Value of oligoclonal band study in clinically isolated syndromes and multiple sclerosis

Multiple sclerosis (MS) is the most common demyelinating disease affecting young adults. It is believed to be a T-cell-mediated autoimmune disease. However, lesion development requires additional immune mechanisms involving demyelinating antibodies [1,2]. Thus, it has been shown recently that deposition of IgG and complement activation products are consistently associated with active demyelination in most chronic MS patients [3]. An important clinical evidence of the relevant antibody and B-cell participation in the pathogenesis of the disease is the therapeutic effect of rituximab, a monoclonal anti-CD20, an antigen specifically expressed on B-lymphocyte membrane. It significantly reduced the number of gadolinium-enhancing lesions and relapses in MS patients [4].

These findings are in line with the presence of intrathecal synthesis of oligoclonal IgG bands (OCGB), a hallmark of the disease, which has been included as a supportive criterion for the diagnosis of MS [5]. Nevertheless, with the emergence of MRI as a useful ancillary test in the diagnosis of the disease, less emphasis has been placed on the value of cerebrospinal fluid (CSF) OCGB in the study of the disorder. To maximize the benefit of CSF as a diagnostic paraclinical test, it has been recommended that the most accurate method should be used [6]. Indeed, with the use of newer techniques, CSF testing offers new added value in the diagnosis and assessment of MS.

Demonstration of lesion dissemination in time (DIT) and space (DIS) is necessary for the diagnosis of MS in clinically isolated syndromes (CIS). New MRI criteria were used for that demonstration [5], as they can show some value in predicting the risk for conversion to clinically definite MS in patients with CIS. The validity of these MRI criteria has been evaluated by different groups. A recent multicenter study concluded that MRI requirements for DIS demonstration yielded acceptable specificity, but lower sensitivity than previously reported in predicting the development of MS [7]. DIS can be alternatively shown with the finding of at least two separate MRI-detected lesions consistent with MS in the presence of CSF OCGB [5]. The use of new accurate OCGB techniques achieved more sensitivity, specificity and, even more important for individual patients, higher positive and negative predictive values than MRI criteria in the prediction of conversion to MS [8]. This result was not unexpected, since this new OCGB method had been shown to be highly accurate by its own in such prediction [9], and the relevance of CSF study in CIS prognosis had been previously demonstrated [10]. This technique also proved to be useful in the differential diagnosis of MS, since other oligoclonal IgG band patterns may be found in different CNS inflammatory diseases other than MS [11].

On the other hand, more than a decade ago, it was found that the presence of oligoclonal IgM bands (OCMB), the most accurate method to detect its intrathecal synthesis, showed a prognostic value in CIS [12]. This was recently confirmed in a prospective study, where it was found that the probability of conversion to MS was approximately 90% in CIS patients with OCMB after only 1 year of follow-up [13]. It was also observed that this response persists in serial CSF studies showing that this is not a primary response, which would disappear in months, but a permanent one associated with the development of relapses and disability progression in MS [14]. Moreover, it was found that most OCMB cases developed secondary progressive MS in a series of patients followed for up to 16 years [14]. The relationship of intrathecal IgM synthesis at onset with disability and MRI lesion burden has been subsequently confirmed by other groups [15,16]. Persistent IgM responses are usually produced by CD5⁺ B lymphocytes, a subset of B cells responsible for the secretion of the so-called natural antibodies, which are usually of IgM isotype and directed against nonproteic antigens [17,18]. A high percentage of CD5⁺ B lymphocytes in CSF from patients with aggressive MS have been described [19], and that was also the case for OCMB patients. After specific immunoblots, those persistent OCMB were shown to be directed against different myelin lipids, phosphtidylcholine being the antigen most frequently recognized by CSF IgM [20]. The presence of lipid-specific OCMB (LOCMB) also showed a prognostic value in patients with CIS. In a follow-up study of 48 patients, we observed that all who had LOCMB developed a second relapse, and therefore converted to MS, within only 2 years of evolution. These patients also experienced a significant disability worsening when compared with patients without such bands [20]. However, some CIS patients may have OCMB which did not recognize myelin lipids. This was shown to be a primary response that disappears after follow-up, and was associated with a more benign disease course [21].

The data commented herein provide better understanding of the mechanisms of MS. The close relationship of OCGB and OCMB with MS prognosis and disease course indicates that the CSF oligoclonal response is directly implicated in the immunopathogenesis of the disease, as recently confirmed by other authors [22]. On the other hand, the different CSF oligoclonal patterns described herein seem to distinguish different forms of MS evolution. This would be clinically relevant because prompt identification of different subgroups of MS, not always easy from the clinical point of view at the very early stages, would enable more specific treatment approaches.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.