Advertisement

Acta Neuropathologica

, Volume 133, Issue 1, pp 43–60 | Cite as

Peripheral VH4+ plasmablasts demonstrate autoreactive B cell expansion toward brain antigens in early multiple sclerosis patients

  • Jacqueline R. Rivas
  • Sara J. Ireland
  • Rati Chkheidze
  • William H. Rounds
  • Joseph Lim
  • Jordan Johnson
  • Denise M. O. Ramirez
  • Ann J. Ligocki
  • Ding Chen
  • Alyssa A. Guzman
  • Mark Woodhall
  • Patrick C. Wilson
  • Eric Meffre
  • Charles WhiteIII
  • Benjamin M. Greenberg
  • Patrick Waters
  • Lindsay G. Cowell
  • Ann M. Stowe
  • Nancy L. Monson
Original Paper

Abstract

Plasmablasts are a highly differentiated, antibody secreting B cell subset whose prevalence correlates with disease activity in Multiple Sclerosis (MS). For most patients experiencing partial transverse myelitis (PTM), plasmablasts are elevated in the blood at the first clinical presentation of disease (known as a clinically isolated syndrome or CIS). In this study we found that many of these peripheral plasmablasts are autoreactive and recognize primarily gray matter targets in brain tissue. These plasmablasts express antibodies that over-utilize immunoglobulin heavy chain V-region subgroup 4 (VH4) genes, and the highly mutated VH4+ plasmablast antibodies recognize intracellular antigens of neurons and astrocytes. Most of the autoreactive, highly mutated VH4+ plasmablast antibodies recognize only a portion of cortical neurons, indicating that the response may be specific to neuronal subgroups or layers. Furthermore, CIS-PTM patients with this plasmablast response also exhibit modest reactivity toward neuroantigens in the plasma IgG antibody pool. Taken together, these data indicate that expanded VH4+ peripheral plasmablasts in early MS patients recognize brain gray matter antigens. Peripheral plasmablasts may be participating in the autoimmune response associated with MS, and provide an interesting avenue for investigating the expansion of autoreactive B cells at the time of the first documented clinical event.

Keywords

Plasmablast Multiple sclerosis Autoantibody B cell Antigen receptor genetics 

Notes

Acknowledgements

The authors would like to thank the patients and healthy donors who gave samples for this study. This project was funded by the UT Southwestern CONQUER program and a grant from the National MS Society. Angela Mobley assisted with flow cytometry and sorting and Genevieve Konopka provided the SH-Sy5y cells. Betty Diamond at the Hofstra Northwell School of Medicine Department of Molecular Medicine provided the lupus control antibodies. We also thank E. Sally Ward at Texas A&M University for helpful discussion of this manuscript.

Compliance with ethical standards

Conflict of interest

Nancy Monson reports patent US 8,394,583 B2 on MSPrecise™, a diagnostic tool for predicting conversion to MS.

Supplementary material

401_2016_1627_MOESM1_ESM.docx (35 kb)
Supplementary material 1 (DOCX 34 kb)
401_2016_1627_MOESM2_ESM.pdf (42.8 mb)
Supplementary material 2 (PDF 43866 kb)
401_2016_1627_MOESM3_ESM.pptx (93 kb)
Supplementary material 3 (PPTX 92 kb)
401_2016_1627_MOESM4_ESM.docx (33 kb)
Supplementary material 4 (DOCX 33 kb)

References

  1. 1.
    Adlowitz DG, Barnard J, Biear JN, Cistrone C, Owen T, Wang W, Palanichamy A, Ezealah E, Campbell D, Wei C et al (2015) Expansion of activated peripheral blood memory B cells in rheumatoid arthritis, impact of b cell depletion therapy, and biomarkers of response. PLoS One 10(6):e0128269PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Akbar AN, Henson SM (2011) Are senescence and exhaustion intertwined or unrelated processes that compromise immunity? Nat Rev Immunol 11(4):289–295PubMedCrossRefGoogle Scholar
  3. 3.
    Avery DT, Ellyard JI, Mackay F, Corcoran LM, Hodgkin PD, Tangye SG (2005) Increased expression of CD27 on activated human memory B cells correlates with their commitment to the plasma cell lineage. J Immunol 174(7):4034–4042PubMedCrossRefGoogle Scholar
  4. 4.
    Ayoglu B, Mitsios N, Kockum I, Khademi M, Zandian A, Sjoberg R, Forsstrom B, Bredenberg J, Lima Bomfim I, Holmgren E et al (2016) Anoctamin 2 identified as an autoimmune target in multiple sclerosis. Proc Natl Acad Sci USA 113(8):2188–2193PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Banki K, Colombo E, Sia F, Halladay D, Mattson DH, Tatum AH, Massa PT, Phillips PE, Perl A (1994) Oligodendrocyte-specific expression and autoantigenicity of transaldolase in multiple sclerosis. J Exp Med 180(5):1649–1663PubMedCrossRefGoogle Scholar
  6. 6.
    Bankoti J, Apeltsin L, Hauser SL, Allen S, Albertolle ME, Witkowska HE, von Budingen HC (2014) In multiple sclerosis, oligoclonal bands connect to peripheral B-cell responses. Ann Neurol 75(2):266–276PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Bar-Or A, Antel JP (2016) Central nervous system inflammation across the age span. Curr Opin Neurol 29(3):381–387Google Scholar
  8. 8.
    Beltran E, Obermeier B, Moser M, Coret F, Simo-Castello M, Bosca I, Perez-Miralles F, Villar LM, Senel M, Tumani H et al (2014) Intrathecal somatic hypermutation of IgM in multiple sclerosis and neuroinflammation. Brain 137(Pt 10):2703–2714PubMedCrossRefGoogle Scholar
  9. 9.
    Bennett JL, Haubold K, Ritchie AM, Edwards SJ, Burgoon M, Shearer AJ, Gilden DH, Owens GP (2008) CSF IgG heavy-chain bias in patients at the time of a clinically isolated syndrome. J Neuroimmunol 199(1–2):126–132PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Bennett JL, Lam C, Kalluri SR, Saikali P, Bautista K, Dupree C, Glogowska M, Case D, Antel JP, Owens GP et al (2009) Intrathecal pathogenic anti-aquaporin-4 antibodies in early neuromyelitis optica. Ann Neurol 66(5):617–629PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Bennett JL, O’Connor KC, Bar-Or A, Zamvil SS, Hemmer B, Tedder TF, von Budingen HC, Stuve O, Yeaman MR, Smith TJ et al (2015) B lymphocytes in neuromyelitis optica. Neurol Neuroimmunol Neuroinflamm 2(3):e104PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Blauth K, Soltys J, Matschulat A, Reiter CR, Ritchie A, Baird NL, Bennett JL, Owens GP (2015) Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid cause demyelination of spinal cord explants. Acta Neuropathol 130(6):765–781PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Brandle SM, Obermeier B, Senel M, Bruder J, Mentele R, Khademi M, Olsson T, Tumani H, Kristoferitsch W, Lottspeich F et al (2016) Distinct oligoclonal band antibodies in multiple sclerosis recognize ubiquitous self-proteins. Proc Natl Acad Sci USA 113(28):7864–7869PubMedCrossRefGoogle Scholar
  14. 14.
    Brezinschek HP, Foster SJ, Brezinschek RI, Dorner T, Domiati-Saad R, Lipsky PE (1997) Analysis of the human VH gene repertoire. Differential effects of selection and somatic hypermutation on human peripheral CD5(+)/IgM + and CD5(-)/IgM + B cells. J Clin Invest 99(10):2488–2501PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Bronstein JM, Lallone RL, Seitz RS, Ellison GW, Myers LW (1999) A humoral response to oligodendrocyte-specific protein in MS: a potential molecular mimic. Neurology 53(1):154–161PubMedCrossRefGoogle Scholar
  16. 16.
    Cameron EM, Spencer S, Lazarini J, Harp CT, Ward ES, Burgoon M, Owens GP, Racke MK, Bennett JL, Frohman EM et al (2009) Potential of a unique antibody gene signature to predict conversion to clinically definite multiple sclerosis. J Neuroimmunol 213(1–2):123–130PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Casellas R, Shih TA, Kleinewietfeld M, Rakonjac J, Nemazee D, Rajewsky K, Nussenzweig MC (2001) Contribution of receptor editing to the antibody repertoire. Science 291(5508):1541–1544PubMedCrossRefGoogle Scholar
  18. 18.
    Cepok S, Rosche B, Grummel V, Vogel F, Zhou D, Sayn J, Sommer N, Hartung HP, Hemmer B (2005) Short-lived plasma blasts are the main B cell effector subset during the course of multiple sclerosis. Brain 128(Pt 7):1667–1676PubMedCrossRefGoogle Scholar
  19. 19.
    Chang EH, Volpe BT, Mackay M, Aranow C, Watson P, Kowal C, Storbeck J, Mattis P, Berlin R, Chen H et al (2015) Selective impairment of spatial cognition caused by autoantibodies to the N-methyl-d-aspartate receptor. EBioMedicine 2(7):755–764PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Chihara N, Aranami T, Oki S, Matsuoka T, Nakamura M, Kishida H, Yokoyama K, Kuroiwa Y, Hattori N, Okamoto T et al (2013) Plasmablasts as migratory IgG-producing cells in the pathogenesis of neuromyelitis optica. PLoS One 8(12):e83036PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Colombo E, Banki K, Tatum AH, Daucher J, Ferrante P, Murray RS, Phillips PE, Perl A (1997) Comparative analysis of antibody and cell-mediated autoimmunity to transaldolase and myelin basic protein in patients with multiple sclerosis. J Clin Invest 99(6):1238–1250PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Colombo M, Dono M, Gazzola P, Chiorazzi N, Mancardi G, Ferrarini M (2003) Maintenance of B lymphocyte-related clones in the cerebrospinal fluid of multiple sclerosis patients. Eur J Immunol 33(12):3433–3438PubMedCrossRefGoogle Scholar
  23. 23.
    Colombo M, Dono M, Gazzola P, Roncella S, Valetto A, Chiorazzi N, Mancardi GL, Ferrarini M (2000) Accumulation of clonally related B lymphocytes in the cerebrospinal fluid of multiple sclerosis patients. J Immunol 164(5):2782–2789PubMedCrossRefGoogle Scholar
  24. 24.
    Cristofanilli M, Rosenthal H, Cymring B, Gratch D, Pagano B, Xie B, Sadiq SA (2014) Progressive multiple sclerosis cerebrospinal fluid induces inflammatory demyelination, axonal loss, and astrogliosis in mice. Exp Neurol 261:620–632Google Scholar
  25. 25.
    Cross AH, Waubant E (2011) MS and the B cell controversy. Biochim Biophys Acta 1812(2):231–238PubMedCrossRefGoogle Scholar
  26. 26.
    Disanto G, Morahan JM, Barnett MH, Giovannoni G, Ramagopalan SV (2012) The evidence for a role of B cells in multiple sclerosis. Neurology 78(11):823–832PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Eikelenboom MJ, Petzold A, Lazeron RH, Silber E, Sharief M, Thompson EJ, Barkhof F, Giovannoni G, Polman CH, Uitdehaag BM (2003) Multiple sclerosis: neurofilament light chain antibodies are correlated to cerebral atrophy. Neurology 60(2):219–223PubMedCrossRefGoogle Scholar
  28. 28.
    Elliott C, Lindner M, Arthur A, Brennan K, Jarius S, Hussey J, Chan A, Stroet A, Olsson T, Willison H et al (2012) Functional identification of pathogenic autoantibody responses in patients with multiple sclerosis. Brain 135(Pt 6):1819–1833PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Endo T, Scott DD, Stewart SS, Kundu SK, Marcus DM (1984) Antibodies to glycosphingolipids in patients with multiple sclerosis and SLE. J Immunol 132(4):1793–1797PubMedGoogle Scholar
  30. 30.
    Fairfax KA, Kallies A, Nutt SL, Tarlinton DM (2008) Plasma cell development: from B-cell subsets to long-term survival niches. Semin Immunol 20(1):49–58PubMedCrossRefGoogle Scholar
  31. 31.
    Fialova L, Bartos A, Svarcova J, Zimova D, Kotoucova J, Malbohan I (2013) Serum and cerebrospinal fluid light neurofilaments and antibodies against them in clinically isolated syndrome and multiple sclerosis. J Neuroimmunol 262(1–2):113–120PubMedCrossRefGoogle Scholar
  32. 32.
    Fink K (2012) Origin and function of circulating plasmablasts during acute viral infections. Front Immunol 3:78. doi: 10.3389/fimmu.2012.00078
  33. 33.
    Fraussen J, Claes N, de Bock L, Somers V (2014) Targets of the humoral autoimmune response in multiple sclerosis. Autoimmun Rev 13(11):1126–1137PubMedCrossRefGoogle Scholar
  34. 34.
    Frolich D, Giesecke C, Mei HE, Reiter K, Daridon C, Lipsky PE, Dorner T (2010) Secondary immunization generates clonally related antigen-specific plasma cells and memory B cells. J Immunol 185(5):3103–3110PubMedCrossRefGoogle Scholar
  35. 35.
    Gauld SB, Dal Porto JM, Cambier JC (2002) B cell antigen receptor signaling: roles in cell development and disease. Science 296(5573):1641–1642PubMedCrossRefGoogle Scholar
  36. 36.
    Siegel GJ, Agranoff BW, Albers RW, Fisher SK, Uhler MD (1999) Basic neurochemistry, molecular, cellular and medical aspects. Lippincott-Raven, PhiladelphiaGoogle Scholar
  37. 37.
    Harp C, Lee J, Lambracht-Washington D, Cameron E, Olsen G, Frohman E, Racke M, Monson N (2007) Cerebrospinal fluid B cells from multiple sclerosis patients are subject to normal germinal center selection. J Neuroimmunol 183(1–2):189–199PubMedCrossRefGoogle Scholar
  38. 38.
    Haubold K, Owens GP, Kaur P, Ritchie AM, Gilden DH, Bennett JL (2004) B-lymphocyte and plasma cell clonal expansion in monosymptomatic optic neuritis cerebrospinal fluid. Ann Neurol 56(1):97–107PubMedCrossRefGoogle Scholar
  39. 39.
    Hauser SL, Chan JR, Oksenberg JR (2013) Multiple sclerosis: prospects and promise. Ann Neurol 74(3):317–327PubMedCrossRefGoogle Scholar
  40. 40.
    Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, Bar-Or A, Panzara M, Sarkar N, Agarwal S et al (2008) B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 358(7):676–688PubMedCrossRefGoogle Scholar
  41. 41.
    Heine G, Drozdenko G, Grun JR, Chang HD, Radbruch A, Worm M (2014) Autocrine IL-10 promotes human B-cell differentiation into IgM- or IgG-secreting plasmablasts. Eur J Immunol 44(6):1615–1621PubMedCrossRefGoogle Scholar
  42. 42.
    Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A (2001) Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med 7(3):365–368PubMedCrossRefGoogle Scholar
  43. 43.
    Hohlfeld R, Dornmair K, Meinl E, Wekerle H (2016) 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 15(3):317–331PubMedCrossRefGoogle Scholar
  44. 44.
    Hohlfeld R, Dornmair K, Meinl E, Wekerle H (2015) The search for the target antigens of multiple sclerosis, part 1: autoreactive CD4+ T lymphocytes as pathogenic effectors and therapeutic targets. Lancet Neurol 15(2):198–209Google Scholar
  45. 45.
    Holman DW, Klein RS, Ransohoff RM (2011) The blood-brain barrier, chemokines and multiple sclerosis. Biochim Biophys Acta 1812(2):220–230PubMedCrossRefGoogle Scholar
  46. 46.
    Huerta PT, Kowal C, DeGiorgio LA, Volpe BT, Diamond B (2006) Immunity and behavior: antibodies alter emotion. Proc Natl Acad Sci USA 103(3):678–683PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Irani SR, Alexander S, Waters P, Kleopa KA, Pettingill P, Zuliani L, Peles E, Buckley C, Lang B, Vincent A (2010) Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis. Morvan’s syndrome and acquired neuromyotonia. Brain 133(9):2734–2748PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Jacobi AM, Mei H, Hoyer BF, Mumtaz IM, Thiele K, Radbruch A, Burmester GR, Hiepe F, Dorner T (2010) HLA-DRhigh/CD27high plasmablasts indicate active disease in patients with systemic lupus erythematosus. Ann Rheum Dis 69(1):305–308PubMedCrossRefGoogle Scholar
  49. 49.
    Jang JY, Jeong JG, Jun HR, Lee SC, Kim JS, Kim YS, Kwon MH (2009) A nucleic acid-hydrolyzing antibody penetrates into cells via caveolae-mediated endocytosis, localizes in the cytosol and exhibits cytotoxicity. Cell Mol Life Sci 66(11–12):1985–1997PubMedCrossRefGoogle Scholar
  50. 50.
    Kappos L, Li D, Calabresi PA, O’Connor P, Bar-Or A, Barkhof F, Yin M, Leppert D, Glanzman R, Tinbergen J et al (2011) Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet 378(9805):1779–1787PubMedCrossRefGoogle Scholar
  51. 51.
    Kinnunen T, Chamberlain N, Morbach H, Cantaert T, Lynch M, Preston-Hurlburt P, Herold KC, Hafler DA, Ock C, Meffre E (2013) Specific peripheral B cell tolerance defects in patients with multiple sclerosis. J Clin Invest 123(6):2737–2741Google Scholar
  52. 52.
    Kowal C, DeGiorgio LA, Nakaoka T, Hetherington H, Huerta PT, Diamond B, Volpe BT (2004) Cognition and immunity; antibody impairs memory. Immunity 21(2):179–188PubMedCrossRefGoogle Scholar
  53. 53.
    Kowarik MC, Dzieciatkowska M, Wemlinger S, Ritchie AM, Hemmer B, Owens GP, Bennett JL (2015) The cerebrospinal fluid immunoglobulin transcriptome and proteome in neuromyelitis optica reveals central nervous system-specific B cell populations. J Neuroinflammation 12(19):1–8Google Scholar
  54. 54.
    Krumbholz M, Derfuss T, Hohlfeld R, Meinl E (2012) B cells and antibodies in multiple sclerosis pathogenesis and therapy. Nat Rev Neurol 8(11):613–623PubMedCrossRefGoogle Scholar
  55. 55.
    Lee FE, Halliley JL, Walsh EE, Moscatiello AP, Kmush BL, Falsey AR, Randall TD, Kaminiski DA, Miller RK, Sanz I (2011) Circulating human antibody-secreting cells during vaccinations and respiratory viral infections are characterized by high specificity and lack of bystander effect. J Immunol 186(9):5514–5521PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Li Z, Woo CJ, Iglesias-Ussel MD, Ronai D, Scharff MD (2004) The generation of antibody diversity through somatic hypermutation and class switch recombination. Genes Dev 18(1):1–11PubMedCrossRefGoogle Scholar
  57. 57.
    Ligocki AJ, Rivas JR, Rounds WH, Guzman AA, Li M, Spadaro M, Lahey L, Chen D, Henson PM, Graves D et al (2015) A distinct class of antibodies may be an indicator of gray matter autoimmunity in early and established relapsing remitting multiple sclerosis patients. ASN Neuro 7(5):1–16Google Scholar
  58. 58.
    Ligocki AJ, Rounds WH, Cameron EM, Harp CT, Frohman EM, Courtney AM, Vernino S, Cowell LG, Greenberg B, Monson NL (2013) Expansion of CD27high plasmablasts in transverse myelitis patients that utilize VH4 and JH6 genes and undergo extensive somatic hypermutation. Genes Immun 14(5):291–301Google Scholar
  59. 59.
    Lim PL, Zouali M (2006) Pathogenic autoantibodies: emerging insights into tissue injury. Immunol Lett 103(1):17–26PubMedCrossRefGoogle Scholar
  60. 60.
    Lublin FD, Reingold SC, Cohen JA, Cutter GR, Sorensen PS, Thompson AJ, Wolinsky JS, Balcer LJ, Banwell B, Barkhof F et al (2014) Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology 83(3):278–286PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H (2000) Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 47(6):707–717PubMedCrossRefGoogle Scholar
  62. 62.
    Mathiesen T, von Holst H, Fredrikson S, Wirsen G, Hederstedt B, Norrby E, Sundqvist VA, Wahren B (1989) Total, anti-viral, and anti-myelin IgG subclass reactivity in inflammatory diseases of the central nervous system. J Neurol 236(4):238–242PubMedCrossRefGoogle Scholar
  63. 63.
    McCandless EE, Piccio L, Woerner BM, Schmidt RE, Rubin JB, Cross AH, Klein RS (2008) Pathological expression of CXCL12 at the blood-brain barrier correlates with severity of multiple sclerosis. Am J Pathol 172(3):799–808PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Meffre E, Casellas R, Nussenzweig MC (2000) Antibody regulation of B cell development. Nat Immunol 1(5):379–385PubMedCrossRefGoogle Scholar
  65. 65.
    Meffre E, Davis E, Schiff C, Cunningham-Rundles C, Ivashkiv LB, Staudt LM, Young JW, Nussenzweig MC (2000) Circulating human B cells that express surrogate light chains and edited receptors. Nat Immunol 1(3):207–213PubMedCrossRefGoogle Scholar
  66. 66.
    Minagar A, Alexander JS (2003) Blood-brain barrier disruption in multiple sclerosis. Mult Scler 9(6):540–549PubMedCrossRefGoogle Scholar
  67. 67.
    Monson NL, Brezinschek HP, Brezinschek RI, Mobley A, Vaughan GK, Frohman EM, Racke MK, Lipsky PE (2005) Receptor revision and atypical mutational characteristics in clonally expanded B cells from the cerebrospinal fluid of recently diagnosed multiple sclerosis patients. J Neuroimmunol 158(1–2):170–181PubMedCrossRefGoogle Scholar
  68. 68.
    Morris-Downes MM, McCormack K, Baker D, Sivaprasad D, Natkunarajah J, Amor S (2002) Encephalitogenic and immunogenic potential of myelin-associated glycoprotein (MAG), oligodendrocyte-specific glycoprotein (OSP) and 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase) in ABH and SJL mice. J Neuroimmunol 122(1–2):20–33PubMedCrossRefGoogle Scholar
  69. 69.
    Nutt SL, Hodgkin PD, Tarlinton DM, Corcoran LM (2015) The generation of antibody-secreting plasma cells. Nat Rev Immunol 15(3):160–171PubMedCrossRefGoogle Scholar
  70. 70.
    Odendahl M, Jacobi A, Hansen A, Feist E, Hiepe F, Burmester GR, Lipsky PE, Radbruch A, Dorner T (2000) Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus. J Immunol 165(10):5970–5979PubMedCrossRefGoogle Scholar
  71. 71.
    Omdal R, Brokstad K, Waterloo K, Koldingsnes W, Jonsson R, Mellgren SI (2005) Neuropsychiatric disturbances in SLE are associated with antibodies against NMDA receptors. Eur J Neurol 12(5):392–398PubMedCrossRefGoogle Scholar
  72. 72.
    Onoue H, Satoh JI, Ogawa M, Tabunoki H, Yamamura T (2007) Detection of anti-Nogo receptor autoantibody in the serum of multiple sclerosis and controls. Acta Neurol Scand 115(3):153–160PubMedCrossRefGoogle Scholar
  73. 73.
    Owens GP, Bennett JL, Lassmann H, O’Connor KC, Ritchie AM, Shearer A, Lam C, Yu X, Birlea M, DuPree C et al (2009) Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid. Ann Neurol 65(6):639–649PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Owens GP, Ritchie AM, Burgoon MP, Williamson RA, Corboy JR, Gilden DH (2003) Single-cell repertoire analysis demonstrates that clonal expansion is a prominent feature of the B cell response in multiple sclerosis cerebrospinal fluid. J Immunol 171(5):2725–2733PubMedCrossRefGoogle Scholar
  75. 75.
    Owens GP, Winges KM, Ritchie AM, Edwards S, Burgoon MP, Lehnhoff L, Nielsen K, Corboy J, Gilden DH, Bennett JL (2007) VH4 gene segments dominate the intrathecal humoral immune response in multiple sclerosis. J Immunol 179(9):6343–6351PubMedCrossRefGoogle Scholar
  76. 76.
    Palanichamy A, Apeltsin L, Kuo TC, Sirota M, Wang S, Pitts SJ, Sundar PD, Telman D, Zhao LZ, Derstine M et al (2014) Immunoglobulin class-switched B cells form an active immune axis between CNS and periphery in multiple sclerosis. Sci Transl Med 6(248):248ra106Google Scholar
  77. 77.
    Parratt JD, Prineas JW (2010) Neuromyelitis optica: a demyelinating disease characterized by acute destruction and regeneration of perivascular astrocytes. Mult Scler 16(10):1156–1172PubMedCrossRefGoogle Scholar
  78. 78.
    Qin Y, Duquette P, Zhang Y, Olek M, Da RR, Richardson J, Antel JP, Talbot P, Cashman NR, Tourtellotte WW et al (2003) Intrathecal B-cell clonal expansion, an early sign of humoral immunity, in the cerebrospinal fluid of patients with clinically isolated syndrome suggestive of multiple sclerosis. Lab Invest 83(7):1081–1088PubMedCrossRefGoogle Scholar
  79. 79.
    Qin Y, Duquette P, Zhang Y, Talbot P, Poole R, Antel J (1998) Clonal expansion and somatic hypermutation of V(H) genes of B cells from cerebrospinal fluid in multiple sclerosis. J Clin Invest 102(5):1045–1050PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Racanelli V, Prete M, Musaraj G, Dammacco F, Perosa F (2011) Autoantibodies to intracellular antigens: generation and pathogenetic role. Autoimmun Rev 10(8):503–508PubMedCrossRefGoogle Scholar
  81. 81.
    Ratts RB, Karandikar NJ, Hussain RZ, Choy J, Northrop SC, Lovett-Racke AE, Racke MK (2006) Phenotypic characterization of autoreactive T cells in multiple sclerosis. J Neuroimmunol 178(1–2):100–110PubMedCrossRefGoogle Scholar
  82. 82.
    Ritchie AM, Gilden DH, Williamson RA, Burgoon MP, Yu X, Helm K, Corboy JR, Owens GP (2004) Comparative analysis of the CD19 + and CD138 + cell antibody repertoires in the cerebrospinal fluid of patients with multiple sclerosis. J Immunol 173(1):649–656PubMedCrossRefGoogle Scholar
  83. 83.
    Rounds WH, Ligocki AJ, Levin MK, Greenberg BM, Bigwood DW, Eastman EM, Cowell LG, Monson NL (2014) The antibody genetics of multiple sclerosis: comparing next-generation sequencing to sanger sequencing. Front Neurol 5(166):1–8Google Scholar
  84. 84.
    Rounds WH, Salinas EA, Wilks TB 2nd, Levin MK, Ligocki AJ, Ionete C, Pardo CA, Vernino S, Greenberg BM, Bigwood DW et al (2015) MSPrecise: a molecular diagnostic test for multiple sclerosis using next generation sequencing. Gene 572(2):191–197PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Selvaraj UM, Ortega SB, Hu R, Gilchrist R, Kong X, Partin A, Plautz EJ, Klein RS, Gidday JM, Stowe AM (2016) Preconditioning-induced CXCL12 upregulation minimizes leukocyte infiltration after stroke in ischemia-tolerant mice. J Cereb Blood Flow Metab. doi: 10.1177/0271678X16639327
  86. 86.
    Silber E, Semra YK, Gregson NA, Sharief MK (2002) Patients with progressive multiple sclerosis have elevated antibodies to neurofilament subunit. Neurology 58(9):1372–1381PubMedCrossRefGoogle Scholar
  87. 87.
    Solomon DH, Kavanaugh AJ, Schur PH, American College of Rheumatology Ad Hoc Committee on Immunologic Testing G (2002) Evidence-based guidelines for the use of immunologic tests: antinuclear antibody testing. Arthritis Rheum 47(4):434–444Google Scholar
  88. 88.
    Song YC, Sun GH, Lee TP, Huang JC, Yu CL, Chen CH, Tang SJ, Sun KH (2008) Arginines in the CDR of anti-dsDNA autoantibodies facilitate cell internalization via electrostatic interactions. Eur J Immunol 38(11):3178–3190PubMedCrossRefGoogle Scholar
  89. 89.
    Srivastava R, Aslam M, Kalluri SR, Schirmer L, Buck D, Tackenberg B, Rothhammer V, Chan A, Gold R, Berthele A et al (2012) Potassium channel KIR4.1 as an immune target in multiple sclerosis. N Engl J Med 367(2):115–123PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Stevens A, Weller M, Wietholter H (1992) CSF and serum ganglioside antibody patterns in MS. Acta Neurol Scand 86(5):485–489PubMedCrossRefGoogle Scholar
  91. 91.
    Szmyrka-Kaczmarek M, Pokryszko-Dragan A, Pawlik B, Gruszka E, Korman L, Podemski R, Wiland P, Szechinski J (2012) Antinuclear and antiphospholipid antibodies in patients with multiple sclerosis. Lupus 21(4):412–420PubMedCrossRefGoogle Scholar
  92. 92.
    Tiller T, Meffre E, Yurasov S, Tsuiji M, Nussenzweig MC, Wardemann H (2008) Efficient generation of monoclonal antibodies from single human B cells by single cell RT-PCR and expression vector cloning. J Immunol Methods 329(1–2):112–124PubMedCrossRefGoogle Scholar
  93. 93.
    Trotter J (2005) NG2-positive cells in CNS function and the pathological role of antibodies against NG2 in demyelinating diseases. J Neurol Sci 233(1–2):37–42PubMedCrossRefGoogle Scholar
  94. 94.
    Vincent A, Buckley C, Schott JM, Baker I, Dewar BK, Detert N, Clover L, Parkinson A, Bien CG, Omer S et al (2004) Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis. Brain 127(Pt 3):701–712PubMedGoogle Scholar
  95. 95.
    von Budingen HC, Gulati M, Kuenzle S, Fischer K, Rupprecht TA, Goebels N (2010) Clonally expanded plasma cells in the cerebrospinal fluid of patients with central nervous system autoimmune demyelination produce “oligoclonal bands”. J Neuroimmunol 218(1–2):134–139CrossRefGoogle Scholar
  96. 96.
    von Budingen HC, Harrer MD, Kuenzle S, Meier M, Goebels N (2008) Clonally expanded plasma cells in the cerebrospinal fluid of MS patients produce myelin-specific antibodies. Eur J Immunol 38(7):2014–2023CrossRefGoogle Scholar
  97. 97.
    von Budingen HC, Kuo TC, Sirota M, van Belle CJ, Apeltsin L, Glanville J, Cree BA, Gourraud PA, Schwartzburg A, Huerta G et al (2012) B cell exchange across the blood-brain barrier in multiple sclerosis. J Clin Invest 122(12):4533–4543CrossRefGoogle Scholar
  98. 98.
    Vu T, Myers LW, Ellison GW, Mendoza F, Bronstein JM (2001) T-cell responses to oligodendrocyte-specific protein in multiple sclerosis. J Neurosci Res 66(3):506–509PubMedCrossRefGoogle Scholar
  99. 99.
    Waldman M, Madaio MP (2005) Pathogenic autoantibodies in lupus nephritis. Lupus 14(1):19–24PubMedCrossRefGoogle Scholar
  100. 100.
    Wang LD, Clark MR (2003) B-cell antigen-receptor signalling in lymphocyte development. Immunology 110(4):411–420PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Wardemann H, Yurasov S, Schaefer A, Young JW, Meffre E, Nussenzweig MC (2003) Predominant autoantibody production by early human B cell precursors. Science 301(5638):1374–1377PubMedCrossRefGoogle Scholar
  102. 102.
    Willis SN, Stathopoulos P, Chastre A, Compton SD, Hafler DA, O’Connor KC (2015) Investigating the antigen specificity of multiple sclerosis central nervous system-derived immunoglobulins. Front Immunol 6(600)Google Scholar
  103. 103.
    Winger RC, Zamvil SS (2016) Antibodies in multiple sclerosis oligoclonal bands target debris. Proc Natl Acad Sci USA 113(28):7696–7698PubMedCrossRefGoogle Scholar
  104. 104.
    Winges KM, Gilden DH, Bennett JL, Yu X, Ritchie AM, Owens GP (2007) Analysis of multiple sclerosis cerebrospinal fluid reveals a continuum of clonally related antibody-secreting cells that are predominantly plasma blasts. J Neuroimmunol 192(1–2):226–234PubMedCrossRefGoogle Scholar
  105. 105.
    Wrammert J, Koutsonanos D, Li GM, Edupuganti S, Sui J, Morrissey M, McCausland M, Skountzou I, Hornig M, Lipkin WI et al (2011) Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection. J Exp Med 208(1):181–193Google Scholar
  106. 106.
    Yanase K, Smith RM, Puccetti A, Jarett L, Madaio MP (1997) Receptor-mediated cellular entry of nuclear localizing anti-DNA antibodies via myosin 1. J Clin Invest 100(1):25–31PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Zar JH (2010) Biostatistical analysis. Prentice Hall Inc, Upper Saddle RiverGoogle Scholar
  108. 108.
    Zekeridou A, Lennon VA (2015) Aquaporin-4 autoimmunity. Neurol Neuroimmunol Neuroinflamm 2(4):e110PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Zhang J, Jacobi AM, Wang T, Berlin R, Volpe BT, Diamond B (2009) Polyreactive autoantibodies in systemic lupus erythematosus have pathogenic potential. J Autoimmun 33(3–4):270–274PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Jacqueline R. Rivas
    • 1
  • Sara J. Ireland
    • 1
  • Rati Chkheidze
    • 2
  • William H. Rounds
    • 1
  • Joseph Lim
    • 1
  • Jordan Johnson
    • 1
  • Denise M. O. Ramirez
    • 1
  • Ann J. Ligocki
    • 1
  • Ding Chen
    • 1
  • Alyssa A. Guzman
    • 1
  • Mark Woodhall
    • 3
  • Patrick C. Wilson
    • 4
  • Eric Meffre
    • 5
  • Charles WhiteIII
    • 2
  • Benjamin M. Greenberg
    • 1
  • Patrick Waters
    • 3
  • Lindsay G. Cowell
    • 6
  • Ann M. Stowe
    • 1
  • Nancy L. Monson
    • 1
    • 7
  1. 1.Department of Neurology and NeurotherapeuticsUT SouthwesternDallasUSA
  2. 2.Department of PathologyUT SouthwesternDallasUSA
  3. 3.Department of Clinical NeurosciencesUniversity of OxfordOxfordUK
  4. 4.Department of Biomedical SciencesUniversity of ChicagoChicagoUSA
  5. 5.Department of ImmunobiologyYale University School of MedicineNew HavenUSA
  6. 6.Department of Clinical ScienceUT SouthwesternDallasUSA
  7. 7.Department of ImmunologyUT SouthwesternDallasUSA

Personalised recommendations