Oligoclonal band

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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, especially in multiple sclerosis.

Two methods of analysis are possible: (a) protein electrophoresis, a method of analyzing the composition of fluids, also known as "agarose gel electrophoresis/Coomassie Blue staining", and (b) the combination of isoelectric focusing/silver staining. The latter is more sensitive.<ref>,

 Oligoclonal bands in cerebrospinal fluids: significance of corresponding bands in serum for diagnosis of multiple sclerosis, 
 Clinical Chemistry, 
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 PMID: 3359616,
 
 
 Full text,</ref>

For the analysis of cerebrospinal fluid, a patient has a lumbar puncture performed, which collects some of his or her cerebrospinal fluid. The blood serum can be gained from a clotted blood sample. 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 CNS). Therefore, it is normal to subtract bands in serum from bands in CSF when investigating CNS diseases.

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.<ref>,

 Intrathecal lipid-specific oligoclonal IgM synthesis associates with retinal axonal loss in multiple sclerosis, 
 Journal of the Neurological Sciences, 
 2016,
 Vol. 360,
 pp. 41–44,
 DOI: 10.1016/j.jns.2015.11.030,
 PMID: 26723970,</ref><ref>Villar Luis M., 
 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, 
 2015,
 Vol. 77(Issue: 3),
 pp. 447–457,
 DOI: 10.1002/ana.24345,
 PMID: 25581547,</ref> The presence of these IgM OCBs is associated with a more severe course.<ref>, 
 Cerebrospinal fluid CXCL13 in clinically isolated syndrome patients: Association with oligoclonal IgM bands and prediction of Multiple Sclerosis diagnosis, 
 Neuroimmunology, 
 2015,
 Vol. 283,
 pp. 64–69,
 DOI: 10.1016/j.jneuroim.2015.04.011,
 PMID: 26004159,
 
 
 Full text,</ref>

Typically for a OCB analysis, the CSF is concentrated and the serum is diluted. After this dilution/concentration prealbumin appears as higher on CSF. Albumin 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.<ref>,

 Henry's clinical diagnosis and management by laboratory methods, 
 23rd edition, 
 St. Louis, Mo.: 
  
  
  
 ISBN 9780323413152,</ref>

New techniques like "capillary isoelectric focusing immunoassay" are able to detect IgG OCBs in more than 95% of multiple sclerosis patients.<ref name="Halbgebauer">,

 Detection of intrathecal immunoglobulin G synthesis by capillary isoelectric focusing immunoassay in oligoclonal band negative multiple sclerosis, 
 Journal of Neurology, 
 2016,
 Vol. 263(Issue: 5),
 pp. 954–960,
 DOI: 10.1007/s00415-016-8094-3,
 PMID: 26995358,</ref>

Even more than 12 OCBs can appear in MS.<ref>Dalla Costa Gloria,

 Clinical significance of the number of oligoclonal bands in patients with clinically isolated syndromes, 
 Neuroimmunology, 
 2015,
 Vol. 289,
 pp. 62–67,
 DOI: 10.1016/j.jneuroim.2015.10.009,
 PMID: 26616872,</ref> 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.<ref>, 
 Distinct oligoclonal band antibodies in multiple sclerosis recognize ubiquitous self-proteins, 
 Proceedings of the National Academy of Sciences, 
 2016,
 Vol. 113(Issue: 28),
 pp. 7864–7869,
 DOI: 10.1073/pnas.1522730113,
 PMID: 27325759,
 PMC: 4948369,</ref>

In 40% of MS patients with OCBs, antibodies specific to the viruses HHV-6 and EBV have been found.<ref>,

 Oligoclonal bands in multiple sclerosis reactive against two herpesviruses and association with magnetic resonance imaging findings, 
 Multiple Sclerosis, 
 2014,
 Vol. 20(Issue: 1),
 pp. 27–34,
 DOI: 10.1177/1352458513490545,
 PMID: 23722324,
 PMC: 5001156,</ref>

HHV-6 specific OCBs have also been found in other demyelinating diseases.<ref>,

 Intrathecal human herpesvirus 6 antibodies in multiple sclerosis and other demyelinating diseases presenting as oligoclonal bands in cerebrospinal fluid, 
 Journal of Neuroimmunology, 
 2011,
 Vol. 237(Issue: 1–2),
 pp. 93–7,
 DOI: 10.1016/j.jneuroim.2011.06.012,
 PMID: 21767883,</ref><ref>, 
 HHV-6-positivity in diseases with demyelination, 
 Journal of Clinical Virology, 
 2014,
 Vol. 61(Issue: 2),
 pp. 216–9,
 DOI: 10.1016/j.jcv.2014.07.006,
 PMID: 25088617,</ref> A lytic protein of HHV-6A virus was identified as the target of HHV-6 specific oligoclonal bands.<ref>, 
 Identification of the major HHV-6 antigen recognized by cerebrospinal fluid IgG in multiple sclerosis, 
 European Journal of Neurology, 
 2014,
 Vol. 21(Issue: 8),
 pp. 1096–101,
 DOI: 10.1111/ene.12435,
 PMID: 24724742,</ref>

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.<ref>,

 Antibodies in multiple sclerosis oligoclonal bands target debris, 
 Proceedings of the National Academy of Sciences, 
 2016,
 Vol. 113(Issue: 28),
 pp. 7696–8,
 DOI: 10.1073/pnas.1609246113,
 PMID: 27357674,
 PMC: 4948325,</ref> 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.<ref>,

 Oligoclonal bands and antibody responses in Multiple Sclerosis, 
 Journal of Neurology, 
 2002,
 Vol. 249(Issue: 4),
 pp. 375–389,
 DOI: 10.1007/s004150200026,
 PMID: 11967640,</ref> At least for those with european ancestry.<ref>An Goris et al. Genetic variants are major determinants of CSF antibody levels in multiple sclerosis, Brain. 2015 Mar; 138(3): 632–643. 2015 Jan 23. doi:  10.1093/brain/awu405, Template:PMC, Quote "OCBs are reported to be observed in 90–95% of patients in Northern Europe, and are composed predominantly of IgG"</ref> 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)<ref>Bernitsas E, Khan O, Razmjou S, Tselis A, Bao F, Caon C, Millis S, Seraji-Bozorgzad N, 
 Cerebrospinal fluid humoral immunity in the differential diagnosis of multiple sclerosis, 
 PLoS One, 
 
 Vol. 12(Issue: 7),
 
 DOI: 10.1371/journal.pone.0181431,
 PMID: 28727770,
 PMC: 5519077,</ref>

Other application for OCB's 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.<ref>,

 Pattern II and pattern III MS are entities distinct from pattern I MS: evidence from cerebrospinal fluid analysis, 
 J Neuroinflammation, 
 
 Vol. 14(Issue: 1),
 pp. 171,
 DOI: 10.1186/s12974-017-0929-z,
 PMID: 28851393,
 PMC: 5576197,</ref>

Heterogeneity

It has been reported that oligoclonal bands are nearly absent in patients with pattern II and pattern III lesion types.<ref>,

 Pattern II and pattern III MS are entities distinct from pattern I MS: evidence from cerebrospinal fluid analysis, 
 Journal of Neuroinflammation, 
 2017,
 Vol. 14(Issue: 1),
 
 DOI: 10.1186/s12974-017-0929-z,
 PMID: 28851393,
 PMC: 5576197,</ref>

Six groups of patients are usually separatd, based on OCBs:<ref>Pinar Asli,

 Cerebrospinal fluid oligoclonal banding patterns and intrathecal immunoglobulin synthesis: Data comparison from a wide patient group, 
 Neurological Sciences and Neurophysiology, 
 2018,
 Vol. 35,
 pp. 21–28,
 DOI: 10.5152/NSN.2018.10247,</ref>

• type 1, no bands in CSF and serum;
• type 2, oligoclonal IgG bands in CSF,
• type 3, oligoclonal bands in CSF and serum with additional bands in CSF;
• type 4, identical oligoclonal bands in CSF and serum,
• type 5, monoclonal bands in CSF and serum,
• type 6, presence of a single band limited to the CSF.

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.<ref>,

 kFLC Index: a novel approach in early diagnosis of Multiple Sclerosis, 
 International Journal of Scientific Research, 
 
 Vol. 4(Issue: 8),
 
 
 
 
 
 Full text,</ref>

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.<ref name="Hottenrott">Hottenrott Tilman, Dersch Rick, Berger Benjamin, Rauer Sebastian, Eckenweiler Matthias, Huzly Daniela, Stich Oliver,

 The intrathecal, polyspecific antiviral immune response in neurosarcoidosis, acute disseminated encephalomyelitis and autoimmune encephalitis compared to multiple sclerosis in a tertiary hospital cohort, 
 Fluids Barriers CNS, 
 2015,
 Vol. 12,
 
 DOI: 10.1186/s12987-015-0024-8,
 PMID: 26652013,
 PMC: 4677451,</ref>

In some reports the MRZR showed a lower sensitivity than OCB (70% vs. 100%), but a higher specificity (69% vs. 92%) for MS.<ref name="Hottenrott"/>

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 are found in:

• Multiple sclerosis<ref>,

 Infectious causes of multiple sclerosis, 
 The Lancet Neurology, 
 
 Vol. 4(Issue: 3),
 pp. 195–202,
 DOI: 10.1016/S1474-4422(05)01017-3,
 PMID: 15721830,</ref>

• Lyme disease<ref>,

 Oligoclonal Borrelia burgdorferi-specific IgG antibodies in cerebrospinal fluid in Lyme neuroborreliosis, 
 The Journal of Infectious Diseases, 
 
 Vol. 161(Issue: 6),
 pp. 1194–202,
 DOI: 10.1093/infdis/161.6.1194,
 PMID: 2345300,</ref>

• Neuromyelitis optica (Devic's disease)<ref>,

 Oligoclonal bands in Devic's neuromyelitis optica and multiple                 sclerosis: differences in repeated cerebrospinal fluid examinations, 
 Multiple Sclerosis Journal, 
 
 Vol. 10(Issue: 1),
 pp. 2–4,
 DOI: 10.1191/1352458504ms988oa,
 PMID: 14760945,</ref>

• Systemic lupus erythematosus<ref>,

 Cerebrospinal fluid immunoglobulin abnormalities in systemic lupus erythematosus, 
 Journal of Neurology, Neurosurgery, and Psychiatry, 
 
 Vol. 48(Issue: 8),
 pp. 807–13,
 DOI: 10.1136/jnnp.48.8.807,
 PMID: 3875690,
 PMC: 1028453,
 
 Full text,</ref>

• Neurosarcoidosis<ref>,

 Neurosarcoidosis, 
 Current Neuropharmacology, 
 
 Vol. 9(Issue: 3),
 pp. 429–436,
 DOI: 10.2174/157015911796557975,
 PMID: 22379457,
 PMC: 3151597,</ref>

• Subacute sclerosing panencephalitis<ref>,

 Identification of virus-specific oligoclonal bands in subacute sclerosing panencephalitis by immunofixation after isoelectric focusing and peroxidase staining, 
 Journal of Clinical Microbiology, 
 
 Vol. 16(Issue: 5),
 pp. 985–7,
 
 PMID: 6185532,
 PMC: 272519,</ref>

• Subarachnoid hemorrhage<ref>,

 Oligoclonal immunoglobulin G in acute subarachnoid hemorrhage and stroke., 
 Neurology, 
 
 Vol. 36(Issue: 3),
 pp. 395–7,
 DOI: 10.1212/wnl.36.3.395,
 PMID: 3951707,</ref>

• Syphilis<ref>,

 An evaluation of oligoclonal banding and CSF IgG index in the diagnosis of neurosyphilis, 
 Sexually Transmitted Diseases, 
 
 Vol. 17(Issue: 2),
 pp. 75–9,
 DOI: 10.1097/00007435-199004000-00006,
 PMID: 2193408,</ref>

• Primary central nervous system lymphoma<ref>,

 A Systematic Approach to the Diagnosis of Suspected Central Nervous System Lymphoma, 
 JAMA Neurology, 
 
 Vol. 70(Issue: 3),
 pp. 311–9,
 DOI: 10.1001/jamaneurol.2013.606,
 PMID: 23319132,
 PMC: 4135394,</ref>

• Sjögren's syndrome<ref>,

 Primary Sjögren's syndrome with central nervous system disease mimicking multiple sclerosis, 
 Annals of Internal Medicine, 
 
 Vol. 104(Issue: 3),
 pp. 323–30,
 DOI: 10.7326/0003-4819-104-3-323,
 PMID: 3946977,</ref>

• Guillain–Barré syndrome
• Meningeal carcinomatosis<ref>,

 Oligoclonal bands in meningeal carcinomatosis, 
 Archives of Neurology, 
 
 Vol. 40(Issue: 13),
 pp. 832,
 DOI: 10.1001/archneur.1983.04050120082023,
 PMID: 6639419,
 
 
 Full text,</ref>

• Multiple myeloma<ref>,

 Oligoclonal bands in patients with multiple myeloma: Its emergence per se could not be translated to improved survival, 
 Cancer Science, 
 
 Vol. 105(Issue: 11),
 pp. 1442–1446,
 DOI: 10.1111/cas.12527,
 PMID: 25182124,
 PMC: 4462372,</ref>

• Parry–Romberg syndrome

External links

• Oligoclonal bands in multiple sclerosis - The Medical School, Birmingham University
• Oligoclonal Bands in CSF - ClinLab Navigator