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Open Access 01-12-2023 | Multiple Sclerosis | Research

Transcriptome alterations in peripheral blood B cells of patients with multiple sclerosis receiving immune reconstitution therapy

Authors: Michael Hecker, Brit Fitzner, Nina Boxberger, Elena Putscher, Robby Engelmann, Wendy Bergmann, Michael Müller, Isis Ludwig-Portugall, Margit Schwartz, Stefanie Meister, Ales Dudesek, Alexander Winkelmann, Dirk Koczan, Uwe Klaus Zettl

Published in: Journal of Neuroinflammation | Issue 1/2023

Abstract

Background

Multiple sclerosis (MS) is a chronic, inflammatory and neurodegenerative disease that leads to irreversible damage to the brain and spinal cord. The goal of so-called "immune reconstitution therapies" (IRTs) is to achieve long-term disease remission by eliminating a pathogenic immune repertoire through intense short-term immune cell depletion. B cells are major targets for effective immunotherapy in MS.

Objectives

The aim of this study was to analyze the gene expression pattern of B cells before and during IRT (i.e., before B-cell depletion and after B-cell repopulation) to better understand the therapeutic effects and to identify biomarker candidates of the clinical response to therapy.

Methods

B cells were obtained from blood samples of patients with relapsing–remitting MS (n = 50), patients with primary progressive MS (n = 13) as well as healthy controls (n = 28). The patients with relapsing MS received either monthly infusions of natalizumab (n = 29) or a pulsed IRT with alemtuzumab (n = 15) or cladribine (n = 6). B-cell subpopulation frequencies were determined by flow cytometry, and transcriptome profiling was performed using Clariom D arrays. Differentially expressed genes (DEGs) between the patient groups and controls were examined with regard to their functions and interactions. We also tested for differences in gene expression between patients with and without relapse following alemtuzumab administration.

Results

Patients treated with alemtuzumab or cladribine showed on average a > 20% lower proportion of memory B cells as compared to before IRT. This was paralleled by profound transcriptome shifts, with > 6000 significant DEGs after adjustment for multiple comparisons. The top DEGs were found to regulate apoptosis, cell adhesion and RNA processing, and the most highly connected nodes in the network of encoded proteins were ESR2, PHB and RC3H1. Higher mRNA levels of BCL2, IL13RA1 and SLC38A11 were seen in patients with relapse despite IRT, though these differences did not pass the false discovery rate correction.

Conclusions

We show that B cells circulating in the blood of patients with MS undergoing IRT present a distinct gene expression signature, and we delineated the associated biological processes and gene interactions. Moreover, we identified genes whose expression may be an indicator of relapse risk, but further studies are needed to verify their potential value as biomarkers.

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Filippi M, Bar-Or A, Piehl F, Preziosa P, Solari A, Vukusic S, Rocca MA. Multiple sclerosis. Nat Rev Dis Primers. 2018;4(1):43. https://doi.org/10.1038/s41572-018-0041-4.CrossRefPubMed

Walton C, King R, Rechtman L, Kaye W, Leray E, Marrie RA, Robertson N, La Rocca N, Uitdehaag B, van der Mei I, Wallin M, Helme A, Angood Napier C, Rijke N, Baneke P. Rising prevalence of multiple sclerosis worldwide: insights from the Atlas of MS, third edition. Mult Scler. 2020;26(14):1816–21. https://doi.org/10.1177/1352458520970841.CrossRefPubMedPubMedCentral

Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, Correale J, Fazekas F, Filippi M, Freedman MS, Fujihara K, Galetta SL, Hartung HP, Kappos L, Lublin FD, Marrie RA, Miller AE, Miller DH, Montalban X, Mowry EM, Sorensen PS, Tintoré M, Traboulsee AL, Trojano M, Uitdehaag BMJ, Vukusic S, Waubant E, Weinshenker BG, Reingold SC, Cohen JA. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17(2):162–73. https://doi.org/10.1016/S1474-4422(17)30470-2.CrossRefPubMed

Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sørensen PS, Thompson AJ, Wolinsky JS, Balcer LJ, Banwell B, Barkhof F, Bebo B Jr, Calabresi PA, Clanet M, Comi G, Fox RJ, Freedman MS, Goodman AD, Inglese M, Kappos L, Kieseier BC, Lincoln JA, Lubetzki C, Miller AE, Montalban X, O’Connor PW, Petkau J, Pozzilli C, Rudick RA, Sormani MP, Stüve O, Waubant E, Polman CH. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83(3):278–86. https://doi.org/10.1212/WNL.0000000000000560.CrossRefPubMedPubMedCentral

Olsson T, Barcellos LF, Alfredsson L. Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nat Rev Neurol. 2017;13(1):25–36. https://doi.org/10.1038/nrneurol.2016.187.CrossRefPubMed

Hecker M, Bühring J, Fitzner B, Rommer PS, Zettl UK. Genetic, environmental and lifestyle determinants of accelerated telomere attrition as contributors to risk and severity of multiple sclerosis. Biomolecules. 2021;11(10):1510. https://doi.org/10.3390/biom11101510.CrossRefPubMedPubMedCentral

McGinley MP, Goldschmidt CH, Rae-Grant AD. Diagnosis and treatment of multiple sclerosis: a review. JAMA. 2021;325(8):765–79. https://doi.org/10.1001/jama.2020.26858.CrossRefPubMed

Hauser SL, Cree BAC. Treatment of multiple sclerosis: a review. Am J Med. 2020;133(12):1380–1390.e2. https://doi.org/10.1016/j.amjmed.2020.05.049.CrossRefPubMedPubMedCentral

Rommer PS, Milo R, Han MH, Satyanarayan S, Sellner J, Hauer L, Illes Z, Warnke C, Laurent S, Weber MS, Zhang Y, Stuve O. Immunological aspects of approved MS therapeutics. Front Immunol. 2019;10:1564. https://doi.org/10.3389/fimmu.2019.01564.CrossRefPubMedPubMedCentral

10.

Sorensen PS, Sellebjerg F. Pulsed immune reconstitution therapy in multiple sclerosis. Ther Adv Neurol Disord. 2019;12:1756286419836913. https://doi.org/10.1177/1756286419836913.CrossRefPubMedPubMedCentral

11.

Lünemann JD, Ruck T, Muraro PA, Bar-Or A, Wiendl H. Immune reconstitution therapies: concepts for durable remission in multiple sclerosis. Nat Rev Neurol. 2020;16(1):56–62. https://doi.org/10.1038/s41582-019-0268-z.CrossRefPubMed

12.

Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ, Hartung HP, Havrdova E, Selmaj KW, Weiner HL, Miller T, Fisher E, Sandbrink R, Lake SL, Margolin DH, Oyuela P, Panzara MA, Compston DA, CARE-MS II investigators. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet. 2012;380(9856):1829–39. https://doi.org/10.1016/S0140-6736(12)61768-1.CrossRefPubMed

13.

Berger T, Elovaara I, Fredrikson S, McGuigan C, Moiola L, Myhr KM, Oreja-Guevara C, Stoliarov I, Zettl UK. Alemtuzumab use in clinical practice: recommendations from european multiple sclerosis experts. CNS Drugs. 2017;31(1):33–50. https://doi.org/10.1007/s40263-016-0394-8.CrossRefPubMed

14.

Ruck T, Bittner S, Wiendl H, Meuth SG. Alemtuzumab in multiple sclerosis: mechanism of action and beyond. Int J Mol Sci. 2015;16(7):16414–39. https://doi.org/10.3390/ijms160716414.CrossRefPubMedPubMedCentral

15.

Giovannoni G, Comi G, Cook S, Rammohan K, Rieckmann P, SoelbergSørensen P, Vermersch P, Chang P, Hamlett A, Musch B, Greenberg SJ, CLARITY Study Group. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010;362(5):416–26. https://doi.org/10.1056/NEJMoa0902533.CrossRefPubMed

16.

Wiendl H. Cladribine—an old newcomer for pulsed immune reconstitution in MS. Nat Rev Neurol. 2017;13(10):573–4. https://doi.org/10.1038/nrneurol.2017.119.CrossRefPubMed

17.

Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G, de Seze J, Giovannoni G, Hartung HP, Hemmer B, Lublin F, Rammohan KW, Selmaj K, Traboulsee A, Sauter A, Masterman D, Fontoura P, Belachew S, Garren H, Mairon N, Chin P, Wolinsky JS, ORATORIO Clinical Investigators. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2017;376(3):209–20. https://doi.org/10.1056/NEJMoa1606468.CrossRefPubMed

18.

Lamb YN. Ocrelizumab: a review in multiple sclerosis. Drugs. 2022;82(3):323–34. https://doi.org/10.1007/s40265-022-01672-9.CrossRefPubMedPubMedCentral

19.

Winkelmann A, Loebermann M, Reisinger EC, Hartung HP, Zettl UK. Disease-modifying therapies and infectious risks in multiple sclerosis. Nat Rev Neurol. 2016;12(4):217–33. https://doi.org/10.1038/nrneurol.2016.21.CrossRefPubMed

20.

Wiendl H, Gold R, Berger T, Derfuss T, Linker R, Mäurer M, Aktas O, Baum K, Berghoff M, Bittner S, Chan A, Czaplinski A, Deisenhammer F, Di Pauli F, Du Pasquier R, Enzinger C, Fertl E, Gass A, Gehring K, Gobbi C, Goebels N, Guger M, Haghikia A, Hartung HP, Heidenreich F, Hoffmann O, Kallmann B, Kleinschnitz C, Klotz L, Leussink VI, Leutmezer F, Limmroth V, Lünemann JD, Lutterotti A, Meuth SG, Meyding-Lamadé U, Platten M, Rieckmann P, Schmidt S, Tumani H, et al. Multiple sclerosis therapy consensus group (MSTCG): position statement on disease-modifying therapies for multiple sclerosis (white paper). Ther Adv Neurol Disord. 2021;14:17562864211039648. https://doi.org/10.1177/17562864211039648.CrossRefPubMedPubMedCentral

21.

Soldan SS, Lieberman PM. Epstein–Barr virus and multiple sclerosis. Nat Rev Microbiol. 2023;21(1):51–64. https://doi.org/10.1038/s41579-022-00770-5.CrossRefPubMed

22.

Bjornevik K, Cortese M, Healy BC, Kuhle J, Mina MJ, Leng Y, Elledge SJ, Niebuhr DW, Scher AI, Munger KL, Ascherio A. Longitudinal analysis reveals high prevalence of Epstein–Barr virus associated with multiple sclerosis. Science. 2022;375(6578):296–301. https://doi.org/10.1126/science.abj8222.CrossRefPubMed

23.

Abrahamyan S, Eberspächer B, Hoshi MM, Aly L, Luessi F, Groppa S, Klotz L, Meuth SG, Schroeder C, Grüter T, Tackenberg B, Paul F, Then-Bergh F, Kümpfel T, Weber F, Stangel M, Bayas A, Wildemann B, Heesen C, Zettl U, Warnke C, Antony G, Hessler N, Wiendl H, Bittner S, Hemmer B, Gold R, Salmen A, Ruprecht K, German Competence Network Multiple Sclerosis (KKNMS); Other members of the KKNMS that acted as collaborators in this study. Complete Epstein–Barr virus seropositivity in a large cohort of patients with early multiple sclerosis. J Neurol Neurosurg Psychiatry. 2020;91(7):681–6. https://doi.org/10.1136/jnnp-2020-322941.CrossRefPubMed

24.

Cencioni MT, Mattoscio M, Magliozzi R, Bar-Or A, Muraro PA. B cells in multiple sclerosis—from targeted depletion to immune reconstitution therapies. Nat Rev Neurol. 2021;17(7):399–414. https://doi.org/10.1038/s41582-021-00498-5.CrossRefPubMed

25.

Comi G, Bar-Or A, Lassmann H, Uccelli A, Hartung HP, Montalban X, Sørensen PS, Hohlfeld R, Hauser SL, Expert Panel of the 27th Annual Meeting of the European Charcot Foundation. Role of B cells in multiple sclerosis and related disorders. Ann Neurol. 2021;89(1):13–23. https://doi.org/10.1002/ana.25927.CrossRefPubMed

26.

Jelcic I, Al Nimer F, Wang J, Lentsch V, Planas R, Jelcic I, Madjovski A, Ruhrmann S, Faigle W, Frauenknecht K, Pinilla C, Santos R, Hammer C, Ortiz Y, Opitz L, Grönlund H, Rogler G, Boyman O, Reynolds R, Lutterotti A, Khademi M, Olsson T, Piehl F, Sospedra M, Martin R. Memory B cells activate brain-homing, autoreactive CD4⁺ T cells in multiple sclerosis. Cell. 2018;175(1):85–100.e23. https://doi.org/10.1016/j.cell.2018.08.011.CrossRefPubMedPubMedCentral

27.

Fraussen J, Claes N, Van Wijmeersch B, van Horssen J, Stinissen P, Hupperts R, Somers V. B cells of multiple sclerosis patients induce autoreactive proinflammatory T cell responses. Clin Immunol. 2016;173:124–32. https://doi.org/10.1016/j.clim.2016.10.001.CrossRefPubMed

28.

Guo MH, Sama P, LaBarre BA, Lokhande H, Balibalos J, Chu C, Du X, Kheradpour P, Kim CC, Oniskey T, Snyder T, Soghoian DZ, Weiner HL, Chitnis T, Patsopoulos NA. Dissection of multiple sclerosis genetics identifies B and CD4+ T cells as driver cell subsets. Genome Biol. 2022;23(1):127. https://doi.org/10.1186/s13059-022-02694-y.CrossRefPubMedPubMedCentral

29.

Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K. Memory B cells are major targets for effective immunotherapy in relapsing multiple sclerosis. EBioMedicine. 2017;16:41–50. https://doi.org/10.1016/j.ebiom.2017.01.042.CrossRefPubMedPubMedCentral

30.

Thompson SA, Jones JL, Cox AL, Compston DA, Coles AJ. B-cell reconstitution and BAFF after alemtuzumab (Campath-1H) treatment of multiple sclerosis. J Clin Immunol. 2010;30(1):99–105. https://doi.org/10.1007/s10875-009-9327-3.CrossRefPubMed

31.

Baker D, Herrod SS, Alvarez-Gonzalez C, Giovannoni G, Schmierer K. Interpreting lymphocyte reconstitution data from the pivotal Phase 3 trials of alemtuzumab. JAMA Neurol. 2017;74(8):961–9. https://doi.org/10.1001/jamaneurol.2017.0676.CrossRefPubMedPubMedCentral

32.

Rolfes L, Pfeuffer S, Huntemann N, Schmidt M, Su C, Skuljec J, Aslan D, Hackert J, Kleinschnitz K, Hagenacker T, Pawlitzki M, Ruck T, Kleinschnitz C, Meuth SG, Pul R. Immunological consequences of cladribine treatment in multiple sclerosis: a real-world study. Mult Scler Relat Disord. 2022;64: 103931. https://doi.org/10.1016/j.msard.2022.103931.CrossRefPubMed

33.

Moser T, Schwenker K, Seiberl M, Feige J, Akgün K, Haschke-Becher E, Ziemssen T, Sellner J. Long-term peripheral immune cell profiling reveals further targets of oral cladribine in MS. Ann Clin Transl Neurol. 2020;7(11):2199–212. https://doi.org/10.1002/acn3.51206.CrossRefPubMedPubMedCentral

34.

Baker D, Pryce G, Herrod SS, Schmierer K. Potential mechanisms of action related to the efficacy and safety of cladribine. Mult Scler Relat Disord. 2019;30:176–86. https://doi.org/10.1016/j.msard.2019.02.018.CrossRefPubMed

35.

Wiendl H, Schmierer K, Hodgkinson S, Derfuss T, Chan A, Sellebjerg F, Achiron A, Montalban X, Prat A, De Stefano N, Barkhof F, Leocani L, Vermersch P, Chudecka A, Mwape C, Holmberg KH, Boschert U, Roy S. Specific patterns of immune cell dynamics may explain the early onset and prolonged efficacy of cladribine tablets: a MAGNIFY-MS substudy. Neurol Neuroimmunol Neuroinflamm. 2023;10(1): e200048. https://doi.org/10.1212/NXI.0000000000200048.CrossRefPubMed

36.

Ceronie B, Jacobs BM, Baker D, Dubuisson N, Mao Z, Ammoscato F, Lock H, Longhurst HJ, Giovannoni G, Schmierer K. Cladribine treatment of multiple sclerosis is associated with depletion of memory B cells. J Neurol. 2018;265(5):1199–209. https://doi.org/10.1007/s00415-018-8830-y.CrossRefPubMedPubMedCentral

37.

Duddy M, Niino M, Adatia F, Hebert S, Freedman M, Atkins H, Kim HJ, Bar-Or A. Distinct effector cytokine profiles of memory and naive human B cell subsets and implication in multiple sclerosis. J Immunol. 2007;178(10):6092–9. https://doi.org/10.4049/jimmunol.178.10.6092.CrossRefPubMed

38.

Baker D, Herrod SS, Alvarez-Gonzalez C, Zalewski L, Albor C, Schmierer K. Both cladribine and alemtuzumab may effect MS via B-cell depletion. Neurol Neuroimmunol Neuroinflamm. 2017;4(4): e360. https://doi.org/10.1212/NXI.0000000000000360.CrossRefPubMedPubMedCentral

39.

Kousin-Ezewu O, Azzopardi L, Parker RA, Tuohy O, Compston A, Coles A, Jones J. Accelerated lymphocyte recovery after alemtuzumab does not predict multiple sclerosis activity. Neurology. 2014;82(24):2158–64. https://doi.org/10.1212/WNL.0000000000000520.CrossRefPubMedPubMedCentral

40.

Gilmore W, Lund BT, Li P, Levy AM, Kelland EE, Akbari O, Groshen S, Cen SY, Pelletier D, Weiner LP, Javed A, Dunn JE, Traboulsee AL. Repopulation of T, B, and NK cells following alemtuzumab treatment in relapsing-remitting multiple sclerosis. J Neuroinflamm. 2020;17(1):189. https://doi.org/10.1186/s12974-020-01847-9.CrossRef

41.

Wiendl H, Carraro M, Comi G, Izquierdo G, Kim HJ, Sharrack B, Tornatore C, Daizadeh N, Chung L, Jacobs AK, Hogan RJ, Wychowski LV, Van Wijmeersch B, CARE-MS I, CARE-MS II, and CAMMS03409 Investigators. Lymphocyte pharmacodynamics are not associated with autoimmunity or efficacy after alemtuzumab. Neurol Neuroimmunol Neuroinflamm. 2019;7(1): e635. https://doi.org/10.1212/NXI.0000000000000635.CrossRefPubMedPubMedCentral

42.

Hecker M, Fitzner B, Putscher E, Schwartz M, Winkelmann A, Meister S, Dudesek A, Koczan D, Lorenz P, Boxberger N, Zettl UK. Implication of genetic variants in primary microRNA processing sites in the risk of multiple sclerosis. EBioMedicine. 2022;80: 104052. https://doi.org/10.1016/j.ebiom.2022.104052.CrossRefPubMedPubMedCentral

43.

Putscher E, Hecker M, Fitzner B, Boxberger N, Schwartz M, Koczan D, Lorenz P, Zettl UK. Genetic risk variants for multiple sclerosis are linked to differences in alternative pre-mRNA splicing. Front Immunol. 2022;13: 931831. https://doi.org/10.3389/fimmu.2022.931831.CrossRefPubMedPubMedCentral

44.

Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33(11):1444–52. https://doi.org/10.1212/wnl.33.11.1444.CrossRefPubMed

45.

Cossarizza A, Chang HD, Radbruch A, Abrignani S, Addo R, Akdis M, Andrä I, Andreata F, Annunziato F, Arranz E, Bacher P, Bari S, Barnaba V, Barros-Martins J, Baumjohann D, Beccaria CG, Bernardo D, Boardman DA, Borger J, Böttcher C, Brockmann L, Burns M, Busch DH, Cameron G, Cammarata I, Cassotta A, Chang Y, Chirdo FG, Christakou E, Čičin-Šain L, Cook L, Corbett AJ, Cornelis R, Cosmi L, Davey MS, De Biasi S, De Simone G, Del Zotto G, Delacher M, Di Rosa F, et al. Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition). Eur J Immunol. 2021;51(12):2708–3145. https://doi.org/10.1002/eji.202170126.CrossRefPubMed

46.

Morbach H, Eichhorn EM, Liese JG, Girschick HJ. Reference values for B cell subpopulations from infancy to adulthood. Clin Exp Immunol. 2010;162(2):271–9. https://doi.org/10.1111/j.1365-2249.2010.04206.x.CrossRefPubMedPubMedCentral

47.

Thorarinsdottir K, Camponeschi A, Gjertsson I, Mårtensson IL. CD21 -/low B cells: a snapshot of a unique B cell subset in health and disease. Scand J Immunol. 2015;82(3):254–61. https://doi.org/10.1111/sji.12339.CrossRefPubMed

48.

Megyola C, Ye J, Bhaduri-McIntosh S. Identification of a sub-population of B cells that proliferates after infection with Epstein–Barr virus. Virol J. 2011;8:84. https://doi.org/10.1186/1743-422X-8-84.CrossRefPubMedPubMedCentral

49.

Monaco G, Chen H, Poidinger M, Chen J, de Magalhães JP, Larbi A. flowAI: automatic and interactive anomaly discerning tools for flow cytometry data. Bioinformatics. 2016;32(16):2473–80. https://doi.org/10.1093/bioinformatics/btw191.CrossRefPubMed

50.

Bretz F, Hothorn T, Westfall P. Multiple comparisons using R. Boca Raton (FL): CRC Press; 2010.

51.

Bates D, Mächler M, Bolker B, Walker S. Fitting linear mixed-effects models using lme4. J Stat Softw. 2015;67(1):1–48.CrossRef

52.

Fox J, Weisberg S. An R companion to applied regression. 3rd ed. Thousand Oaks (CA): SAGE Publications; 2018.

53.

Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Series B Stat Methodol. 1995;57(1):289–300.

54.

Monaco G, Lee B, Xu W, Mustafah S, Hwang YY, Carré C, Burdin N, Visan L, Ceccarelli M, Poidinger M, Zippelius A, de Magalhães JP, Larbi A. RNA-Seq signatures normalized by mRNA abundance allow absolute deconvolution of human immune cell types. Cell Rep. 2019;26(6):1627–1640.e7. https://doi.org/10.1016/j.celrep.2019.01.041.CrossRefPubMedPubMedCentral

55.

Falcon S, Gentleman R. Using GOstats to test gene lists for GO term association. Bioinformatics. 2007;23(2):257–8. https://doi.org/10.1093/bioinformatics/btl567.CrossRefPubMed

56.

Safran M, Rosen N, Twik M, BarShir R, Stein TI, Dahary D, Fishilevich S, Lancet D. The GeneCards Suite. In: Abugessaisa I, Kasukawa T (eds). Practical guide to life science databases. Springer, Singapore. 2021. https://doi.org/10.1007/978-981-16-5812-9_2.

57.

Franz M, Rodriguez H, Lopes C, Zuberi K, Montojo J, Bader GD, Morris Q. GeneMANIA update 2018. Nucleic Acids Res. 2018;46(W1):W60–4. https://doi.org/10.1093/nar/gky311.CrossRefPubMedPubMedCentral

58.

Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13(11):2498–504. https://doi.org/10.1101/gr.1239303.CrossRefPubMedPubMedCentral

59.

Sellner J, Rommer PS. Immunological consequences of “immune reconstitution therapy” in multiple sclerosis: a systematic review. Autoimmun Rev. 2020;19(4): 102492. https://doi.org/10.1016/j.autrev.2020.102492.CrossRefPubMed

60.

Kverneland AH, Streitz M, Geissler E, Hutchinson J, Vogt K, Boës D, Niemann N, Pedersen AE, Schlickeiser S, Sawitzki B. Age and gender leucocytes variances and references values generated using the standardized ONE-Study protocol. Cytometry A. 2016;89(6):543–64. https://doi.org/10.1002/cyto.a.22855.CrossRefPubMed

61.

Oras A, Quirant-Sanchez B, Popadic D, Thunberg S, Winqvist O, Heck S, Cwikowski M, Riemann D, Seliger B, Martinez Caceres E, Uibo R, Giese T. Comprehensive flow cytometric reference intervals of leukocyte subsets from six study centers across Europe. Clin Exp Immunol. 2020;202(3):363–78. https://doi.org/10.1111/cei.13491.CrossRefPubMedPubMedCentral

62.

Jalusic KO, Ellenberger D, Rommer P, Stahmann A, Zettl U, Berger K. Effect of applying inclusion and exclusion criteria of phase III clinical trials to multiple sclerosis patients in routine clinical care. Mult Scler. 2021;27(12):1852–63. https://doi.org/10.1177/1352458520985118.CrossRefPubMedPubMedCentral

63.

Samjoo IA, Worthington E, Drudge C, Zhao M, Cameron C, Häring DA, Stoneman D, Klotz L, Adlard N. Efficacy classification of modern therapies in multiple sclerosis. J Comp Eff Res. 2021;10(6):495–507. https://doi.org/10.2217/cer-2020-0267.CrossRefPubMed

64.

Ziemssen T, Bass AD, Berkovich R, Comi G, Eichau S, Hobart J, Hunter SF, LaGanke C, Limmroth V, Pelletier D, Pozzilli C, Schippling S, Sousa L, Traboulsee A, Uitdehaag BMJ, Van Wijmeersch B, Choudhry Z, Daizadeh N, Singer BA, CARE-MS I, CARE-MS II, CAMMS03409, and TOPAZ investigators. Efficacy and safety of alemtuzumab through 9 years of follow-up in patients with highly active disease: post hoc analysis of CARE-MS I and II patients in the TOPAZ extension study. CNS Drugs. 2020;34(9):973–88. https://doi.org/10.1007/s40263-020-00749-x.CrossRefPubMedPubMedCentral

65.

De Stefano N, Sormani MP, Giovannoni G, Rammohan K, Leist T, Coyle PK, Dangond F, Keller B, Alexandri N, Galazka A. Analysis of frequency and severity of relapses in multiple sclerosis patients treated with cladribine tablets or placebo: the CLARITY and CLARITY extension studies. Mult Scler. 2022;28(1):111–20. https://doi.org/10.1177/13524585211010294.CrossRefPubMed

66.

Planas R, Jelčić I, Schippling S, Martin R, Sospedra M. Natalizumab treatment perturbs memory- and marginal zone-like B-cell homing in secondary lymphoid organs in multiple sclerosis. Eur J Immunol. 2012;42(3):790–8. https://doi.org/10.1002/eji.201142108.CrossRefPubMed

67.

Traub JW, Pellkofer HL, Grondey K, Seeger I, Rowold C, Brück W, Husseini L, Häusser-Kinzel S, Weber MS. Natalizumab promotes activation and pro-inflammatory differentiation of peripheral B cells in multiple sclerosis patients. J Neuroinflamm. 2019;16(1):228. https://doi.org/10.1186/s12974-019-1593-2.CrossRef

68.

Cuculiza Henriksen A, Ammitzbøll C, Petersen ER, McWilliam O, Sellebjerg F, von Essen MR, Romme Christensen J. Natalizumab differentially affects plasmablasts and B cells in multiple sclerosis. Mult Scler Relat Disord. 2021;52: 102987. https://doi.org/10.1016/j.msard.2021.102987.CrossRefPubMed

69.

Gjertsson I, McGrath S, Grimstad K, Jonsson CA, Camponeschi A, Thorarinsdottir K, Mårtensson IL. A close-up on the expanding landscape of CD21-/low B cells in humans. Clin Exp Immunol. 2022;210(3):217–29. https://doi.org/10.1093/cei/uxac103.CrossRefPubMedPubMedCentral

70.

Bar-Or A, Li R. Cellular immunology of relapsing multiple sclerosis: interactions, checks, and balances. Lancet Neurol. 2021;20(6):470–83. https://doi.org/10.1016/S1474-4422(21)00063-6.CrossRefPubMed

71.

Xu W, Seok J, Mindrinos MN, Schweitzer AC, Jiang H, Wilhelmy J, Clark TA, Kapur K, Xing Y, Faham M, Storey JD, Moldawer LL, Maier RV, Tompkins RG, Wong WH, Davis RW, Xiao W, Inflammation and Host Response to Injury Large-Scale Collaborative Research Program. Human transcriptome array for high-throughput clinical studies. Proc Natl Acad Sci U S A. 2011;108(9):3707–12. https://doi.org/10.1073/pnas.1019753108.CrossRefPubMedPubMedCentral

72.

Nazarov PV, Muller A, Kaoma T, Nicot N, Maximo C, Birembaut P, Tran NL, Dittmar G, Vallar L. RNA sequencing and transcriptome arrays analyses show opposing results for alternative splicing in patient derived samples. BMC Genomics. 2017;18(1):443. https://doi.org/10.1186/s12864-017-3819-y.CrossRefPubMedPubMedCentral

73.

Erdei A, Kovács KG, Nagy-Baló Z, Lukácsi S, Mácsik-Valent B, Kurucz I, Bajtay Z. New aspects in the regulation of human B cell functions by complement receptors CR1, CR2, CR3 and CR4. Immunol Lett. 2021;237:42–57. https://doi.org/10.1016/j.imlet.2021.06.006.CrossRefPubMed

74.

Verbeek JS, Hirose S, Nishimura H. The complex association of FcγRIIb with autoimmune susceptibility. Front Immunol. 2019;10:2061. https://doi.org/10.3389/fimmu.2019.02061.CrossRefPubMedPubMedCentral

75.

Cotton RN, Wegrecki M, Cheng TY, Chen YL, Veerapen N, Le Nours J, Orgill DP, Pomahac B, Talbot SG, Willis R, Altman JD, de Jong A, Van Rhijn I, Clark RA, Besra GS, Ogg G, Rossjohn J, Moody DB. CD1a selectively captures endogenous cellular lipids that broadly block T cell response. J Exp Med. 2021;218(7): e20202699. https://doi.org/10.1084/jem.20202699.CrossRefPubMedPubMedCentral

76.

Lim TS, Goh JK, Mortellaro A, Lim CT, Hämmerling GJ, Ricciardi-Castagnoli P. CD80 and CD86 differentially regulate mechanical interactions of T-cells with antigen-presenting dendritic cells and B-cells. PLoS ONE. 2012;7(9): e45185. https://doi.org/10.1371/journal.pone.0045185.CrossRefPubMedPubMedCentral

77.

Marsh-Wakefield F, Juillard P, Ashhurst TM, Juillard A, Shinko D, Putri GH, Read MN, McGuire HM, Byrne SN, Hawke S, Grau GE. Peripheral B-cell dysregulation is associated with relapse after long-term quiescence in patients with multiple sclerosis. Immunol Cell Biol. 2022;100(6):453–67. https://doi.org/10.1111/imcb.12552.CrossRefPubMedPubMedCentral

78.

Walter MR. The molecular basis of IL-10 function: from receptor structure to the onset of signaling. Curr Top Microbiol Immunol. 2014;380:191–212. https://doi.org/10.1007/978-3-662-43492-5_9.CrossRefPubMedPubMedCentral

79.

Ghalamfarsa G, Mahmoudi M, Mohammadnia-Afrouzi M, Yazdani Y, Anvari E, Hadinia A, Ghanbari A, Setayesh M, Yousefi M, Jadidi-Niaragh F. IL-21 and IL-21 receptor in the immunopathogenesis of multiple sclerosis. J Immunotoxicol. 2016;13(3):274–85. https://doi.org/10.3109/1547691X.2015.1089343.CrossRefPubMed

80.

Jones JL, Phuah CL, Cox AL, Thompson SA, Ban M, Shawcross J, Walton A, Sawcer SJ, Compston A, Coles AJ. IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H). J Clin Invest. 2009;119(7):2052–61. https://doi.org/10.1172/JCI37878.CrossRefPubMedPubMedCentral

81.

Berchtold MW, Villalobo A. The many faces of calmodulin in cell proliferation, programmed cell death, autophagy, and cancer. Biochim Biophys Acta. 2014;1843(2):398–435. https://doi.org/10.1016/j.bbamcr.2013.10.021.CrossRefPubMed

82.

Yang Q, Tian S, Liu Z, Dong W. Knockdown of RIPK2 inhibits proliferation and migration, and induces apoptosis via the NF-κB signaling pathway in gastric cancer. Front Genet. 2021;12: 627464. https://doi.org/10.3389/fgene.2021.627464.CrossRefPubMedPubMedCentral

83.

Zhang M, Liu J, Li M, Zhang S, Lu Y, Liang Y, Zhao K, Li Y. Insulin-like growth factor 1/insulin-like growth factor 1 receptor signaling protects against cell apoptosis through the PI3K/AKT pathway in glioblastoma cells. Exp Ther Med. 2018;16(2):1477–82. https://doi.org/10.3892/etm.2018.6336.CrossRefPubMedPubMedCentral

84.

Zhang X, Yan C, Zhan X, Li L, Lei J, Shi Y. Structure of the human activated spliceosome in three conformational states. Cell Res. 2018;28(3):307–22. https://doi.org/10.1038/cr.2018.14.CrossRefPubMedPubMedCentral

85.

Goldfarb KC, Cech TR. Targeted CRISPR disruption reveals a role for RNase MRP RNA in human preribosomal RNA processing. Genes Dev. 2017;31(1):59–71. https://doi.org/10.1101/gad.286963.116.CrossRefPubMedPubMedCentral

86.

Jarrous N, Mani D, Ramanathan A. Coordination of transcription and processing of tRNA. FEBS J. 2022;289(13):3630–41. https://doi.org/10.1111/febs.15904.CrossRefPubMed

87.

Bratkovič T, Božič J, Rogelj B. Functional diversity of small nucleolar RNAs. Nucleic Acids Res. 2020;48(4):1627–51. https://doi.org/10.1093/nar/gkz1140.CrossRefPubMed

88.

Pancho A, Aerts T, Mitsogiannis MD, Seuntjens E. Protocadherins at the crossroad of signaling pathways. Front Mol Neurosci. 2020;13:117. https://doi.org/10.3389/fnmol.2020.00117.CrossRefPubMedPubMedCentral

89.

Tamura N, Ohno K, Katayama T, Kanayama N, Sato K. The PDZ-LIM protein CLP36 is required for actin stress fiber formation and focal adhesion assembly in BeWo cells. Biochem Biophys Res Commun. 2007;364(3):589–94. https://doi.org/10.1016/j.bbrc.2007.10.064.CrossRefPubMed

90.

Fearnley GW, Young KA, Edgar JR, Antrobus R, Hay IM, Liang WC, Martinez-Martin N, Lin W, Deane JE, Sharpe HJ. The homophilic receptor PTPRK selectively dephosphorylates multiple junctional regulators to promote cell-cell adhesion. Elife. 2019;8: e44597. https://doi.org/10.7554/eLife.44597.CrossRefPubMedPubMedCentral

91.

Mal R, Magner A, David J, Datta J, Vallabhaneni M, Kassem M, Manouchehri J, Willingham N, Stover D, Vandeusen J, Sardesai S, Williams N, Wesolowski R, Lustberg M, Ganju RK, Ramaswamy B, Cherian MA. Estrogen receptor beta (ERβ): a ligand activated tumor suppressor. Front Oncol. 2020;10: 587386. https://doi.org/10.3389/fonc.2020.587386.CrossRefPubMedPubMedCentral

92.

Mishra S, Murphy LC, Murphy LJ. The Prohibitins: emerging roles in diverse functions. J Cell Mol Med. 2006;10(2):353–63. https://doi.org/10.1111/j.1582-4934.2006.tb00404.x.CrossRefPubMed

93.

Lucas CR, Cordero-Nieves HM, Erbe RS, McAlees JW, Bhatia S, Hodes RJ, Campbell KS, Sanders VM. Prohibitins and the cytoplasmic domain of CD86 cooperate to mediate CD86 signaling in B lymphocytes. J Immunol. 2013;190(2):723–36. https://doi.org/10.4049/jimmunol.1201646.CrossRefPubMed

94.

Jiang T, Wang J, Li C, Cao G, Wang X. Prohibitins: a key link between mitochondria and nervous system diseases. Oxid Med Cell Longev. 2022;2022:7494863. https://doi.org/10.1155/2022/7494863.CrossRefPubMedPubMedCentral

95.

Tan D, Zhou M, Kiledjian M, Tong L. The ROQ domain of Roquin recognizes mRNA constitutive-decay element and double-stranded RNA. Nat Struct Mol Biol. 2014;21(8):679–85. https://doi.org/10.1038/nsmb.2857.CrossRefPubMedPubMedCentral

96.

Srivastava M, Duan G, Kershaw NJ, Athanasopoulos V, Yeo JH, Ose T, Hu D, Brown SH, Jergic S, Patel HR, Pratama A, Richards S, Verma A, Jones EY, Heissmeyer V, Preiss T, Dixon NE, Chong MM, Babon JJ, Vinuesa CG. Roquin binds microRNA-146a and Argonaute2 to regulate microRNA homeostasis. Nat Commun. 2015;6:6253. https://doi.org/10.1038/ncomms7253.CrossRefPubMed

97.

Moser T, Hoepner L, Schwenker K, Seiberl M, Feige J, Akgün K, Haschke-Becher E, Ziemssen T, Sellner J. Cladribine alters immune cell surface molecules for adhesion and costimulation: further insights to the mode of action in multiple sclerosis. Cells. 2021;10(11):3116. https://doi.org/10.3390/cells10113116.CrossRefPubMedPubMedCentral

98.

Green DR. The mitochondrial pathway of apoptosis part II: The BCL-2 protein family. Cold Spring Harb Perspect Biol. 2022;14(6): a041046. https://doi.org/10.1101/cshperspect.a041046.CrossRefPubMed

99.

Tischner D, Woess C, Ottina E, Villunger A. Bcl-2-regulated cell death signalling in the prevention of autoimmunity. Cell Death Dis. 2010;1(6): e48. https://doi.org/10.1038/cddis.2010.27.CrossRefPubMedPubMedCentral

100.

Bardwell PD, Gu J, McCarthy D, Wallace C, Bryant S, Goess C, Mathieu S, Grinnell C, Erickson J, Rosenberg SH, Schwartz AJ, Hugunin M, Tarcsa E, Elmore SW, McRae B, Murtaza A, Wang LC, Ghayur T. The Bcl-2 family antagonist ABT-737 significantly inhibits multiple animal models of autoimmunity. J Immunol. 2009;182(12):7482–9. https://doi.org/10.4049/jimmunol.0802813.CrossRefPubMed

101.

Junttila IS. Tuning the cytokine responses: an update on interleukin (IL)-4 and IL-13 receptor complexes. Front Immunol. 2018;9:888. https://doi.org/10.3389/fimmu.2018.00888.CrossRefPubMedPubMedCentral

102.

Ochi H, Osoegawa M, Wu XM, Minohara M, Horiuchi I, Murai H, Furuya H, Kira J. Increased IL-13 but not IL-5 production by CD4-positive T cells and CD8-positive T cells in multiple sclerosis during relapse phase. J Neurol Sci. 2002;201(1–2):45–51. https://doi.org/10.1016/s0022-510x(02)00189-2.CrossRefPubMed

103.

Ghezzi L, Cantoni C, Cignarella F, Bollman B, Cross AH, Salter A, Galimberti D, Cella M, Piccio L. T cells producing GM-CSF and IL-13 are enriched in the cerebrospinal fluid of relapsing MS patients. Mult Scler. 2020;26(10):1172–86. https://doi.org/10.1177/1352458519852092.CrossRefPubMed

104.

Bröer S. The SLC38 family of sodium-amino acid co-transporters. Pflugers Arch. 2014;466(1):155–72. https://doi.org/10.1007/s00424-013-1393-y.CrossRefPubMed

105.

Aggarwal T, Patil S, Ceder M, Hayder M, Fredriksson R. Knockdown of SLC38 transporter ortholog—CG13743 reveals a metabolic relevance in drosophila. Front Physiol. 2020;10:1592. https://doi.org/10.3389/fphys.2019.01592.CrossRefPubMedPubMedCentral

106.

Pfeuffer S, Ruck T, Pul R, Rolfes L, Korsukewitz C, Pawlitzki M, Wildemann B, Klotz L, Kleinschnitz C, Scalfari A, Wiendl H, Meuth SG. Impact of previous disease-modifying treatment on effectiveness and safety outcomes, among patients with multiple sclerosis treated with alemtuzumab. J Neurol Neurosurg Psychiatry. 2021;92(9):1007–13. https://doi.org/10.1136/jnnp-2020-325304.CrossRefPubMed

107.

Lee J, Hyeon DY, Hwang D. Single-cell multiomics: technologies and data analysis methods. Exp Mol Med. 2020;52(9):1428–42. https://doi.org/10.1038/s12276-020-0420-2.CrossRefPubMedPubMedCentral

108.

Ruck T, Barman S, Schulte-Mecklenbeck A, Pfeuffer S, Steffen F, Nelke C, Schroeter CB, Willison A, Heming M, Müntefering T, Melzer N, Krämer J, Lindner M, Riepenhausen M, Gross CC, Klotz L, Bittner S, Muraro PA, Schneider-Hohendorf T, Schwab N, Meyer Zu Hörste G, Goebels N, Meuth SG, Wiendl H. Alemtuzumab-induced immune phenotype and repertoire changes: implications for secondary autoimmunity. Brain. 2022;145(5):1711–25. https://doi.org/10.1093/brain/awac064.CrossRefPubMedPubMedCentral

109.

Ruschil C, Gabernet G, Kemmerer CL, Jarboui MA, Klose F, Poli S, Ziemann U, Nahnsen S, Kowarik MC. Cladribine treatment specifically affects peripheral blood memory B cell clones and clonal expansion in multiple sclerosis patients. Front Immunol. 2023;14:1133967. https://doi.org/10.3389/fimmu.2023.1133967.CrossRefPubMedPubMedCentral

Title: Transcriptome alterations in peripheral blood B cells of patients with multiple sclerosis receiving immune reconstitution therapy
Authors: Michael Hecker
Brit Fitzner
Nina Boxberger
Elena Putscher
Robby Engelmann
Wendy Bergmann
Michael Müller
Isis Ludwig-Portugall
Margit Schwartz
Stefanie Meister
Ales Dudesek
Alexander Winkelmann
Dirk Koczan
Uwe Klaus Zettl
Publication date: 01-12-2023
Publisher: BioMed Central
Keywords: Multiple Sclerosis
Alemtuzumab
Cladribine
Natalizumab
Alemtuzumab
Biomarkers
Published in: Journal of Neuroinflammation / Issue 1/2023
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-023-02859-x

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Transcriptome alterations in peripheral blood B cells of patients with multiple sclerosis receiving immune reconstitution therapy

Abstract

Background

Objectives

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Objectives

Methods

Results

Conclusions

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