Skip to main content
SpringerLink
Log in

Immunoglobulins in Cerebrospinal Fluid

  • Chapter
  • First Online:
Cerebrospinal Fluid in Clinical Neurology

Abstract

The assessment of intrathecally synthesised immunoglobulin is an important part of routine cerebrospinal fluid (CSF) analysis. Immunoglobulins can be detected in normal CSF and are derived from plasma. The appearance of immunoglobulins in normal CSF is readily explained by size-dependent diffusion across blood-CSF barriers, and their concentrations increase with the general increase in CSF protein concentrations observed in a wide range of neurological diseases. Therefore, methods that take the normal diffusion of immunoglobulins into account are needed for quantitative assessment of intrathecal immunoglobulin synthesis. Intrathecally synthesised immunoglobulins are usually of restricted clonality, and electrophoresis-based methods can be used for detecting this in the form of oligoclonal bands. These methods depend on comparing paired CSF and blood samples. Qualitative analyses for the assessment of intrathecally synthesised oligoclonal bands are more technically demanding, but are more sensitive for the detection of intrathecal immunoglobulin synthesis, and are less susceptible to artefacts induced by blood-CSF barrier disturbances than quantitative methods. The same general principles apply both for the detection of total intrathecal immunoglobulin synthesis and for the detection of specific antibody responses in infectious or autoimmune conditions.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 139.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Andersson M, Varez-Cermeno J, Bernardi G et al (1994) Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report. J Neurol Neurosurg Psychiatry 57:897–902

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Beltran E, Obermeier B, Moser M et al (2014) Intrathecal somatic hypermutation of IgM in multiple sclerosis and neuroinflammation. Brain 137:2703–2714

    Google Scholar 

  • Berland R, Wortis HH (2002) Origins and functions of B-1 cells with notes on the role of CD5. Annu Rev Immunol 20:253–300

    Article  CAS  PubMed  Google Scholar 

  • Broz P, Monack DM (2013) Newly described pattern recognition receptors team up against intracellular pathogens. Nat Rev Immunol 13:551–565

    Article  CAS  PubMed  Google Scholar 

  • Carson MJ, Doose JM, Melchior B et al (2006) CNS immune privilege: hiding in plain sight. Immunol Rev 213:48–65

    Article  PubMed Central  PubMed  Google Scholar 

  • Cazac BB, Roes J (2000) TGF-beta receptor controls B cell responsiveness and induction of IgA in vivo. Immunity 13:443–451

    Article  CAS  PubMed  Google Scholar 

  • Chen K, Xu W, Wilson M et al (2009) Immunoglobulin D enhances immune surveillance by activating antimicrobial, proinflammatory and B cell-stimulating programs in basophils. Nat Immunol 10:889–898

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Crotty S (2011) Follicular helper CD4 T cells (TFH). Annu Rev Immunol 29:621–663

    Article  CAS  PubMed  Google Scholar 

  • Deisenhammer F, Bartos A, Egg R et al (2006) Guidelines on routine cerebrospinal fluid analysis. Report from an EFNS task force. Eur J Neurol 13:913–922

    Article  CAS  PubMed  Google Scholar 

  • Delacroix DL, Dive C, Rambaud JC et al (1982) IgA subclasses in various secretions and in serum. Immunology 47:383–385

    CAS  PubMed Central  PubMed  Google Scholar 

  • Delpech B, Lichtblau E (1972) Immunochemical estimation of IgG and albumin in cerebrospinal fluid. Clin Chim Acta 37:15–23

    Article  CAS  PubMed  Google Scholar 

  • Dorta-Contreras AJ, Noris-Garcia E, Escobar-Perez X et al (2005) IgG1, IgG2 and IgE intrathecal synthesis in Angiostrongylus cantonensis meningoencephalitis. J Neurol Sci 238:65–70

    Article  CAS  PubMed  Google Scholar 

  • Fagarasan S, Kawamoto S, Kanagawa O et al (2010) Adaptive immune regulation in the gut: T cell-dependent and T cell-independent IgA synthesis. Annu Rev Immunol 28:243–273

    Article  CAS  PubMed  Google Scholar 

  • Felgenhauer K, Reiber H (1992) The diagnostic significance of antibody specificity indices in multiple sclerosis and herpes virus induced diseases of the nervous system. Clin Investig 70:28–37

    Article  CAS  PubMed  Google Scholar 

  • Felgenhauer K, Renner E (1977) Hydrodynamic radii versus molecular weights in clearance studies of urine and cerebrospinal fluid. Ann Clin Biochem 14:100–104

    Article  CAS  PubMed  Google Scholar 

  • Felgenhauer K, Schadlich HJ (1987) The compartmental IgM and IgA response within the central nervous system. J Neurol Sci 77:125–135

    Article  CAS  PubMed  Google Scholar 

  • Felgenhauer K, Schliep G, Rapic N (1976) Evaluation of the blood-CSF barrier by protein gradients and the humoral immune response within the central nervous system. J Neurol Sci 30:113–128

    Article  CAS  PubMed  Google Scholar 

  • Freedman MS, Thompson EJ, Deisenhammer F et al (2005) Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: a consensus statement. Arch Neurol 62:865–870

    Article  PubMed  Google Scholar 

  • Ganrot K, Laurell CB (1974) Measurement of IgG and albumin content of cerebrospinal fluid, and its interpretation. Clin Chem 20:571–573

    CAS  PubMed  Google Scholar 

  • Gonzalez SF, Degn SE, Pitcher LA et al (2011) Trafficking of B cell antigen in lymph nodes. Annu Rev Immunol 29:215–233

    Article  CAS  PubMed  Google Scholar 

  • Gordon LB, Knopf PM, Cserr HF (1992) Ovalbumin is more immunogenic when introduced into brain or cerebrospinal fluid than into extracerebral sites. J Neuroimmunol 40:81–87

    Article  CAS  PubMed  Google Scholar 

  • Greve B, Magnusson CG, Melms A et al (2001) Immunoglobulin isotypes reveal a predominant role of type 1 immunity in multiple sclerosis. J Neuroimmunol 121:120–125

    Article  CAS  PubMed  Google Scholar 

  • Harling-Berg C, Knopf PM, Merriam J et al (1989) Role of cervical lymph nodes in the systemic humoral immune response to human serum albumin microinfused into rat cerebrospinal fluid. J Neuroimmunol 25:185–193

    Article  CAS  PubMed  Google Scholar 

  • Harling-Berg CJ, Knopf PM, Cserr HF (1991) Myelin basic protein infused into cerebrospinal fluid suppresses experimental autoimmune encephalomyelitis. J Neuroimmunol 35:45–51

    Article  CAS  PubMed  Google Scholar 

  • Harwood NE, Batista FD (2010) Early events in B cell activation. Annu Rev Immunol 28:185–210

    Article  CAS  PubMed  Google Scholar 

  • Heyzer-Williams LJ, Heyzer-Williams MG (2005) Antigen-specific memory B cell development. Annu Rev Immunol 23:487–513

    Article  Google Scholar 

  • Holmgren J, Czerkinsky C (2005) Mucosal immunity and vaccines. Nat Med 11:S45–S53

    Article  CAS  PubMed  Google Scholar 

  • Keir G, Luxton RW, Thompson EJ (1990) Isoelectric focusing of cerebrospinal fluid immunoglobulin G: an annotated update. Ann Clin Biochem 27(Pt 5):436–443

    Article  CAS  PubMed  Google Scholar 

  • Knopf PM, Cserr HF, Nolan SC et al (1995) Physiology and immunology of lymphatic drainage of interstitial and cerebrospinal fluid from the brain. Neuropathol Appl Neurobiol 21:175–180

    Article  CAS  PubMed  Google Scholar 

  • Kostulas VK, Link H, Lefvert AK (1987) Oligoclonal IgG bands in cerebrospinal fluid. Principles for demonstration and interpretation based on findings in 1114 neurological patients. Arch Neurol 44:1041–1044

    Article  CAS  PubMed  Google Scholar 

  • Kurosaki T, Shinohara H, Baba Y (2010) B cell signaling and fate decision. Annu Rev Immunol 28:21–55

    Article  CAS  PubMed  Google Scholar 

  • Link H, Tibbling G (1977) Principles of albumin and IgG analyses in neurological disorders. III. Evaluation of IgG synthesis within the central nervous system in multiple sclerosis. Scand J Clin Lab Invest 37:397–401

    Article  CAS  PubMed  Google Scholar 

  • Lolli F, Halawa I, Link H (1989) Intrathecal synthesis of IgG, IgA, IgM and IgD in untreated multiple sclerosis and controls. Acta Neurol Scand 80:238–247

    Article  CAS  PubMed  Google Scholar 

  • Luxton RW, Thompson EJ (1990) Affinity distributions of antigen-specific IgG in patients with multiple sclerosis and in patients with viral encephalitis. J Immunol Methods 131:277–282

    Article  CAS  PubMed  Google Scholar 

  • Luxton RW, Zeman A, Holzel H et al (1995) Affinity of antigen-specific IgG distinguishes multiple sclerosis from encephalitis. J Neurol Sci 132:11–19

    Article  CAS  PubMed  Google Scholar 

  • Mavra M, Luxton R, Keir G et al (1992) Oligoclonal immunoglobulin D in the cerebrospinal fluid of neurologic patients. Neurology 42:1244–1245

    Article  CAS  PubMed  Google Scholar 

  • Mavra M, Drulovic J, Levic Z et al (1999) CNS tumours: oligoclonal immunoglobulin D in cerebrospinal fluid and serum. Acta Neurol Scand 100:117–118

    Article  CAS  PubMed  Google Scholar 

  • McLean BN, Luxton RW, Thompson EJ (1990) A study of immunoglobulin G in the cerebrospinal fluid of 1007 patients with suspected neurological disease using isoelectric focusing and the Log IgG-Index. A comparison and diagnostic applications. Brain 113(Pt 5):1269–1289

    Article  PubMed  Google Scholar 

  • Mebius RE, Kraal G (2005) Structure and function of the spleen. Nat Rev Immunol 5:606–616

    Article  CAS  PubMed  Google Scholar 

  • Miller JF, De Burgh PM, Grant GA (1965) Thymus and the production of antibody-plaque-forming cells. Nature 208:1332–1334

    Article  CAS  PubMed  Google Scholar 

  • Neefjes J, Jongsma ML, Paul P et al (2011) Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nat Rev Immunol 11:823–836

    CAS  PubMed  Google Scholar 

  • Nutt SL, Tarlinton DM (2011) Germinal center B and follicular helper T cells: siblings, cousins or just good friends? Nat Immunol 12:472–477

    Article  CAS  PubMed  Google Scholar 

  • Obermeier B, Mentele R, Malotka J et al (2008) Matching of oligoclonal immunoglobulin transcriptomes and proteomes of cerebrospinal fluid in multiple sclerosis. Nat Med 14:688–693

    Article  CAS  PubMed  Google Scholar 

  • Obermeier B, Lovato L, Mentele R et al (2011) Related B cell clones that populate the CSF and CNS of patients with multiple sclerosis produce CSF immunoglobulin. J Neuroimmunol 233:245–248

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Öhman S (1994) Points of view concerning the diffusion theory for blood-CSF barrier function and dysfunction. J Neurol Sci 126:240–245

    Article  PubMed  Google Scholar 

  • Öhman S, Forsberg P, Nelson N et al (1989) An improved formula for the judgement of intrathecally produced IgG in the presence of blood brain barrier damage. Clin Chim Acta 181:265–272

    Article  PubMed  Google Scholar 

  • Öhman S, Ernerudh J, Forsberg P et al (1992) Comparison of seven formulae and isoelectrofocusing for determination of intrathecally produced IgG in neurological diseases. Ann Clin Biochem 29(Pt 4):405–410

    Article  PubMed  Google Scholar 

  • Öhman S, Ernerudh J, Forsberg P et al (1993) Improved formulae for the judgement of intrathecally produced IgA and IgM in the presence of blood CSF barrier damage. Ann Clin Biochem 30(Pt 5):454–462

    Article  PubMed  Google Scholar 

  • Öhman S, Ernerudh J, Roberg M et al (1995) Determination of total and herpes simplex virus specific monomeric and dimeric IgA in serum and cerebrospinal fluid by ultracentrifugation. Ann Clin Biochem 32(Pt 6):550–556

    Article  PubMed  Google Scholar 

  • Padilla-Docal B, Dorta-Contreras AJ, Bu-Coifiu-Fanego R et al (2008) Intrathecal synthesis of IgE in children with eosinophilic meningoencephalitis caused by Angiostrongylus cantonensis. Cerebrospinal Fluid Res 5:18

    Article  PubMed Central  PubMed  Google Scholar 

  • Palanichamy A, Apeltsin L, Kuo TC et al (2014) Immunoglobulin class-switched B cells form an active immune axis between CNS and periphery in multiple sclerosis. Sci Transl Med 6:248ra106

    Article  PubMed  Google Scholar 

  • Paul WE (2008) Fundamental immunology. Lippincott, Williams & Wilkins, Philadelphia

    Google Scholar 

  • Reiber H (1994) Flow rate of cerebrospinal fluid (CSF)–a concept common to normal blood-CSF barrier function and to dysfunction in neurological diseases. J Neurol Sci 122:189–203

    Article  CAS  PubMed  Google Scholar 

  • Sellebjerg F, Christiansen M, Rasmussen LS et al (1996) The cerebrospinal fluid in multiple sclerosis. Quantitative assessment of intrathecal immunoglobulin synthesis by empirical formulae. Eur J Neurol 3:548–559

    Article  Google Scholar 

  • Sellebjerg F, Christiansen M, Nielsen PM et al (1998) Cerebrospinal fluid measures of disease activity in patients with multiple sclerosis. Mult Scler 4:475–479

    Article  CAS  PubMed  Google Scholar 

  • Sharief MK, Thompson EJ (1991) Intrathecal immunoglobulin M synthesis in multiple sclerosis. Relationship with clinical and cerebrospinal fluid parameters. Brain 114(Pt 1A):181–195

    PubMed  Google Scholar 

  • Sharief MK, Thompson EJ (1992) Distribution of cerebrospinal fluid oligoclonal IgM bands in neurological diseases: a comparison between agarose electrophoresis and isoelectric focusing. J Neurol Sci 109:83–87

    Article  CAS  PubMed  Google Scholar 

  • Shishido SN, Varahan S, Yuan K et al (2012) Humoral innate immune response and disease. Clin Immunol 144:142–158

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sprent J, Surh CD (2011) Normal T cell homeostasis: the conversion of naive cells into memory-phenotype cells. Nat Immunol 12:478–484

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Tangye SG, Ma CS, Brink R et al (2013) The good, the bad and the ugly – TFH cells in human health and disease. Nat Rev Immunol 13:412–426

    Article  CAS  PubMed  Google Scholar 

  • Thompson EJ (1988) The CSF proteins: a biochemical approach. Elsevier, Amsterdam

    Google Scholar 

  • van Vlasselaer P, Punnonen J, de Vries JE (1992) Transforming growth factor-beta directs IgA switching in human B cells. J Immunol 148:2062–2067

    PubMed  Google Scholar 

  • Victora GD, Nussenzweig MC (2012) Germinal centers. Annu Rev Immunol 30:429–457

    Article  CAS  PubMed  Google Scholar 

  • Villar LM, Masjuan J, Gonzalez-Porque P et al (2002) Intrathecal IgM synthesis predicts the onset of new relapses and a worse disease course in MS. Neurology 59:555–559

    Article  CAS  PubMed  Google Scholar 

  • Villar LM, Masjuan J, Gonzalez-Porque P et al (2003) Intrathecal IgM synthesis is a prognostic factor in multiple sclerosis. Ann Neurol 53:222–226

    Article  CAS  PubMed  Google Scholar 

  • Vos Q, Lees A, Wu ZQ et al (2000) B-cell activation by T-cell-independent type 2 antigens as an integral part of the humoral immune response to pathogenic microorganisms. Immunol Rev 176:154–170

    Article  CAS  PubMed  Google Scholar 

  • Vrethem M, Fernlund I, Ernerudh J et al (2004) Prognostic value of cerebrospinal fluid IgA and IgG in multiple sclerosis. Mult Scler 10:469–471

    Article  PubMed  Google Scholar 

  • Woo AH, Cserr HF, Knopf PM (1993) Elevated cerebrospinal fluid IgA in humans and rats is not associated with secretory component. J Neuroimmunol 44:129–135

    Article  CAS  PubMed  Google Scholar 

  • Zan H, Cerutti A, Dramitinos P et al (1998) CD40 engagement triggers switching to IgA1 and IgA2 in human B cells through induction of endogenous TGF-beta: evidence for TGF-beta but not IL-10-dependent direct S mu → S alpha and sequential S mu → S gamma, S gamma → S alpha DNA recombination. J Immunol 161:5217–5225

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Danish Multiple Sclerosis Center, Department of Neurology Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    Finn Sellebjerg

Authors
  1. Finn Sellebjerg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Finn Sellebjerg .

Editor information

Editors and Affiliations

  1. Department of Neurology, Innsbruck Medical University, Innsbruck, Austria

    Florian Deisenhammer

  2. Department of Neurology, Danish Multiple Sclerosis Center Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    Finn Sellebjerg

  3. Department of Clinical Chemistry, VU University Medical Center Amsterdam Neurochemistry Laboratory and Biobank, Amsterdam, The Netherlands

    Charlotte E Teunissen

  4. Department of Neurology, University of Ulm, Ulm, Germany

    Hayrettin Tumani

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Sellebjerg, F. (2015). Immunoglobulins in Cerebrospinal Fluid. In: Deisenhammer, F., Sellebjerg, F., Teunissen, C., Tumani, H. (eds) Cerebrospinal Fluid in Clinical Neurology. Springer, Cham. https://doi.org/10.1007/978-3-319-01225-4_10

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-01225-4_10

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-01224-7

  • Online ISBN: 978-3-319-01225-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation