Mechanisms of brain protection against autoimmune inflammation
Abstract
A significant number of unique antigens expressed in the brain can activate an adaptive immune response, increasing the risk of autoimmune inflammation in the central nervous system (CNS). As a result, a complex protection system exists in the CNS to prevent autoimmune reactions. In addition to the blood-brain- and blood-cerebrospinal fluid-barriers, we discuss complex systems of antigen drainage and circulation of antigen-presenting cells in the CNS. Moreover, the interaction of the CNS with the peripheral immune system typically occurs in specific areas (choroid plexuses, perivascular spaces, and brain meninges), and resident cells of the innate immune system (macrophages, microglia, astrocytes) have limited opportunities for antigen presentation and do not migrate to regional lymph nodes. There are signs of activation of adaptive immunity against CNS antigens in normal conditions, which, however, do not lead to autoimmune diseases. The review covers the mechanisms of maintaining natural immune self-tolerance in the CNS and their failure in autoimmune CNS pathology.
About the Authors
A. I. Volkov
Federal Center of Brain and Neurotechnologies, FMBA of Russia
Russian Federation
Russian Federation
Andrey Igorevich Volkov
Department of Neuroimmunology
1, Ostrovityanov St., Build 10, Moscow 117997
M. V. Melnikov
Federal Center of Brain and Neurotechnologies, FMBA of Russia; N.I. Pirogov Russian National Research Medical University, Ministry of Health of Russia; Institute of Immunology FMBA of Russia
Russian Federation
Russian Federation
Department of Neuroimmunology
Department of Neurology, Neurosurgery, and Medical Genetics
Laboratory of Clinical Immunology
1, Ostrovityanov St., Build 10, Moscow 117997
1, Ostrovityanov St., Moscow 117997
24, Kashirskoe Shosse, Moscow 115522
A. N. Boyko
Federal Center of Brain and Neurotechnologies, FMBA of Russia; N.I. Pirogov Russian National Research Medical University, Ministry of Health of Russia
Russian Federation
Russian Federation
Department of Neuroimmunology
Department of Neurology, Neurosurgery, and Medical Genetics
1, Ostrovityanov St., Build 10, Moscow 117997
1, Ostrovityanov St., Moscow 117997
References
1. De Laere M, Berneman ZN, Cools N. To the Brain and Back: Migratory Paths of Dendritic Cells in Multiple Sclerosis. J Neuropathol Exp Neurol. 2018 Mar 1;77(3):178-92. doi: 10.1093/jnen/nlx114
2. Melnikov MV, Paschenkov MV, Boyko AN. Dendritic cells in multiple sclerosis. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova. 2017;117(2):22-30 (In Russ.).
3. Kivisäkk P, Mahad DJ, Callahan MK, et al. Human cerebrospinal fluid central memory CD4+ T cells: evidence for trafficking through choroid plexus and meninges via P-selectin. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8389-94. doi: 10.1073/pnas.1433000100. Epub 2003 Jun 26.
4. Provencio JJ, Kivisäkk P, Tucky BH, et al. Comparison of ventricular and lumbar cerebrospinal fluid T cells in non-inflammatory neurological disorder (NIND) patients. J Neuroimmunol. 2005 Jun;163(1-2):179-84. doi: 10.1016/j.jneuroim.2005.03.003. Epub 2005 Apr 22.
5. Ransohoff RM, Engelhardt B. The anatomical and cellular basis of immune surveillance in the central nervous system. Nat Rev Immunol. 2012 Sep;12(9):623-35. doi: 10.1038/nri3265. Epub 2012 Aug 20.
6. De Graaf MT, Smitt PA, Luitwieler RL, et al. Central memory CD4+ T cells dominate the normal cerebrospinal fluid. Cytometry B Clin Cytom. 2011 Jan;80(1):43-50. doi: 10.1002/cyto.b.20542
7. Sallusto F, Impellizzieri D, Basso C, et al. T-cell trafficking in the central nervous system. Immunol Rev. 2012 Jul;248(1):216-27. doi: 10.1111/j.1600-065X.2012.01140.x
8. Steinbach K, Vincenti I, Kreutzfeldt M, et al. Brain-resident memory T cells represent an autonomous cytotoxic barrier to viral infection. J Exp Med. 2016 Jul 25;213(8):1571-87. doi: 10.1084/jem.20151916. Epub 2016 Jul 4.
9. Ghersi-Egea JF, Strazielle N, Catala M, et al. Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease. Acta Neuropathol. 2018 Mar;135(3):337-61. doi: 10.1007/s00401-018-1807-1. Epub 2018 Jan 24.
10. Baruch K, Ron-Harel N, Gal H, et al. CNS-specific immunity at the choroid plexus shifts toward destructive Th2 inflammation in brain aging. Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2264-9. doi: 10.1073/pnas.1211270110. Epub 2013 Jan 18.
11. Kunis G, Baruch K, Rosenzweig N, et al. IFN-γ-dependent activation of the brain's choroid plexus for CNS immune surveillance and repair. Brain. 2013 Nov;136(Pt 11):3427-40. doi: 10.1093/brain/awt259. Epub 2013 Oct 1.
12. Hochmeister S, Zeitelhofer M, Bauer J, et al. After injection into the striatum, in vitrodifferentiated microglia- and bone marrowderived dendritic cells can leave the central nervous system via the blood stream. Am J Pathol. 2008 Dec;173(6):1669-81. doi: 10.2353/ajpath.2008.080234. Epub 2008 Oct 30.
13. Mohammad MG, Tsai VW, Ruitenberg MJ, et al. Immune cell trafficking from the brain maintains CNS immune tolerance. J Clin Invest. 2014 Mar;124(3):1228-41. doi: 10.1172/JCI71544. Epub 2014 Feb 24.
14. Plog BA, Nedergaard M. The Glymphatic System in Central Nervous System Health and Disease: Past, Present, and Future. Annu Rev Pathol. 2018 Jan 24;13:379-94. doi: 10.1146/annurev-pathol-051217-111018
15. Abbott NJ, Pizzo ME, Preston JE, et al. The role of brain barriers in fluid movement in the CNS: is there a 'glymphatic' system? Acta Neuropathol. 2018 Mar;135(3):387-407. doi: 10.1007/s00401-018-1812-4. Epub 2018 Feb 10.
16. Hablitz LM, Vinitsky HS, Sun Q, et al. Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia. Sci Adv. 2019 Feb 27;5(2):eaav5447. doi: 10.1126/sciadv.aav5447. eCollection 2019 Feb.
17. Albargothy NJ, Johnston DA, MacGregor-Sharp M, et al. Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways. Acta Neuropathol. 2018 Jul;136(1):139-52. doi: 10.1007/s00401-018-1862-7. Epub 2018 May 12.
18. Papadopoulos Z, Herz J, Kipnis J. Meningeal Lymphatics: From Anatomy to Central Nervous System Immune Surveillance. J Immunol. 2020 Jan 15;204(2):286-93. doi: 10.4049/jimmunol.1900838
19. Rua R, McGavern DB. Advances in Meningeal Immunity. Trends Mol Med. 2018 Jun;24(6):542-59. doi: 10.1016/j.molmed.2018.04.003. Epub 2018 May 3.
20. Sandrone S, Moreno-Zambrano D, Kipnis J, van Gijn J. A (delayed) history of the brain lymphatic system. Nat Med. 2019 Apr;25(4):538-40. doi: 10.1038/s41591-019-0417-3
21. Schläger C, Körner H, Krueger M, et al. Effector T-cell trafficking between the leptomeninges and the cerebrospinal fluid. Nature. 2016 Feb 18;530(7590):349-53. doi: 10.1038/nature16939. Epub 2016 Feb 10.
22. Hatfield JK, Brown MA. Group 3 innate lymphoid cells accumulate and exhibit diseaseinduced activation in the meninges in EAE. Cell Immunol. 2015 Oct;297(2):69-79. doi: 10.1016/j.cellimm.2015.06.006. Epub 2015 Jul 2.
23. Pekny M, Pekna M, Messing A, et al. Astrocytes: a central element in neurological diseases. Acta Neuropathol. 2016 Mar;131(3):323-45. doi: 10.1007/s00401-015-1513-1. Epub 2015 Dec 15.
24. Brambilla R. The contribution of astrocytes to the neuroinflammatory response in multiple sclerosis and experimental autoimmune encephalomyelitis. Acta Neuropathol. 2019 May;137(5):757-83. doi: 10.1007/s00401-019-01980-7. Epub 2019 Mar 7.
25. Sims NR, Yew WP. Reactive astrogliosis in stroke: Contributions of astrocytes to recovery of neurological function. Neurochem Int. 2017 Jul;107:88-103. doi: 10.1016/j.neuint.2016.12.016. Epub 2017 Jan 3.
26. Guerrero BL, Sicotte NL. Microglia in Multiple Sclerosis: Friend or Foe? Front Immunol. 2020 Mar 20;11:374. doi: 10.3389/fimmu.2020.00374. eCollection 2020.
27. Gharagozloo M, Gris KV, Mahvelati T, et al. NLR-Dependent Regulation of Inflammation in Multiple Sclerosis. Front Immunol. 2018 Jan 18;8:2012. doi: 10.3389/fimmu.2017.02012. eCollection 2017.
28. Melnikov M, Sviridova A, Rogovskii V, et al. Serotoninergic system targeting in multiple sclerosis: the prospective for pathogenetic therapy. Mult Scler Relat Disord. 2021 Mar 10;51:102888. doi: 10.1016/j.msard.2021.102888. Epub ahead of print.
29. Yogev N, Frommer F, Lukas D, et al. Dendritic cells ameliorate autoimmunity in the CNS by controlling the homeostasis of PD-1 receptor(+) regulatory T cells. Immunity. 2012 Aug 24;37(2):264-75. doi: 10.1016/j.immuni.2012.05.025. Epub 2012 Aug 16.
30. Kozhieva MKh, Mel'nikov MV, Rogovsky VS, et al. Gut human microbiota and multiple sclerosis. Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova. 2017;117(10-2):11-9. doi: 10.17116/jnevro201711710211-19 (In Russ.).
31. Malinova TS, Dijkstra CD, de Vries HE. Serotonin: A mediator of the gut-brain axis in multiple sclerosis. Mult Scler. 2018 Aug;24(9):1144-50. doi: 10.1177/1352458517739975. Epub 2017 Nov 9.
32. Castillo-Alvarez F, Marzo-Sola ME. Role of intestinal microbiota in the development of multiple sclerosis. Neurologia. 2017 Apr;32(3):175-84. doi: 10.1016/j.nrl.2015.07.005. Epub 2015 Sep 14.
33. Feige J, Moser T, Bieler L, et al. Vitamin D Supplementation in Multiple Sclerosis: A Critical Analysis of Potentials and Threats. Nutrients. 2020 Mar 16;12(3):783. doi: 10.3390/nu12030783
34. Morris G, Reiche EMV, Murru A, et al. Multiple Immune-Inflammatory and Oxidative and Nitrosative Stress Pathways Explain the Frequent Presence of Depression in Multiple Sclerosis. Mol Neurobiol. 2018 Aug;55(8):6282-306. doi: 10.1007/s12035-017-0843-5. Epub 2018 Jan 2.
35. Libbey JE, Cusick MF, Fujinami RS. Role of pathogens in multiple sclerosis. Int Rev Immunol. Jul-Aug 2014;33(4):266-83. doi: 10.3109/08830185.2013.823422. Epub 2013 Nov 22.
36. Bar-Or A, Pender MP, Khanna R, et al. Epstein-Barr Virus in Multiple Sclerosis: Theory and Emerging Immunotherapies. Trends Mol Med. 2020 Mar;26(3):296-310.
37. Gabibov AG, Belogurov AA Jr, Lomakin YaA, et al. Combinatorial antibody library from multiple sclerosis patients reveals antibodies that cross-react with myelin basic protein and EBV antigen. FASEB J. 2011 Dec;25(12):4211-21. doi: 10.1096/fj.11-190769. Epub 2011 Aug 22.
38. Patel J, Balabanov R. Molecular mechanisms of oligodendrocyte injury in multiple sclerosis and experimental autoimmune encephalomyelitis. Int J Mol Sci. 2012;13(8):10647-59. doi: 10.3390/ijms130810647. Epub 2012 Aug 23.
39. Melnikov M, Sharanova S, Sviridova A, et al. The influence of glatiramer acetate on Th17-immune response in multiple sclerosis. PLoS One. 2020 Oct 30;15(10):e0240305. doi: 10.1371/journal.pone.0240305. eCollection 2020.
40. Krishnamoorthy G, Lassmann H, Wekerle H, Holz A. Spontaneous opticospinal encephalomyelitis in a double-transgenic mouse model of autoimmune T cell/B cell cooperation. J Clin Invest. 2006 Sep;116(9):2385-92. doi: 10.1172/JCI28330
41. Pöllinger B, Krishnamoorthy G, Berer K, et al. Spontaneous relapsing-remitting EAE in the SJL/J mouse: MOG-reactive transgenic T cells recruit endogenous MOG-specific B cells. J Exp Med. 2009 Jun 8;206(6):1303-16. doi: 10.1084/jem.20090299. Epub 2009 Jun 1.
42. Titus HE, Chen Y, Podojil JR, et al. Pre-clinical and Clinical Implications of «Inside-Out» vs. «Outside-In» Paradigms in Multiple Sclerosis Etiopathogenesis. Front Cell Neurosci. 2020 Oct 27;14:599717. doi: 10.3389/fncel.2020.599717. eCollection 2020.
43. Li R, Rezk A, Miyazaki Y, et al. Canadian B cells in MS Team. Proinflammatory GMCSF-producing B cells in multiple sclerosis and B cell depletion therapy. Sci Transl Med. 2015 Oct 21;7(310):310ra166. doi: 10.1126/scitranslmed.aab4176
44. Cepok S, Zhou D, Vogel F, et al. The immune response at onset and during recovery from Borrelia burgdorferi meningoradiculitis. Arch Neurol. 2003 Jun;60(6):849-55. doi: 10.1001/archneur.60.6.849
45. Rupprecht TA, Plate A, Adam M, et al. The chemokine CXCL13 is a key regulator of B cell recruitment to the cerebrospinal fluid in acute Lyme neuroborreliosis. J Neuroinflammation. 2009 Dec 30;6:42. doi: 10.1186/1742-2094-6-42
46. DiSano KD, Gilli F, Pachner AR. Intrathecally produced CXCL13: A predictive biomarker in multiple sclerosis. Mult Scler J Exp Transl Clin. 2020 Dec 16;6(4):2055217320981396. doi: 10.1177/2055217320981396. eCollection Oct-Dec 2020.
Review
Supporting agencies: The research was carried out within the state assignment № АААА-А19-119042590021-0.
For citations:
Volkov A.I., Melnikov M.V., Boyko A.N. Mechanisms of brain protection against autoimmune inflammation. Neurology, Neuropsychiatry, Psychosomatics. 2021;13(1S):4-9. (In Russ.) https://doi.org/10.14412/2074-2711-2021-1S-4-9
Views: 202
Email this article 