Oligoclonal band

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Proteins separated by SDS-PAGE, Coomassie brilliant blue staining Coomassie3.jpg
Proteins separated by SDS-PAGE, Coomassie brilliant blue staining

Oligoclonal bands (OCBs) are bands of immunoglobulins that are seen when a patient's blood serum, or cerebrospinal fluid (CSF) is analyzed. They are used in the diagnosis of various neurological and blood diseases. Oligoclonal bands are present in the CSF of more than 95% of patients with clinically definite multiple sclerosis. [1]

Contents

Two methods of analysis are possible: (a) protein electrophoresis, a method of analyzing the composition of fluids, also known as "SDS-PAGE (sodium dodecyl sulphate polyacrylamide gel electrophoresis)/Coomassie blue staining", and (b) the combination of isoelectric focusing/silver staining. The latter is more sensitive. [2]

For the analysis of cerebrospinal fluid, a sample is first collected via lumbar puncture (LP). Normally it is assumed that all the proteins that appear in the CSF, but are not present in the serum, are produced intrathecally (inside the central nervous system). Therefore, it is normal to subtract bands in serum from bands in CSF when investigating CNS diseases. A sample of blood serum is usually obtained from a clotted blood sample taken around the time of the LP.

Oligoclonal bands in multiple sclerosis

OCBs are especially important for multiple sclerosis (MS). In MS, normally only OCBs made of immunoglobulin G antibodies are considered, though sometimes other proteins can be taken into account, like lipid-specific immunoglobulin M. [3] [4] The presence of these IgM OCBs is associated with a more severe course. [5]

Typically for an OCB analysis, the CSF is concentrated and the serum is diluted. After this dilution/concentration prealbumin appears as higher on CSF. Albumin is typically the dominant band on both fluids. Transferrin is another prominent protein on CSF column because its small molecular size easily increases its filtration in to CSF. CSF has a relatively higher concentration of prealbumin than does serum. As expected large molecular proteins are absent in CSF column. After all these bands are localized, OCBs should be assessed in the γ region which normally hosts small group of polyclonal immunoglobulins. [6]

New techniques like "capillary isoelectric focusing immunoassay" are able to detect IgG OCBs in more than 95% of multiple sclerosis patients. [7]

Even more than 12 OCBs can appear in MS. [8] Each one of them represent antibody proteins (or protein fragments) secreted by plasma cells, although why exactly these bands are present, and which proteins these bands represent, has not yet been fully elucidated. The target antigens for these antibodies are not easy to find because it requires to isolate a single kind of protein in each band, though new techniques are able to do so. [9]

In 40% of MS patients with OCBs, antibodies specific to the viruses HHV-6 and EBV have been found. [10]

HHV-6 specific OCBs have also been found in other demyelinating diseases. [11] [12] A lytic protein of HHV-6A virus was identified as the target of HHV-6 specific oligoclonal bands. [13]

Though early theories assumed that the OCBs were somehow pathogenic autoantigens, recent research has shown that the IgG present in the OCBs are antibodies against debris, and therefore, OCBs seem to be just a secondary effect of MS. [14] Nevertheless, OCBs remain useful as a biomarker.

Diagnostic value in MS

Oligoclonal bands are an important indicator in the diagnosis of multiple sclerosis. Up to 95% of all patients with multiple sclerosis have permanently observable oligoclonal bands [15] at least for those with European ancestry. [16] The last available reports in 2017 were pointing to a sensitivity of 98% and specificity of 87% for differential diagnosis versus MS mimickers (specificity respect unselected population should be equal or higher). [17]

Other application for OCBs is as a tool to classify patients. It is known since long ago that OCB negative MS patients have a slower evolution. Some reports point that the underlying condition that causes the MS lesions in these patients is different. There are four pathological patterns of damage, and in the majority of patients with pattern II and III brain lesions oligoclonal bands are absent or only transiently present. [18]

Heterogeneity

It has been reported that oligoclonal bands are nearly absent in patients with pattern II and pattern III lesion types. [19]

Six groups of patients are usually separated, based on OCBs: [20]

Type 2 and 3 indicate intrathecal synthesis, and the rest are considered as negative results (No MS).

Alternatives

The main importance of oligoclonal bands was to demonstrate the production of intrathecal immunoglobins (IgGs) for establishing a MS diagnosis. Currently alternative methods for detection of this intrathecal synthesis have been published, and therefore it has lost some of its importance in this area.

A specially interesting method are free light chains (FLC), specially the kappa-FLCs (kFLCs). Several authors have reported that the nephelometric and ELISA FLCs determination is comparable with OCBs as markers of IgG synthesis, and kFLCs behave even better than oligoclonal bands. [21]

Another alternative to oligoclonal bands for MS diagnosis is the MRZ-reaction (MRZR), a polyspecific antiviral immune response against the viruses of measles, rubella and zoster found in 1992. [22]

In some reports the MRZR showed a lower sensitivity than OCB (70% vs. 100%), but a higher specificity (92% vs. 69%) for MS. [22]

Bands in other diseases

The presence of one band (a monoclonal band) may be considered serious, such as lymphoproliferative disease, or may simply be normal—it must be interpreted in the context of each specific patient. More bands may reflect the presence of a disease.

Diseases associated

Oligoclonal bands may be found in:

Related Research Articles

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References

  1. ↑ Correale J, de los Milagros M, Molinas B (2002). "Oligoclonal bands and antibody responses in Multiple Sclerosis". Journal of Neurology. 249 (4): 375–389. doi: 10.1007/s004150200026 . PMID   11967640. S2CID   21523820.
  2. ↑ Davenport RD, Keren DF (1988). "Oligoclonal bands in cerebrospinal fluids: significance of corresponding bands in serum for diagnosis of multiple sclerosis". Clinical Chemistry. 34 (4): 764–5. doi: 10.1093/clinchem/34.4.764 . PMID   3359616.
  3. ↑ Álvarez-Cermeño JC, Muñoz-Negrete FJ, Costa-Frossard L, Sainz de la Maza S, Villar LM, Rebolleda G (2016). "Intrathecal lipid-specific oligoclonal IgM synthesis associates with retinal axonal loss in multiple sclerosis". Journal of the Neurological Sciences. 360: 41–44. doi:10.1016/j.jns.2015.11.030. PMID   26723970. S2CID   4724614.
  4. ↑ Villar Luis M.; et al. (2015). "Lipid-specific immunoglobulin M bands in cerebrospinal fluid are associated with a reduced risk of developing progressive multifocal leukoencephalopathy during treatment with natalizumab". Annals of Neurology. 77 (3): 447–457. doi:10.1002/ana.24345. PMID   25581547. S2CID   20377417.
  5. ↑ Ferraro D, et al. (2015). "Cerebrospinal fluid CXCL13 in clinically isolated syndrome patients: Association with oligoclonal IgM bands and prediction of Multiple Sclerosis diagnosis" (PDF). Neuroimmunology. 283: 64–69. doi:10.1016/j.jneuroim.2015.04.011. hdl: 11380/1118697 . PMID   26004159. S2CID   41252743.
  6. ↑ McPherson, Richard A.; Pincus, Matthew R. (2017-04-05). Henry's clinical diagnosis and management by laboratory methods. McPherson, Richard A.,, Pincus, Matthew R. (23rd ed.). St. Louis, Mo. ISBN   9780323413152. OCLC   949280055.{{cite book}}: CS1 maint: location missing publisher (link)
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  16. ↑ Goris A, Pauwels I, Gustavsen MW, van Son B, Hilven K, Bos SD, Celius EG, Berg-Hansen P, Aarseth J, Myhr KM, D'Alfonso S, Barizzone N, Leone MA, Martinelli Boneschi F, Sorosina M, Liberatore G, Kockum I, Olsson T, Hillert J, Alfredsson L, Bedri SK, Hemmer B, Buck D, Berthele A, Knier B, Biberacher V, van Pesch V, Sindic C, Bang Oturai A, Søndergaard HB, Sellebjerg F, Jensen PE, Comabella M, Montalban X, Pérez-Boza J, Malhotra S, Lechner-Scott J, Broadley S, Slee M, Taylor B, Kermode AG, Gourraud PA, Sawcer SJ, Andreassen BK, Dubois B, Harbo HF (2015). "Genetic variants are major determinants of CSF antibody levels in multiple sclerosis". Brain. 138 (3): 632–43. doi:10.1093/brain/awu405. PMC   4408440 . PMID   25616667.{{cite journal}}: CS1 maint: multiple names: authors list (link), Quote "OCBs are reported to be observed in 90–95% of patients in Northern Europe, and are composed predominantly of IgG"
  17. ↑ Bernitsas E, Khan O, Razmjou S, Tselis A, Bao F, Caon C, Millis S, Seraji-Bozorgzad N (Jul 2017). "Cerebrospinal fluid humoral immunity in the differential diagnosis of multiple sclerosis". PLOS ONE. 12 (7): e0181431. Bibcode:2017PLoSO..1281431B. doi: 10.1371/journal.pone.0181431 . PMC   5519077 . PMID   28727770.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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  19. ↑ Jarius S, König FB, Metz I, Ruprecht K, Paul F, Brück W, Wildemann B (2017). "Pattern II and pattern III MS are entities distinct from pattern I MS: evidence from cerebrospinal fluid analysis". Journal of Neuroinflammation. 14 (1): 171. doi: 10.1186/s12974-017-0929-z . PMC   5576197 . PMID   28851393.
  20. ↑ Pinar Asli (2018). "Cerebrospinal fluid oligoclonal banding patterns and intrathecal immunoglobulin synthesis: Data comparison from a wide patient group". Neurological Sciences and Neurophysiology. 35: 21–28. doi: 10.5152/NSN.2018.10247 .
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  26. ↑ Ernerudh, J; Olsson, T; Lindström, F; Skogh, T (August 1985). "Cerebrospinal fluid immunoglobulin abnormalities in systemic lupus erythematosus". Journal of Neurology, Neurosurgery, and Psychiatry. 48 (8): 807–13. doi:10.1136/jnnp.48.8.807. PMC   1028453 . PMID   3875690.
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  30. ↑ Jones, HD; Urquhart, N; Mathias, RG; Banerjee, SN (1989). "An evaluation of oligoclonal banding and CSF IgG index in the diagnosis of neurosyphilis". Sexually Transmitted Diseases. 17 (2): 75–9. doi: 10.1097/00007435-199004000-00006 . PMID   2193408. S2CID   36567041.
  31. ↑ Scott, Brian J.; Douglas, Vanja C.; Tihan, Tarik; Rubenstein, James L.; Josephson, S. Andrew (1 March 2013). "A Systematic Approach to the Diagnosis of Suspected Central Nervous System Lymphoma". JAMA Neurology. 70 (3): 311–9. doi:10.1001/jamaneurol.2013.606. PMC   4135394 . PMID   23319132.
  32. ↑ Alexander, EL; Malinow, K; Lejewski, JE; Jerdan, MS; Provost, TT; Alexander, GE (March 1986). "Primary Sjögren's syndrome with central nervous system disease mimicking multiple sclerosis". Annals of Internal Medicine. 104 (3): 323–30. doi:10.7326/0003-4819-104-3-323. PMID   3946977.
  33. ↑ Duguid, JR; Layzer, R; Panitch, H (December 1983). "Oligoclonal bands in meningeal carcinomatosis". Archives of Neurology. 40 (13): 832. doi:10.1001/archneur.1983.04050120082023. PMID   6639419.
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