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Decoding intrathecal immunoglobulins and B cells in the CNS: their synthesis, function, and regulation

Modulation of immune responses mediated by different B cells is a potential therapeutic approach toward ameliorating several CNS disorders

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Pages 67-79 | Received 08 Oct 2019, Accepted 26 Dec 2019, Published online: 13 Jan 2020

References

  • Louveau A, Smirnov I, Keyes TJ, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015;523(7560):337–341. doi:10.1038/nature14432.
  • Cserr HF, Harling-Berg CJ, Knopf PM. Drainage of brain extracellular fluid into blood and deep cervical lymph and its immunological significance. Brain Pathol. 1992;2(4):269–276. doi:10.1111/j.1750-3639.1992.tb00703.x.
  • Aspelund A, Antila S, Proulx ST, et al. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med. 2015;212(7):991–999. doi:10.1084/jem.20142290.
  • Prinz M, Priller J. The role of peripheral immune cells in the CNS in steady state and disease. Nat Neurosci. 2017;20(2):136–144. doi:10.1038/nn.4475.
  • Ginhoux F, Greter M, Leboeuf M, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science. 2010;330(6005):841–845. doi:10.1126/science.1194637.
  • Negi N, Das BK. CNS: Not an immunoprivilaged site anymore but a virtual secondary lymphoid organ. Int Rev Immunol. 2018;37(1):57–68. doi:10.1080/08830185.2017.1357719.
  • Kivisakk P, Imitola J, Rasmussen S, et al. Localizing central nervous system immune surveillance: meningeal antigen-presenting cells activate T cells during experimental autoimmune encephalomyelitis. Ann Neurol. 2009;65:457–469. doi:10.1002/ana.21379.
  • Greter M, Lelios I, Croxford AL. Microglia versus myeloid cell nomenclature during brain inflammation. Front Immunol. 2015;6:249. doi:10.3389/fimmu.2015.00249.
  • Bechmann I, Kwidzinski E, Kovac AD, et al. Turnover of rat brain perivascular cells. Exp Neurol. 2001;168(2):242–249. doi:10.1006/exnr.2000.7618.
  • Mrdjen D, Pavlovic A, Hartmann FJ, et al. High-dimensional single-cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health, aging, and disease. Immunity. 2018;48(3):599. doi:10.1016/j.immuni.2018.02.014.
  • 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;213(8):1571–1587. doi:10.1084/jem.20151916.
  • Kivisakk 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 USA. 2003;100:8389–8394. doi:10.1073/pnas.1433000100.
  • Cayrol R, Wosik K, Berard JL, et al. Activated leukocyte cell adhesion molecule promotes leukocyte trafficking into the central nervous system. Nat Immunol. 2008;9(2):137–145. doi:10.1038/ni1551.
  • Lehmann-Horn K, Sagan SA, Bernard CC, et al. B-cell very late antigen-4 deficiency reduces leukocyte recruitment and susceptibility to central nervous system autoimmunity. Ann Neurol. 2015;77(5):902–908. doi:10.1002/ana.24387.
  • Alter A, Duddy M, Hebert S, et al. Determinants of human B cell migration across brain endothelial cells. J Immunol. 2003;170(9):4497–4505. doi:10.4049/jimmunol.170.9.4497.
  • Krumbholz M, Theil D, Cepok S, et al. Chemokines in multiple sclerosis: CXCL12 and CXCL13 up-regulation is differentially linked to CNS immune cell recruitment. Brain. 2006;129(1):200–211. doi:10.1093/brain/awh680.
  • Allen CD, Ansel KM, Low C, et al. Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Nat Immunol. 2004;5(9):943–952. doi:10.1038/ni1100.
  • Corcione A, Casazza S, Ferretti E, et al. Recapitulation of B cell differentiation in the central nervous system of patients with multiple sclerosis. Proc Natl Acad Sci USA. 2004;101(30):11064–11069. doi:10.1073/pnas.0402455101.
  • Lesley R, Xu Y, Kalled SL, et al. Reduced competitiveness of autoantigen-engaged B cells due to increased dependence on BAFF. Immunity. 2004;20(4):441–453. doi:10.1016/S1074-7613(04)00079-2.
  • Thangarajh M, Masterman T, Hillert J, et al. A proliferation-inducing ligand (APRIL) is expressed by astrocytes and is increased in multiple sclerosis. Scand J Immunol. 2007;65(1):92–98. doi:10.1111/j.1365-3083.2006.01867.x.
  • Seyler TM, Park YW, Takemura S, et al. BLyS and APRIL in rheumatoid arthritis. J Clin Invest. 2005;115(11):3083–3092. doi:10.1172/JCI25265.
  • Stohl W, Metyas S, Tan SM, et al. B lymphocyte stimulator overexpression in patients with systemic lupus erythematosus: longitudinal observations. Arthritis Rheum. 2003;48(12):3475–3486. doi:10.1002/art.11354.
  • Khairnar V, Duhan V, Maney SK, et al. CEACAM1 induces B-cell survival and is essential for protective antiviral antibody production. Nat Commun. 2015;6(1):6217. doi:10.1038/ncomms7217.
  • Rovituso DM, Scheffler L, Wunsch M, et al. CEACAM1 mediates B cell aggregation in central nervous system autoimmunity. Sci Rep. 2016;6(1):29847. doi:10.1038/srep29847.
  • Banks WA, Terrell B, Farr SA, et al. Passage of amyloid beta protein antibody across the blood-brain barrier in a mouse model of Alzheimer's disease. Peptides. 2002;23(12):2223–2226. doi:10.1016/S0196-9781(02)00261-9.
  • Puthenparampil M, Federle L, Miante S, et al. BAFF Index and CXCL13 levels in the cerebrospinal fluid associate respectively with intrathecal IgG synthesis and cortical atrophy in multiple sclerosis at clinical onset. J Neuroinflammation. 2017;14(1):11. doi:10.1186/s12974-016-0785-2.
  • Stauch C, Reiber H, Rauchenzauner M, et al. Intrathecal IgM synthesis in pediatric MS is not a negative prognostic marker of disease progression: quantitative versus qualitative IgM analysis. Mult Scler. 2011;17(3):327–334. doi:10.1177/1352458510388543.
  • Bonnan M. Intrathecal IgG synthesis: a resistant and valuable target for future multiple sclerosis treatments. Mult Scler Int. 2015;2015:296184. doi:10.1155/2015/296184.
  • DiSano KD, Royce DB, Gilli F, et al. Central nervous system inflammatory aggregates in the Theiler's virus model of progressive multiple sclerosis. Front Immunol. 2019;10:1821.
  • Tau GZ, Peterson BS. Normal development of brain circuits. Neuropsychopharmacol.. 2010;35(1):147–168. doi:10.1038/npp.2009.115.
  • Domingues HS, Portugal CC, Socodato R, et al. Oligodendrocyte, astrocyte, and microglia crosstalk in myelin development, damage, and repair. Front Cell Dev Biol. 2016;4:71. doi:10.3389/fcell.2016.00071.
  • Kiray H, Lindsay SL, Hosseinzadeh S, et al. The multifaceted role of astrocytes in regulating myelination. Exp Neurol. 2016;283:541–549. doi:10.1016/j.expneurol.2016.03.009.
  • Chung JB, Silverman M, Monroe JG. Transitional B cells: step by step towards immune competence. Trends Immunol. 2003;24(6):343–349.
  • Fereidan-Esfahani M, Nayfeh T, Warrington A, et al. IgM natural autoantibodies in physiology and the treatment of disease. Methods Mol Biol. 2019;1904:53–81. doi:10.1007/978-1-4939-8958-4_3.
  • Xu X, Ng SM, Hassouna E, et al. Human-derived natural antibodies: biomarkers and potential therapeutics. Future Neurol. 2015;10(1):25–39. doi:10.2217/fnl.14.62.
  • Elkon K, Casali P. Nature and functions of autoantibodies. Nat Rev Rheumatol. 2008;4(9):491–498. doi:10.1038/ncprheum0895.
  • Baumgarth N. B-1 cell heterogeneity and the regulation of natural and antigen-induced IgM production. Front Immunol. 2016;7:324. doi:10.3389/fimmu.2016.00324.
  • Baumgarth N. The double life of a B-1 cell: self-reactivity selects for protective effector functions. Nat Rev Immunol. 2011;11(1):34–46. doi:10.1038/nri2901.
  • Youinou P, Jamin C, Lydyard PM. CD5 expression in human B-cell populations. Immunol Today. 1999;20(7):312–316. doi:10.1016/S0167-5699(99)01476-0.
  • Marie-Cardine A, Divay F, Dutot I, et al. Transitional B cells in humans: characterization and insight from B lymphocyte reconstitution after hematopoietic stem cell transplantation. Clin Immunol. 2008;127(1):14–25. doi:10.1016/j.clim.2007.11.013.
  • Tanabe S, Yamashita T. B-1a lymphocytes promote oligodendrogenesis during brain development. Nat Neurosci. 2018;21(4):506–516. doi:10.1038/s41593-018-0106-4.
  • Jaseb K, Purrahman D, Shahrabi S, et al. Prognostic significance of aberrant CD5 expression in B-cell leukemia. Oncol Rev. 2019;13(1):400. doi:10.4081/oncol.2019.400.
  • Lobo PI. Role of natural autoantibodies and natural IgM anti-leucocyte autoantibodies in health and disease. Front Immunol. 2016;7:198. doi:10.3389/fimmu.2016.00198.
  • Bagnara D, Squillario M, Kipling D, et al. A reassessment of IgM memory subsets in humans. J Immunol. 2015;195(8):3716–3724. doi:10.4049/jimmunol.1500753.
  • Avrameas S, Alexopoulos H, Moutsopoulos HM. Natural autoantibodies: an undersugn hero of the immune system and autoimmune disorders-a point of view. Front Immunol. 2018;9:1320. doi:10.3389/fimmu.2018.01320.
  • Swanson PA, 2nd, McGavern DB. Viral diseases of the central nervous system. Curr Opin Virol. 2015;11:44–54. doi:10.1016/j.coviro.2014.12.009.
  • Louveau A, Plog BA, Antila S, et al. Understanding the functions and relationships of the glymphatic system and meningeal lymphatics. J Clin Invest. 2017;127(9):3210–3219. doi:10.1172/JCI90603.
  • Engelhardt B, Vajkoczy P, Weller RO. The movers and shapers in immune privilege of the CNS. Nat Immunol. 2017;18(2):123–131. doi:10.1038/ni.3666.
  • Stern JN, Yaari G, Vander Heiden JA, et al. B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes. Sci Transl Med. 2014;6(248):248ra107. doi:10.1126/scitranslmed.3008879.
  • Tourtellotte WW, Potvin AR, Fleming JO, et al. Multiple sclerosis: measurement and validation of central nervous system IgG synthesis rate. Neurology. 1980;30(3):240–244. doi:10.1212/WNL.30.3.240.
  • Mitsdoerffer M, Peters A. Tertiary lymphoid organs in central nervous system autoimmunity. Front Immunol. 2016;7:451. doi:10.3389/fimmu.2016.00451.
  • Aloisi F, Pujol-Borrell R. Lymphoid neogenesis in chronic inflammatory diseases. Nat Rev Immunol. 2006;6(3):205–217. doi:10.1038/nri1786.
  • Li R, Bar-Or A. The multiple roles of B cells in multiple sclerosis and their implications in multiple sclerosis therapies. Cold Spring Harb Perspect Med. 2019;9(4):a029108. doi:10.1101/cshperspect.a029108.
  • LeBien TW, Tedder TF. B lymphocytes: how they develop and function. Blood. 2008;112(5):1570–1580. doi:10.1182/blood-2008-02-078071.
  • Li R, Patterson KR, Bar-Or A. Reassessing B cell contributions in multiple sclerosis. Nat Immunol. 2018;19(7):696–707. doi:10.1038/s41590-018-0135-x.
  • Palanichamy A, Apeltsin L, Kuo TC, et al. Immunoglobulin class-switched B cells form an active immune axis between CNS and periphery in multiple sclerosis. Sci Transl Med. 2014;6(248):248ra106. doi:10.1126/scitranslmed.3008930.
  • Cid C, Regidor I, Alcazar A. Anti-heat shock protein 90beta antibodies are detected in patients with multiple sclerosis during remission. J Neuroimmunol. 2007;184(1-2):223–226. doi:10.1016/j.jneuroim.2006.11.001.
  • Hohlfeld R, Dornmair K, Meinl E, et al. The search for the target antigens of multiple sclerosis, part 2: CD8+ T cells, B cells, and antibodies in the focus of reverse-translational research. Lancet Neurol. 2016;15(3):317–331. doi:10.1016/S1474-4422(15)00313-0.
  • Arneth BM. Impact of B cells to the pathophysiology of multiple sclerosis. J Neuroinflammation. 2019;16(1):128. doi:10.1186/s12974-019-1517-1.
  • Probstel AK, Sanderson NS, Derfuss T. B cells and autoantibodies in multiple sclerosis. Int J Mol Sci. 2015;16:16576–16592. doi:10.3390/ijms160716576.
  • Wanleenuwat P, Iwanowski P. Role of B cells and antibodies in multiple sclerosis. Mult Scler Relat Disord. 2019;36:101416. doi:10.1016/j.msard.2019.101416.
  • von Budingen HC, Kuo TC, Sirota M, et al. B cell exchange across the blood-brain barrier in multiple sclerosis. J Clin Invest. 2012;122:4533–4543. doi:10.1172/JCI63842.
  • Dhaeze T, Peelen E, Hombrouck A, et al. Circulating follicular regulatory T cells are defective in multiple sclerosis. J Immunol. 2015;195(3):832–840. doi:10.4049/jimmunol.1500759.
  • Dombrowski Y, O'Hagan T, Dittmer M, et al. Regulatory T cells promote myelin regeneration in the central nervous system. Nat Neurosci. 2017;20(5):674–680. doi:10.1038/nn.4528.
  • Knier B, Hiltensperger M, Sie C, et al. Myeloid-derived suppressor cells control B cell accumulation in the central nervous system during autoimmunity. Nat Immunol. 2018;19(12):1341–1351. doi:10.1038/s41590-018-0237-5.
  • Knippenberg S, Peelen E, Smolders J, et al. Reduction in IL-10 producing B cells (Breg) in multiple sclerosis is accompanied by a reduced naive/memory Breg ratio during a relapse but not in remission. J Neuroimmunol. 2011;239(1-2):80–86. doi:10.1016/j.jneuroim.2011.08.019.
  • Pfuhl C, Grittner U, Giess RM, et al. Intrathecal IgM production is a strong risk factor for early conversion to multiple sclerosis. Neurology. 2019; 15:620–621.
  • Gasperi C, Salmen A, Antony G, et al. Association of intrathecal immunoglobulin G synthesis with disability worsening in multiple sclerosis. JAMA Neurol. 2019;76(7):841–849. doi:10.1001/jamaneurol.2019.0905.
  • Wright BR, Warrington AE, Edberg DD, et al. Cellular mechanisms of central nervous system repair by natural autoreactive monoclonal antibodies. Arch Neurol. 2009;66(12):1456–1459. doi:10.1001/archneurol.2009.262.
  • Gholamzad M, Ebtekar M, Ardestani MS, et al. A comprehensive review on the treatment approaches of multiple sclerosis: currently and in the future. Inflamm Res. 2019;68(1):25–38. doi:10.1007/s00011-018-1185-0.
  • Nguyen AL, Gresle M, Marshall T, et al. Monoclonal antibodies in the treatment of multiple sclerosis: emergence of B-cell-targeted therapies. Br J Pharmacol. 2017;174(13):1895–1907. doi:10.1111/bph.13780.
  • Juanatey A, Blanco-Garcia L, Tellez N. Ocrelizumab: its efficacy and safety in multiple sclerosis. Rev Neurol. 2018;66(12):423–433.
  • Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358(7):676–688. doi:10.1056/NEJMoa0706383.
  • Sorensen PS, Lisby S, Grove R, et al. Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: a phase 2 study. Neurology. 2014;82(7):573–581. doi:10.1212/WNL.0000000000000125.
  • Scolding NJ, Pasquini M, Reingold SC, et al. Cell-based therapeutic strategies for multiple sclerosis. Brain. 2017;140(11):2776–2796. doi:10.1093/brain/awx154.
  • Kuperstein I, Broersen K, Benilova I, et al. Neurotoxicity of Alzheimer's disease Abeta peptides is induced by small changes in the Abeta42 to Abeta40 ratio. EMBO J. 2010;29(19):3408–3420. doi:10.1038/emboj.2010.211.
  • Hansen DV, Hanson JE, Sheng M. Microglia in Alzheimer's disease. J Cell Biol. 2018;217(2):459–472. doi:10.1083/jcb.201709069.
  • Marsh SE, Abud EM, Lakatos A, et al. The adaptive immune system restrains Alzheimer's disease pathogenesis by modulating microglial function. Proc Natl Acad Sci USA. 2016;113(9):E1316-25. doi:10.1073/pnas.1525466113.
  • Dodel R, Balakrishnan K, Keyvani K, et al. Naturally occurring autoantibodies against beta-amyloid: investigating their role in transgenic animal and in vitro models of Alzheimer's disease. J Neurosci. 2011;31(15):5847–5854. doi:10.1523/JNEUROSCI.4401-10.2011.
  • Klyubin I, Cullen WK, Hu NW, et al. Alzheimer's disease Abeta assemblies mediating rapid disruption of synaptic plasticity and memory. Mol Brain. 2012;5(1):25. doi:10.1186/1756-6606-5-25.
  • Sollvander S, Ekholm-Pettersson F, Brundin RM, et al. Increased number of plasma B cells producing autoantibodies against Abeta42 protofibrils in Alzheimer's disease. J Alzheimers Dis. 2015;48:63–72. doi:10.3233/JAD-150236.
  • Relkin NR, Thomas RG, Rissman RA, et al. A phase 3 trial of IV immunoglobulin for Alzheimer disease. Neurology. 2017;88(18):1768–1775. doi:10.1212/WNL.0000000000003904.
  • Xu L, Pu J. Alpha-synuclein in Parkinson's disease: from pathogenetic dysfunction to potential clinical application. Parkinsons Dis. 2016;2016:1720621. doi:10.1155/2016/1720621.
  • Shalash A, Salama M, Makar M, et al. Elevated serum alpha-synuclein autoantibodies in patients with Parkinson's disease relative to Alzheimer's disease and controls. Front Neurol. 2017;8:720.
  • Kannarkat GT, Boss JM, Tansey MG. The role of innate and adaptive immunity in Parkinson's disease. J Parkinsons Dis. 2013;3(4):493–514. doi:10.3233/JPD-130250.
  • Brudek T, Winge K, Folke J, et al. Autoimmune antibody decline in Parkinson's disease and multiple system atrophy; a step towards immunotherapeutic strategies. Mol Neurodegener. 2017;12(1):44 doi:10.1186/s13024-017-0187-7.
  • Masliah E, Rockenstein E, Adame A, et al. Effects of alpha-synuclein immunization in a mouse model of Parkinson's disease. Neuron. 2005;46(6):857–868. doi:10.1016/j.neuron.2005.05.010.
  • Jankovic J, Goodman I, Safirstein B, et al. Safety and tolerability of multiple ascending doses of PRX002/RG7935, an anti-alpha-synuclein monoclonal antibody, in patients with Parkinson disease: a randomized clinical trial. JAMA Neurol. 2018;75(10):1206–1214. doi:10.1001/jamaneurol.2018.1487.
  • Li X, Koudstaal W, Fletcher L, et al. Naturally occurring antibodies isolated from PD patients inhibit synuclein seeding in vitro and recognize Lewy pathology. Acta Neuropathol. 2019;137(5):825–836. doi:10.1007/s00401-019-01974-5.

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