Faunce D. E., Gomez C. R., Kovacs E. J. (2008). An age-associated increase in pulmonary inflammation after burn injury is abrogated by CXCR2 inhibition. J. Leukoc. Biol. 83 1493–1501. 10.1189/jlb.1007672
- Norden D. M., Muccigrosso M. M., Godbout J. P. (2015). Microglial priming and enhanced reactivity to secondary insult in aging, and traumatic CNS injury, and neurodegenerative disease. Neuropharmacology 96 29–41. 10.1016/j.neuropharm.2014.10.028
- Nyugen J., Agrawal S., Gollapudi S., Gupta S. (2010). Impaired functions of peripheral blood monocyte subpopulations in aged humans. J. Clin. Immunol. 30 806–813. 10.1007/s10875-010-9448-8
- Oberstein T. J., Taha L., Spitzer P., Hellstern J., Herrmann M., Komhuber J., et al. (2018). Imbalance of Circulating T(h)17 and regulatory T cells in Alzheimer’s disease: a case control study. Front. Immunol. 9:1213. 10.3389/fimmu.2018.01213
- Park E., Alberti J., Mehta P., Dalton A., Sersen E., Schuller-Levis G. (2000). Partial impairment of immune functions in peripheral blood leukocytes from aged men with Down’s syndrome. Clin. Immunol. 95 62–69. 10.1006/clim.2000.4834
- Pattabiraman G., Palasiewicz K., Galvin J. P., Ucker D. S. (2017). Aging-associated dysregulation of homeostatic immune response termination (and not initiation). Aging Cell 16 585–593. 10.1111/acel.12589
- Perry V. H., Cunningham C., Holmes C. (2007). Systemic infections and inflammation affect chronic neurodegeneration. Nat. Rev. Immunol. 7 161–167. 10.1038/nri2015
- Pirttila T., Mattinen S., Frey H. (1992). The decrease of CD8-positive lymphocytes in Alzheimer’s disease. J. Neurol. Sci. 107 160–165. 10.1016/0022-510x(92)90284-r
- Price J. L., Morris J. C. (1999). Tangles and plaques in nondemented aging and “preclinical” Alzheimer’s disease Ann. Neurol. 45 358–368. 10.1002/1531-8249(199903)45:3<358::aid-ana12>;2-x
- Prinz M., Erny D., Hagemeyer N. (2017). Ontogeny and homeostasis of CNS myeloid cells. Nat. Immunol. 18 385–392. 10.1038/ni.3703
- Prinz M., Priller J. (2017). The role of peripheral immune cells in the CNS in steady state and disease. Nat. Neurosci. 20 136–144. 10.1038/nn.4475
- Readhead B., Haure-Mirande J. V., Funk C. C., Richards M. A., Shannon P., Haroutunian V., et al. (2018). Multiscale analysis of independent Alzheimer’s cohorts finds disruption of molecular, genetic, and clinical networks by Human Herpesvirus. Neuron 99 64–82.e7.
- Reale M., Iarlori C., Gambi F., Feliciani C., Salone A., Toma L., et al. (2004). Treatment with an acetylcholinesterase inhibitor in Alzheimer patients modulates the expression and production of the pro-inflammatory and anti-inflammatory cytokines. J. Neuroimmunol. 148 162–171. 10.1016/j.jneuroim.2003.11.003
- Rembach A., Watt A. D., Wilson W. J., Rainey-Smith S., Ellis K. A., Rowe C. C., et al. (2014). An increased neutrophil-lymphocyte ratio in Alzheimer’s disease is a function of age and is weakly correlated with neocortical amyloid accumulation. J. Neuroimmunol. 273 65–71. 10.1016/j.jneuroim.2014.05.005
- Rezai-Zadeh K., Gate D., Szekely C. A., Town T. (2009). Can peripheral leukocytes be used as Alzheimer’s disease biomarkers? Expert Rev. Neurother. 9 1623–1633. 10.1586/ern.09.118
- Ribeiro R. M., Perelson A. S. (2007). Determining thymic output quantitatively: using models to interpret experimental T-cell receptor excision circle (TREC) data. Immunol. Rev. 216 21–34. 10.1111/j.1600-065x.2006.00493.x
- Richartz-Salzburger E., Batra A., Stransky E., Laske C., Kohler N., Bartels M., et al. (2007). Altered lymphocyte distribution in Alzheimer’s disease. J. Psychiatr. Res. 41 174–178. 10.1016/j.jpsychires.2006.01.010
- Rizzo R. (2020). Controversial role of Herpesviruses in Alzheimer’s disease. PLoS Pathog. 16:e1008575. 10.1371/journal.ppat.1008575
- Rocha N. P., Teixeira A. L., Coelho F. M., Caramelli P., Guimaraes H. C., Barbosa I. G., et al. (2012). Peripheral blood mono-nuclear cells derived from Alzheimer’s disease patients show elevated baseline levels of secreted cytokines but resist stimulation with beta-amyloid peptide. Mol. Cell. Neurosci. 49 77–84. 10.1016/j.mcn.2011.09.005
- Rosenkranz D., Weyer S., Tolosa E., Gaenslen A., Berg D., Leyhe T., et al. (2007). Higher frequency of regulatory T cells in the elderly and increased suppressive activity in neurodegeneration. J. Neuroimmunol. 188 117–127. 10.1016/j.jneuroim.2007.05.011
- Rosenzweig N., Dvir-Szternfeld R., Tsitsou-Kampeli A., Keren-Shaul H., Ben-Yehuda H., Weill-Raynal P., et al. (2019). PD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model. Nat. Commun. 10:465.
- Saresella M., Calabrese E., Marventano I., Piancone F., Gatti A., Calvo M. G., et al. (2010). PD1 negative and PD1 positive CD4+ T regulatory cells in mild cognitive impairment and Alzheimer’s disease. J. Alzheimers Dis. 21 927–938. 10.3233/jad-2010-091696
- Schmitt F. A., Nelson P. T., Abner E., Scheff S., Jicha G. A., Smith C., et al. (2012). University of Kentucky Sanders-Brown healthy brain aging volunteers: donor characteristics, procedures and neuropathology. Curr. Alzheimer Res. 9 724–733. 10.2174/156720512801322591
- Schmitt V., Rink L., Uciechowski P. (2013). The Th17/Treg balance is disturbed during aging. Exp. Gerontol. 48 1379–1386. 10.1016/j.exger.2013.09.003
- Seidler S., Zimmermann H. W., Bartneck M., Trautwein C., Tacke F. (2010). Age-dependent alterations of monocyte subsets and monocyte-related chemokine pathways in healthy adults. BMC Immunol. 11:30. 10.1186/1471-2172-11-30
- Shahidehpour R. K., Higdon R. E., Crawford N. G., Neltner J. H., Ighodaro E. T., Patel E., et al. (2021). Dystrophic microglia are associated with neurodegenerative disease and not healthy aging in the human brain. Neurobiol. Aging 99 19–27. 10.1016/j.neurobiolaging.2020.12.003
- Shalit F., Sredni B., Brodie C., Kott E., Huberman M. (1995). T lymphocyte subpopulations and activation markers correlate with severity of Alzheimer’s disease. Clin. Immunol. Immunopathol. 75 246–250. 10.1006/clin.1995.1078
- Shaw A. C., Joshi S., Greenwood H., Panda A., Lord J. M. (2010). Aging of the innate immune system. Curr. Opin. Immunol. 22 507–513.
- Singh V. K. (1994). Studies of neuroimmune markers in Alzheimer’s disease. Mol. Neurobiol. 9 73–81. 10.1007/bf02816106
- Singh V. K., Fudenberg H. H., Brown F. R. (1987). Immunologic dysfunction: simultaneous study of Alzheimer’s and older Down’s patients. Mech. Ageing Dev. 37 257–264. 10.1016/0047-6374(86)90043-6
- Skias D., Bania M., Reder A. T., Luchins D., Antel J. P. (1985). Senile dementia of Alzheimer’s type (SDAT): reduced T8+-cell-mediated suppressor activity. Neurology 35 1635–1638. 10.1212/wnl.35.11.1635
- Sommer A., Winner B., Prots I. (2017). The Trojan horse - neuroinflammatory impact of T cells in neurodegenerative diseases. Mol. Neurodegener. 12:78.
- Spani C., Suter T., Derungs R., Ferretti M. T., Welt T., Wirth F., et al. (2015). Reduced beta-amyloid pathology in an APP transgenic mouse model of Alzheimer’s disease lacking functional B and T cells. Acta Neuropathol. Commun. 3:71.
- Su C., Zhao K., Xia H., Xu Y. (2019). Peripheral inflammatory biomarkers in Alzheimer’s disease and mild cognitive impairment: a systematic review and meta-analysis. Psychogeriatrics 19 300–309. 10.1111/psyg.12403
- Swardfager W., Lanctot K., Rothenburg L., Wong A., Cappell J., Herrmann N. (2010). A meta-analysis of cytokines in Alzheimer’s disease. Biol. Psychiatry 68 930–941.
- Templeton A. J., Ace O., Mcnamara M. G., Al-Mubarak M., Vera-Badillo F. E., Hermanns T., et al. (2014a). Prognostic role of platelet to lymphocyte ratio in solid tumors: a systematic review and meta-analysis. Cancer Epidemiol. Biomarkers Prev. 23 1204–1212. 10.1158/1055-9965.epi-14-0146
- Templeton A. J., Mcnamara M. G., Seruga B., Vera-Badillo F. E., Aneja P., Ocana A., et al. (2014b). Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J. Natl. Cancer Inst. 106:dju124.
- Thakur K. T., Miller E. H., Glendinning M. D., Al-Dalahmah O., Banu M. A., Boehme A. K., et al. (2021). COVID-19 neuropathology at Columbia University Irving Medical Center/New York Presbyterian Hospital. Brain. 10.1093/brain/awab148 [Epub ahead of print].
- Tollefson G. D., Godes M., Warren J. B., Haus E., Luxenberg M., Garvey M. (1989). Lymphopenia in primary degenerative dementia. J. Psychiatr. Res. 23 191–199. 10.1016/0022-3956(89)90024-1
- Trieb K., Ransmayr G., Sgonc R., Lassmann H., Grubeckloebenstein B. (1996). APP peptides stimulate lymphocyte proliferation in normals, but not in patients with Alzheimer’s disease. Neurobiol. Aging 17 541–547. 10.1016/0197-4580(96)00068-1
- Unger M. S., Li E., Scharnagl L., Poupardin R., Altendorfer B., Mrowetz H., et al. (2020). CD8(+) T-cells infiltrate Alzheimer’s disease brains and regulate neuronal- and synapse-related gene expression in APP-PS1 transgenic mice. Brain Behav. Immun. 89 67–86. 10.1016/j.bbi.2020.05.070
- van der Willik K. D., Fani L., Rizopoulos D., Licher S., Fest J., Schagen S. B., et al. (2019). Balance between innate versus adaptive immune system and the risk of dementia: a population-based cohort study. J. Neuroinflammation 16:68.
- van Duin D., Mohanty S., Thomas V., Ginter S., Montgomery R. R., Fikrig E., et al. (2007). Age-associated defect in human TLR-1/2 function. J. Immunol. 178 970–975. 10.4049/jimmunol.178.2.970
- Velardi E., Tsai J. J., Van Den Brink M. R. M. (2020). T cell regeneration after immunological injury. Nat. Rev. Immunol. 21 277–291. 10.1038/s41577-020-00457-z
- Vukmanovic-Stejic M., Rustin M. H., Nikolich-Zugich J., Akbar A. N. (2011). Immune responses in the skin in old age. Curr. Opin. Immunol. 23 525–531. 10.1016/j.coi.2011.05.008
- Waisman A., Ginhoux F., Greter M., Bruttger J. (2015). Homeostasis of microglia in the adult brain: review of novel microglia depletion systems. Trends Immunol. 36 625–636. 10.1016/j.it.2015.08.005
- Wenisch C., Patruta S., Daxbock F., Krause R., Horl W. (2000). Effect of age on human neutrophil function. J. Leukoc. Biol. 67 40–45. 10.1002/jlb.67.1.40
- Wertheimer A. M., Bennett M. S., Park B., Uhrlaub J. L., Martinez C., Pulko V., et al. (2014). Aging and cytomegalovirus infection differentially and jointly affect distinct circulating T cell subsets in humans. J. Immunol. 192 2143–2155. 10.4049/jimmunol.1301721
- Zlokovic B. V., Gottesman R. F., Bernstein K. E., Seshadri S., Mckee A., Snyder H., et al. (2020). Vascular contributions to cognitive impairment and dementia (VCID): a report from the 2018 National Heart, Lung, and Blood Institute and National Institute of Neurological Disorders and Stroke Workshop. Alzheimers Dement. 16 1714–1733. 10.1002/alz.12157
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