Intrathecal synthesis of oligoclonal IgG in patients with Viliuisk encephalomyelitis: The relationship between oligoclonal bands and clinical features.

Viliuisk encephalomyelitis (VE) is a neurodegenerative disease that afflicts aboriginal people of Yakutia in Siberia with unknown etiology. Oligoclonal IgG bands (OCBs) were discovered in the VE patients (Green et al., 2003). In this study we analysed the association of OCBs with clinical symptoms in 58 VE patients. Positive oligoclonal IgG are associated with a shorter duration of disease (p=0.002), older age of onset (p=0.023) and high frequency of main neurological VE symptoms such as dementia, frontal dysbasia, bulbar disorders, muscle atrophy and centrally caused pelvic disorders. Our results show that the OCBs in VE patients are associated with more severe central nervous system (CNS) damage and may cause secondary complications in the course of the disease.

Neuroprotective and anti-inflammatory mechanisms are activated early in optic neuritis.

OBJECTIVE: The aim of the study was to investigate the expression of different immunological mediators in blood and CSF in patients with acute ON and to estimate whether they were implicated in pro- or anti-inflammatory or even regulatory reactions in comparison with a healthy control group (HC). METHODS: Sixty-four patients between 18 and 59 years of age suffering by acute ON, onset of <4 weeks, were included in the study. Visual tests and brain magnetic resonance imaging (MRI) were performed in ON. Blood and CSF samples were collected from untreated patients and from a gender- and age-matched voluntary HC (n = 32). The mRNA expression of distinct cytokines and neurotrophic factors was assessed by semi/quantitative real-time PCR (RT-PCR). RESULTS: Brain- and glial cell-derived neurotrophic factor (BDNF and GDNF) and interleukin 10 (IL-10) expression was significantly increased in the CSF compared to the blood in both ON and HC (P < 0.001). In the CSF increased levels of BDNF and GDNF of the ON group were positively correlated with the presence of oligoclonal bands (OB). Additionally, patients with gadolinium (gd+) lesions on brain MRI showed increased levels of IL-5 in blood (P = 0.03). CONCLUSION: Our data indicate that both immuno-regulatory and neuroprotective mechanisms may potentially take place relatively early in the course of the ON. The presence of neurotrophic factors in healthy CSF and their overexpression already during the acute phase of ON supports the alertness of CNS defence mechanisms ready to be activated during degenerative events, such as destruction of the myelin.

Determination of κFLC and κ Index in cerebrospinal fluid: a valid alternative to assess intrathecal immunoglobulin synthesis.

Intrathecal immunoglobulin synthesis is observed in several disorders of the central nervous system, but its detection by current laboratory tests is relatively insensitive and operator depending. We assessed the diagnostic accuracy of a nephelometric assay for k free light chain determination in cerebrospinal fluid and serum. The patients were grouped according to clinical and laboratory criteria. ROC curves for all methods were performed to find the best cut-off value. kFLC Index seems to be more accurate than other parameters. Our data indicate that nephelometric assay for kFLCs in CSF reliably detect intrathecal immunoglobulin synthesis and discriminate multiple sclerosis patients.

Intrathecal oligoclonal IgG synthesis in multiple sclerosis.

The diagnosis of multiple sclerosis is based on dissemination in time and space. Before 2010 lack of evidence for dissemination in space could be substituted by a paraclinical test, cerebrospinal fluid (CSF) oligoclonal bands (OCBs). The present meta-analysis (13,467 patients) shows that the diagnostic specificity of OCB drops from 94% to 61% if inflammatory etiologies are considered. Importantly, this was not caused by poor laboratory practice. This review on CSF OCB further illustrates the conceptional problem of substituting dissemination in space with a biomarker. The potential prognostic value of intrathecal OCB will need to be tested prospectively.

Immunological mechanisms that associate with oligoclonal IgM band synthesis in multiple sclerosis.

We described previously that multiple sclerosis (MS) patients with oligoclonal IgM against myelin lipids (M+) develop an aggressive disease. Our aim was to assess possible mechanisms regulating the production of these antibodies. We studied B cell subsets in 180 patients with MS, and 69 with other neurological diseases. M+ MS patients showed a moderate increase of CD5(+) B-cell percentage in peripheral blood and a considerable augment of these cells in cerebrospinal fluid (CSF) that correlated with intrathecal IgM production. The appearance of CD5(+) B cells into the central nervous system (CNS) was related to increased CXCL13 and TNF-alpha levels in CSF. Moreover, the presence of oligoclonal IgM associated with a SNP at position -376 of the TNF-alpha promoter. These results help to elucidate the B lymphocytes responsible for intrathecal IgM secretion in MS and the origin of this abnormal B-cell response in patients with aggressive MS.

Intrathecal immunoglobulin G synthesis and brain injury by quantitative MRI in multiple sclerosis.

OBJECTIVES: It was the aim of this study to evaluate if the quantitative intrathecal immunoglobulin G (IgG) synthesis correlates with the brain atrophy and the total lesion volume (TLV) in brain magnetic resonance imaging (MRI) of multiple sclerosis (MS) patients. METHODS: A total of 50 patients with relapsing-remitting MS were included in this study. MRIs were performed and cerebrospinal fluid samples were collected during the diagnostic determination when patients were in remission without treatment. RESULTS: At study baseline, IgG index values were elevated in 36 patients (72%), and oligoclonal IgG bands were positive in 42 of 50 patients (84%). Brain MRI was abnormal in 94% of patients, and, compared with healthy controls, brain atrophy was observed in MS patients. A positive correlation among IgG index, cerebrospinal fluid leukocyte count and TLV was observed; the Expanded Disability Status Scale correlated positively with TLV and the number of lesions, although a significant relationship between disability and brain atrophy was not demonstrated. CONCLUSIONS: Although new parameters will be necessary in longitudinal studies to characterize the axonal injury in various stages of the disease, the data suggest that the high intrathecal IgG synthesis may predict a greater brain lesion burden.

Cytokines and intrathecal IgG synthesis in multiple sclerosis patients during clinical remission

Os níveis de citocinas e síntese intratecal de IgG foram dosados no líquido cefalorraquidiano (LCR) e soro, com o objetivo de avaliar a atividade inflamatória em pacientes com esclerose múltipla durante remissão clínica. Foram detectados níveis elevados de citocinas pró-inflamatórias (TNFa e IFNg) no LCR e soro, sem alterações significativas na produção de IL12 e IL10. O perfil de produção das citocinas pró-inflamatórias estava associado ao aumento de leucócitos no LCR, assim como a presença de bandas oligoclonais IgG sugerindo síntese intratecal de IgG. Estes resultados sugerem que mesmo quando a doença está clinicamente silenciosa, a atividade inflamatória está presente nestes pacientes.

Intrathecal synthesis of oligoclonal IgM against myelin lipids predicts an aggressive disease course in MS.

Oligoclonal IgM bands restricted to cerebrospinal fluid are an unfavorable prognostic marker in MS, the most common demyelinating disease of the CNS. We have attempted to identify the B cell subpopulation responsible for oligoclonal IgM secretion and the specificity of these bands. In addition, we explored the relationship between specificity and disease evolution. Intrathecal B cell subpopulations present in 29 MS patients with oligoclonal IgM bands and 52 without them were analyzed. A considerable increase in CD5(+) B lymphocytes was found in patients with oligoclonal IgM bands. These cells mostly secrete IgM antibodies recognizing nonproteic molecules. We also studied whether oligoclonal IgM bands present in cerebrospinal fluid of 53 MS patients were directed against myelin lipids. This was the case in most patients, with phosphatidylcholine being the most frequently recognized lipid. Disease course of 15 patients with oligoclonal IgM against myelin lipids and 33 patients lacking them was followed. Patients with anti-lipid IgM suffered a second relapse earlier, had more relapses, and showed increased disability compared with those without anti-lipid IgM. The presence of intrathecal anti-myelin lipid IgM antibodies is therefore a very accurate predictor of aggressive evolution in MS.

Cytokines and intrathecal IgG synthesis in multiple sclerosis patients during clinical remission.

Cytokines and intrathecal IgG synthesis were determined in the cerebrospinal fluid (CSF) and sera to evaluate inflammatory activity in multiple sclerosis (MS) patients during clinical remission. Although the disease was stable, there had been a significant increase of proinflammatory cytokines such as TNFalpha and IFNgamma in the CSF and serum, with no significant changes of IL12 and IL10 production. The changes in the cytokine production patterns were associated with an increase of leukocytes in the CSF, as well as the presence of oligoclonal bands suggesting intrathecal IgG synthesis. These results suggest that even when the disease is clinically silent, one can observe inflammatory activity in these MS patients.