Other Inflammatory Neurological Disorders Research Articles

Cerebrospinal fluid γδ T cell frequency is age-related: a case-control study of 435 children with inflammatory and non-inflammatory neurological disorders.

Studies of cerebrospinal fluid (CSF) γδ T cells in children are limited, dueespecially to the lack of control data. In adults, gamma/delta T cells (TCR-γδ) residing in the intrathecal space are sometimes involved in neuroinflammation. To evaluate the possible role of γδ T cells in paediatric neuroinflammation, we immunophenotyped cerebrospinal fluid (CSF) and blood lymphocytes using flow cytometry in a case-control study of 100 children with non-inflammatory neurological disorders (NIND), 312 with opsoclonus-myoclonus (OMS) and 23 with other inflammatory neurological disorders (OIND). In NIND, the negative correlation between CSF γδ T cell frequency and patient age was striking: median frequency of 27% in infants and 3·3% in teens. Interindividual variations were largest in the youngest. There was no gender effect. In all OMS, after correcting for age, only a small effect of OMS severity remained. Measurement of markers for γδ T cell activation [human leucocyte antigen D-related (HLA-DR)], maturation (CD45RA, CD45RO) or intracellular cytokine staining [interleukin (IL)-4, interferon (IFN)-γ] failed to discriminate OMS and NIND groups. Of seven OMS immunotherapies/combinations, none altered the frequency of total CSF γδ T cells or subsets significantly. In OIND, the CSF γδ T cell frequency was <10% for single samples of other paraneoplastic disorders [anti-neuronal nuclear antibody (ANNA)-1, PCA-1, teratoma-associated syndrome], cerebellar ataxia (post-infectious, ataxia-telangiectasia), acute disseminated encephalomyelitis, neuroborreliosis and encephalitis. This study provides new insights into CSF γδ T cells in the paediatric population. Although their role in CSF remains elusive, the negative age correlation, resistance to immunotherapy and our age cut-off references for NIND are important findings for the design of future paediatric studies.

Do patients with schizophreniform and bipolar disorders show an intrathecal, polyspecific, antiviral immune response? A pilot study

BackgroundWe previously described inflammatory cerebrospinal fluid (CSF) alterations in a subgroup of patients with schizophreniform disorders and the synthesis of polyspecific intrathecal antibodies against different neurotropic infectious pathogens in some patients with bipolar disorders. Consequently, we have measured the prevalence of a positive MRZ reaction (MRZR)—a marker for a polyspecific, antiviral, intrathecal, humoral immune response composed of three antibody indices for the neurotropic viruses of measles (M), rubella (R), and varicella zoster (Z)—in these patients.MethodsWe analyzed paired CSF and serum samples of 39 schizophreniform and 39 bipolar patients. For comparison, we used a group of 48 patients with other inflammatory neurological disorders (OIND) and a cohort of 203 multiple sclerosis (MS) patients.ResultsWe found a positive MRZR in two patients with schizophreniform disorders (5.1%); both suffered from schizodepressive disorders without any other signs suggestive of MS. None of the bipolar patients (0%) and four members of the OIND group (8.3%) showed a positive MRZR. In the MS cohort, a positive MRZR was found significantly more frequently [in 99 patients (48.8%)] than in the other patient groups (p > 0.001). In summary, we did not find a positive MRZR in a relevant subgroup of patients with schizophreniform or bipolar disorders.ConclusionsOur results indicate that the MRZR is highly specific to MS. Nevertheless, two schizodepressive patients also had a positive MRZR. This finding corresponds to the few MRZR-positive patients with OIND or other autoimmune disorders with central nervous involvement, implicating that the MRZR specificity for MS is high, but not 100%.

In Silico Prediction Analysis of Idiotope-Driven T-B Cell Collaboration in Multiple Sclerosis.

Memory B cells acting as antigen-presenting cells are believed to be important in multiple sclerosis (MS), but the antigen they present remains unknown. We hypothesized that B cells may activate CD4+ T cells in the central nervous system of MS patients by presenting idiotopes from their own immunoglobulin variable regions on human leukocyte antigen (HLA) class II molecules. Here, we use bioinformatics prediction analysis of B cell immunoglobulin variable regions from 11 MS patients and 6 controls with other inflammatory neurological disorders (OINDs), to assess whether the prerequisites for such idiotope-driven T–B cell collaboration are present. Our findings indicate that idiotopes from the complementarity determining region (CDR) 3 of MS patients on average have high predicted affinities for disease associated HLA-DRB1*15:01 molecules and are predicted to be endosomally processed by cathepsin S and L in positions that allows such HLA binding to occur. Additionally, complementarity determining region 3 sequences from cerebrospinal fluid (CSF) B cells from MS patients contain on average more rare T cell-exposed motifs that could potentially escape tolerance and stimulate CD4+ T cells than CSF B cells from OIND patients. Many of these features were associated with preferential use of the IGHV4 gene family by CSF B cells from MS patients. This is the first study to combine high-throughput sequencing of patient immune repertoires with large-scale prediction analysis and provides key indicators for future in vitro and in vivo analyses.

Evaluation of total, ceruloplasmin-associated and type II ferroxidase activities in serum and cerebrospinal fluid of multiple sclerosis patients

Multiple sclerosis (MS) patients have increased brain iron deposition with higher oxidative stress (OxS). These two features can be caused by an inefficient removal of free iron from extracellular compartment. Ferroxidase activity (Feox) exerted by ceruloplasmin (FeoxCp) and by other molecules (FeoxII) appears to have a central role in this process. The aim of this study was to investigate serum and cerebrospinal fluid (CSF) total Feox, FeoxII and FeoxCp activities in MS patients and neurological controls. Serum and CSF Feox activity, FeoxII and FeoxCp activity was measured in 91 relapsing-remitting (RR) MS patients, 79 subjects with other inflammatory neurological disorders (OIND) and 65 with non-inflammatory neurological disorders (NIND), as controls. This study was approved by the Local Committee for Medical Ethics in Research. Serum total Feox activity was lower in MS group than in both NIND and OIND, with only the former control group differing significantly (p<0.001); FeoxII and FeoxCp activities were comparable among the groups. Serum Feox activities were not associated with disease activity as assessed by clinical examination or by Magnetic Resonance Imaging (MRI). Only total Feox activity was detectable in the CSF and was not different in MS compared to either OIND or NIND.In conclusion, a condition of low systemic Feox may increase the susceptibility of MS patients to iron(II) mediated-oxidative damage. This alteration is not reflected in CSF, suggesting that agents endowed with Feox activity might have different impact in iron homeostasis in the central nervous system compared to periphery.

Decreased soluble IFN-β receptor (sIFNAR2) in multiple sclerosis patients: A potential serum diagnostic biomarker

Background: The soluble isoform of the interferon-β (IFN-β) receptor (sIFNAR2) could modulate the activity of both endogenous and systemically administered IFN-β. Previously, we described lower serum sIFNAR2 levels in untreated multiple sclerosis (MS) than in healthy controls (HCs). Objective: To assess sIFNAR2 levels in a new cohort of MS patients and HCs, as well as in patients with clinically isolated syndrome (CIS) and with other inflammatory neurological disorders (OIND) and to assess its ability as a diagnostic biomarker. Methods: The cross-sectional study included 148 MS (84 treatment naive and 64 treated), 87 CIS, 42 OIND, and 96 HCs. Longitudinal study included 94 MS pretreatment and after 1 year of therapy with IFN-β, glatiramer acetate (GA), or natalizumab. sIFNAR2 serum levels were measured by a quantitative ELISA developed and validated in our laboratory. Results: Naive MS and CIS patients showed significantly lower sIFNAR2 levels than HCs and OIND patients. The sensitivity and specificity to discriminate between MS and OIND, for a sIFNAR2 cutoff value of 122.02 ng/mL, were 70.1%, and 79.4%, respectively. sIFNAR2 increased significantly in IFN-β-treated patients during the first year of therapy in contrast to GA- and natalizumab-treated patients who showed non-significant changes. Conclusion: The results suggest that sIFNAR2 could be a potential diagnostic biomarker for MS.

Epstein-Barr virus-specific intrathecal oligoclonal IgG production in relapsing-remitting multiple sclerosis is limited to a subset of patients and is composed of low-affinity antibodies.

BackgroundThe purpose of this study was to investigate intrathecal production and affinity distributions of Epstein-Barr virus (EBV)-specific antibodies in multiple sclerosis (MS) and controls.MethodsCerebrospinal fluid (CSF) and serum concentrations, quantitative intrathecal synthesis, oligoclonal bands (OCB) patterns and affinity distributions of anti-Epstein Barr virus (EBV) antibodies were evaluated in 100 relapsing-remitting MS (RRMS) patients and 200 age- and sex-matched controls with other inflammatory neurological disorders (OIND) and other noninflammatory neurological disorders (NIND).ResultsLevels of anti-EBNA-1 and anti-viral capsid antigen (VCA) IgG were different in both the CSF (P <0.0001 and P <0.01, respectively) and serum (P <0.001 and P <0.05, respectively) among the RRMS, OIND and NIND. An intrathecal synthesis of anti-EBNA-1 IgG and anti-VCA IgG, as indicated by the antibody index, was underrepresented in the RRMS, OIND and NIND (range 1 to 7%). EBV-specific OCB were detected in 24% of the RRMS patients and absent in the controls. High-affinity antibodies were more elevated in the RRMS and in the OIND than in the NIND for CSF anti-EBNA-1 IgG (P <0.0001) and anti-VCA IgG (P <0.0001). After treatment with increasing concentrations of sodium thiocyanate, the EBV-specific IgG OCB had low affinity in all 24 RRMS patients analyzed.ConclusionsOur findings do not support the potential role of an EBV persistent brain chronic infection in MS and suggest that an EBV-specific intrathecal oligoclonal IgG production can occur in a subset of MS patients as part of humoral polyreactivity driven by chronic brain inflammation.

CSF neurofilament light chain is elevated in OMS (decreasing with immunotherapy) and other pediatric neuroinflammatory disorders

Using a panel of seven brain cell-specific biomarkers in cerebrospinal fluid (CSF), pediatric opsoclonus–myoclonus syndrome (OMS) (n=234) was compared to pediatric non-inflammatory neurological controls (n=84) and other inflammatory neurological disorders (OIND) (n=44). Only CSF NFL was elevated in untreated OMS versus controls (+83%). It was 87% higher in OIND than in OMS. On combination treatment with front-loaded ACTH, IVIg, rituximab, median CSF NFL decreased by 60% to control levels. These biochemical data suggest neuronal/axonal injury in some children with OMS without indicators of astrogliosis, and reduction on sufficient immunotherapy.

Cytokines, cytokine antagonists, and soluble adhesion molecules in pediatric OMS and other neuroinflammatory disorders

ObjectiveTo test for hypothesized disease- and treatment-induced changes in cytokines and adhesion molecules in children with opsoclonus-myoclonus syndrome (OMS). MethodsMultiplex bead assay technology was used for simultaneous measurement of 34 soluble cytokines in cerebrospinal fluid (CSF) and serum. Soluble intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) were measured by ELISA. In total, there were 388 children (239 OMS, 114 controls, and 35 other inflammatory neurological disorders (OIND)). ResultsIn untreated OMS, mean CSF IL-6 was elevated 2.3-fold, but 67-fold in OIND, without significant differences in other CSF cytokines. Mean serum concentrations of sIL-2Ra (+50%) and CXCL1 (+70%) (p<0.0001) were also raised. CSF CCL5 was more often detected in untreated OMS than controls (p=0.005), as was serum CCL11 and IL-13 in treated OMS. Mean CSF CCL4 and IL-1Ra were selectively higher in IVIg-treated OMS (p≤0.0001). CSF sICAM-1 was elevated only in OIND (3.3-fold); serum sICAM-1 was higher in untreated OMS (+21%); and sVCAM-1 was not affected. No correlations with OMS severity or duration were identified. ConclusionsNovel cytokine, cytokine antagonist, and soluble adhesion molecule abnormalities due to OMS or treatment were found. However, the normality of much of the data strengthens previous findings implicating B cell mechanisms.

BAFF/APRIL system in pediatric OMS: relation to severity, neuroinflammation, and immunotherapy

BackgroundB-cell dysregulation has been implicated but not fully characterized in pediatric opsoclonus-myoclonus syndrome (OMS), a neuroblastoma-associated neuroinflammatory disorder.ObjectiveTo assess the role of B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), two critical B cell-modulating cytokines, as potential biomarkers of disease activity and treatment biomarkers in OMS.MethodsSoluble BAFF and APRIL were measured in cerebrospinal fluid (CSF) and serum by ELISA in 433 children (296 OMS, 109 controls, 28 other inflammatory neurological disorders (OIND)). BAFF-R receptors on circulating CD19+ B cells were measured by flow cytometry. A blinded scorer rated motor severity on the OMS Evaluation Scale. Immunotherapies were evaluated cross-sectionally and longitudinally.ResultsThe mean CSF BAFF concentration, which was elevated in untreated OMS and OIND, correlated with OMS severity category (P = 0.006), and reduction by adrenocorticotropic hormone or corticotropin (ACTH) (−61%) or corticosteroids (−38%) was seen at each level of severity. In contrast, CSF APRIL was normal in OMS and OIND and unaffected by immunotherapy. When the entire OMS dataset was dichotomized into ‘high’ versus ‘normal’ CSF BAFF concentration, the phenotype of the high group included greater motor severity and number of CSF oligoclonal bands, and a higher concentration of inflammatory chemokines CXCL13 and CXCL10 in CSF and CXCL9 and CCL21 in serum. Serum APRIL was 6.7-fold higher in the intravenous immunoglobulins (IVIg) group, whereas serum BAFF was 2.6-fold higher in the rituximab group. The frequency of B cell BAFF-R expression was similar in untreated and treated OMS. Longitudinal studies of CSF BAFF revealed a significant decline in ACTH-treated patients (with or without rituximab) (P < 0.0001). Longitudinal studies of serum APRIL showed a 2.9-fold increase after 1 to 2 g/kg IVIg monotherapy (P = 0.0003).ConclusionsStriking distinctions in BAFF/APRIL signaling were found. OMS displayed heterogeneity in CSF BAFF expression, which met many but not all criteria as a potential biomarker of disease activity. We speculate that CSF BAFF may have more utility in a biomarker panel than as a stand-alone biomarker, and that the selective upregulation of both serum APRIL by IVIg and BAFF by rituximab, as well as downregulation of CSF BAFF by ACTH/steroids, may have utility as treatment biomarkers.

Biological markers in cerebrospinal fluid for axonal impairment in multiple sclerosis: acetylcholinesterase activity cannot be considered a useful biomarker

An impairment of the cholinergic system activity has been demonstrated in multiple sclerosis (MS). The correlation between the cholinergic system and the cognitive dysfunction in MS has led to studies on the use of acetylcholinesterase inhibitors (AChEI). The acetylcholinesterase (AChE), essential enzyme for the regulation of turnover of acetylcholine, can be considered the most important biochemical indicator of cholinergic signaling in the nervous system. Besides its catalytic properties, AChE has a crucial role in the regulation of the immune function. Based on the role of the AChe in the regulation of cholinergic signaling in the nervous system, the aim of the present study is to evaluate the activity of AChE in different pathological conditions: MS, other inflammatory neurological disorders (OIND) and non-inflammatory neurological disorders (NIND). We measured AChE activity in CSF samples obtained from 34 relapsing-remitting MS patients and, as controls, 40 patients with other inflammatory neurological disorders (OIND) and 40 subjects with other non-inflammatory neurological disorders (NIND). Fluorimetric detection of the AChE in MS patients and in the controls showed no statistically significant differences: 1.507±0.403nmol/ml/min in MS patients, 1.484±0.496nmol/ml/min in OIND and 1.305±0.504nmol/ml/min in NIND. Similar results were obtained in another recent study, using a different method. Further studies must be conducted on a larger number of patients, with different degrees of cognitive impairment. However, AChE measured in CSF can probably not be considered a useful biomarker for the assessment of the functional alterations of cholinergic system in pathological conditions.

Chlamydia pneumoniae–specific intrathecal oligoclonal antibody response is predominantly detected in a subset of multiple sclerosis patients with progressive forms

The purpose of this study was to verify the actual involvement of Chlamydia pneumoniae in multiple sclerosis (MS) by the evaluation of its specific intrathecal humoral immune response in MS. We measured by enzyme-linked immunosorbent assay (ELISA) technique cerebrospinal fluid (CSF) and serum levels of anti-C. pneumoniae immunoglobulin G (IgG) in 27 relapsing-remitting (RR), 9 secondary progressive (SP), and 5 primary progressive (PP) MS patients, grouped according to clinical and magnetic resonance imaging (MRI) evidence of disease activity. Twenty-one patients with other inflammatory neurological disorders (OIND) and 21 with noninflammatory neurological disorders (NIND) were used as controls. Quantitative intrathecal synthesis of anti-C. pneumoniae IgG was determined by antibody-specific index (ASI), whereas the presence of C. pneumoniae-specific CSF oligoclonal IgG bands was assessed by antigen-specific immunoblotting. ASI values indicative of C. pneumoniae-specific intrathecal IgG synthesis were present in a small proportion of MS (29.3%), OIND (33.3%), and NIND (4.8%) patients and were significantly more frequent (P < .05) in total MS and in OIND than in NIND and in SP (P < .01) and PP MS (P < .05) than in RR MS. C. pneumoniae-specific CSF-restricted OCB were detected only in three SP, one PP, and one RR MS patients. These findings suggest that an intrathecal production of anti-C. pneumoniae IgG is part of humoral polyreactivity driven by MS chronic brain inflammation. However, an intrathecal release of C. pneumoniae-specific oligoclonal IgG can occur in a subset of patients with MS progressive forms in whom a C. pneumoniae-persistent brain infection may play a pathogenetic role.

Soluble HLA-G molecules are released as HLA-G5 and not as soluble HLA-G1 isoforms in CSF of patients with relapsing–remitting Multiple Sclerosis

Cerebrospinal fluid (CSF) levels of sHLA-G (sHLA-G1/HLA-G5) molecules and their soluble isoforms HLA-G5 and sHLA-G1 were measured by ELISA procedures in 68 relapsing–remitting Multiple Sclerosis (RR MS) patients, in 67 patients with other inflammatory neurological disorders (OIND) and in 70 subjects with non-inflammatory neurological disorders (NIND). CSF concentrations of sHLA-G1/HLA-G5 and HLA-G5 were higher in RR MS than in OIND and NIND, and in Magnetic Resonance Imaging (MRI) inactive as compared to MRI active RR MS. Our results indicate that the potential implication of sHLA-G proteins in the resolution of MS intrathecal inflammatory response is probably due to HLA-G5 isoform.

Cerebrospinal fluid and serum levels and intrathecal production of active matrix metalloproteinase-9 (MMP-9) as markers of disease activity in patients with multiple sclerosis

In this study, we employed a sensitive activity assay system to measure cerebrospinal fluid (CSF) and serum levels of active matrix metalloproteinase-9 (MMP-9) in 37 relapsing-remitting (RR), 15 secondary progressive (SP) and nine primary progressive (PP) multiple sclerosis (MS) patients, grouped according to clinical and magnetic resonance imaging (MRI) evidence of disease activity. We also studied, as neurological controls, 48 patients with other inflammatory neurological disorders (OIND) and 48 with non-inflammatory neurological disorders (NIND). To assess active MMP-9/TIMP-1 circuit, CSF and serum levels of MMP-9 tissue inhibitor TIMP-1 were quantified by ELISA in the same patient population. CSF mean levels of active MMP-9, CSF active MMP-9/TIMP-1 ratios and intrathecal active MMP-9 synthesis, as indicated by specific index, were more elevated in MS than in NIND (P <0.05, <0.02 and <0.02, respectively), serum active MMP-9/TIMP-1 ratio was higher in MS (P<0.01) and OIND (P<0.02) than in NIND, and serum TIMP-1 concentrations were lower in MS than in NIND (P<0.05). More importantly, serum active MMP-9 mean levels, serum active MMP-9/TIMP-1 ratio and intrathecal production of active MMP-9 were increased in MS patients with clinical (P<0.001, <0.001 and <0.05, respectively) and MRI (P<0.001, <0.001 and <0.02, respectively) disease activity, whereas CSF mean concentrations of active MMP-9 and CSF active MMP-9/TIMP-1 ratio were enhanced only in MS patients with MRI evidence of disease activity (P<0.02 and <0.01, respectively). Altogether, these findings suggest that a shift in MMP-9/TIMP-1 balance towards proteolytic activity of MMP-9 could be relevant in MS immune dysregulation. In addition, our results indicate that CSF and serum levels of active MMP-9 may represent a potential surrogate biomarker for monitoring MS disease activity. In particular, serum active MMP-9/TIMP-1 ratio seems to be a very appropriate indicator of ongoing MS inflammation, since it is easily measurable.

Intrathecal synthesis of soluble HLA-G and HLA-I molecules are reciprocally associated to clinical and MRI activity in patients with multiple sclerosis

The aim of this study was to provide further insight into the effective contribution of classical soluble HLA-A, B and C class Ia (sHLA-I) and non-classical soluble HLA-G class Ib (sHLA-G) molecules in immune dysregulation occurring in multiple sclerosis (MS). We evaluated by enzyme-linked immunosorbent assay (ELISA) technique intrathecal synthesis and cerebrospinal fluid (CSF) and serum levels of sHLA-I and sHLA-G in 69 relapsing-remitting (RR), 21 secondary progressive (SP) and 13 primary progressive (PP) MS patients stratified according to clinical and magnetic resonance imaging (MRI) evidence of disease activity. We also tested, as neurological controls, 91 patients with other inflammatory neurological disorders (OIND) and 92 with non-inflammatory neurological disorders (NIND). Eighty-two healthy volunteers served as further controls for sHLA-I and sHLA-G determinations. An intrathecal production of sHLA-I and sHLA-G detected by specific indexes was significantly more frequent in MS patients than in controls (p<0.01). An intrathecal synthesis of sHLA-I was prevalent in clinically (p<0.02) and MRI active (p<0.001) MS, whereas a CSF-restricted release of sHLA-G predominated in clinically (p<0.01) and MRI stable (p<0.001) MS. sHLA-I levels were low in the serum of clinically active (p<0.001) and high in the CSF of MRI active (p<0.01) MS. Conversely, sHLA-G concentrations were decreased in the serum of clinically stable MS (p<0.01) and increased in the CSF of MRI inactive MS (p<0.001). The trends towards a negative correlation observed between CSF and serum concentrations and intrathecal synthesis of sHLA-I and sHLA-G in patients without evidence of clinical and MRI activity confirmed that intrathecal production and fluctuations in CSF and serum concentrations of sHLA-I and sHLA-G were reciprocal in MS. Our results suggest that, in MS, a balance between classical sHLA-I and non-classical sHLA-G products modulating both MRI and clinical disease activity in opposite directions may exist.

Cerebrospinal fluid molecular demonstration of Chlamydia pneumoniae DNA is associated to clinical and brain magnetic resonance imaging activity in a subset of patients with relapsing-remitting multiple sclerosis.

To further explore the link between Chlamydia pneumoniae and multiple sclerosis (MS), we examined cerebrospinal fluid (CSF) samples from 71 patients with MS and from 72 patients suffering from other inflammatory neurological disorders (OIND) or noninflammatory neurological disorders (NIND). All samples were analysed by a touchdown nested polymerase chain reaction (n-PCR) for C. pneumoniae with primer sets which amplify target sequence genes encoding the major outer membrane protein (MOMP), the 16S rRNA and the Hsp-70 protein. A molecular study was also performed to evaluate genetic diversity among isolates of C. pneumoniae and to compare chlamydial sequences. PCR was found positive in 36.6% of total MS, in 28.1% of OIND and in 37.5% of NIND patients, without any statistical differences among the various groups examined. CSF PCR evidence of C. pneumoniae was significantly more frequent in relapsing-remitting (RR) than in secondary progressive (SP) (P < 0.001) and in primary progressive (PP)MS (P < 0.05), in clinically active than in clinically stable MS (P < 0.05) and in MRI active than in MRI inactive MS (P < 0.001). The analysis of CSF expression of each single C. pneumoniae-specific gene revealed that detectable levels of MOMP were significantly more frequent in MS patients with relapse (P < 0.05), whereas PCR positivity for MOMP and 16S rRNA genes were more represented in MS patients with clinical and MRI evidence of disease activity (P < 0.05). Similar rates for MOMP and 16S rRNA genes were detected in CSF of both MS patients and controls, whereas CSF PCR positivity for Hsp-70 gene was observed in only three active RR MS patients. Sequence analysis revealed significant homologies with C. pneumoniae compared to other Chlamydial spp. These findings confirm that the C. pneumoniae detection within the central nervous system (CNS) is not selectively restricted to MS, but accounts in a variety of neurological diseases. In addition, our results suggest that CSF C. pneumoniae-specific DNA detection can occur in a subset of MS patients with clinical and MRI active RR form in whom a C. pneumoniae brain chronic persistent infection may play a significant role in the development of disease.

Intrathecal production of Chlamydia pneumoniae-specific high-affinity antibodies is significantly associated to a subset of multiple sclerosis patients with progressive forms

The purpose of this study was to provide further insight into the effective relevance of the association between Chlamydia pneumoniae and MS. We evaluated by ELISA technique cerebrospinal fluid (CSF) and serum levels of anti- C. pneumoniae IgG in 46 relapsing–remitting (RR), 14 secondary progressive (SP) and 11 primary progressive (PP) MS patients grouped according to clinical and Magnetic Resonance Imaging (MRI) evidence of disease activity. Fifty-one patients with other inflammatory neurological disorders (OIND) and 52 with non-inflammatory neurological disorders (NIND) were used as controls. A C. pneumoniae-specific intrathecal IgG synthesis as detected by the relative specific index was present in a small proportion of MS (17%), OIND (22%) and NIND (2%) patients and was significantly more frequent in MS and in OIND than in NIND ( p<0.001) and in SP and PP MS than in RR MS patients ( p<0.02). Among the patients with C. pneumoniae-specific intratecally produced antibodies, CSF high-affinity anti- C. pneumoniae IgG were found in the majority of SP or PP MS, occasionally in OIND, but not in RR MS and NIND patients. These findings confirm that the presence of a humoral immune response to C. pneumoniae within the central nervous system (CNS) is not selectively restricted to MS, but is shared by several inflammatory neurological conditions. In addition, our results suggest that an intrathecal production of C. pneumoniae-specific high-affinity IgG can occur in a subset of patients with MS progressive forms in which a C. pneumoniae brain chronic persistent infection may play an important pathogenetic role.

Presence of detectable levels of soluble HLA-G molecules in CSF of relapsing–remitting multiple sclerosis: relationship with CSF soluble HLA-I and IL-10 concentrations and MRI findings

We have investigated the presence of non-classical soluble HLA-G molecules (sHLA-G) in cerebrospinal fluid (CSF) of multiple sclerosis (MS) patients and the possible relationships between CSF levels of sHLA-G, classical soluble HLA-I (sHLA-I) molecules, IL-10 amounts and Magnetic Resonance Imaging (MRI) findings were evaluated. We studied by ELISA technique the sHLA-I, sHLA-G and IL-10 levels in CSF of 50 relapsing–remitting (RR) MS patients stratified according to clinical and MRI evidence of disease activity. Thirty-six patients with other inflammatory neurological disorders (OIND) and 41 with non-inflammatory neurological disorders (NIND) were used as controls. CSF mean levels were significantly higher in MS and OIND than in NIND for sHLA-I ( p<0.001) and in MS than in controls for sHLA-G ( p<0.001), with no differences among the various groups for IL-10 mean concentrations. An increase in CSF sHLA-I was found in MS patients with Gd-enhancing lesions ( p<0.01), while sHLA-G and IL-10 were more represented in MS patients without lesional activity on MRI scans ( p<0.02). In MRI-inactive MS, CSF IL-10 mean concentrations were significantly greater in patients with CSF-detectable levels of sHLA-G than in those without any evidence of CSF sHLA-G expression ( p<0.05). Our findings suggest that CSF classical sHLA-I and non-classical sHLA-G levels may modulate MS activity as assessed by MRI acting in opposite directions. The association observed between sHLA-G and IL-10 when Gd-enhancing lesion resolved indicates a potential immunoregulatory role for IL-10 in the control of MS disease activity by shifting the sHLA-I/sHLA-G balance towards sHLA-G response.

Antibodies against myelin oligodendrocyte glycoprotein in the cerebrospinal fluid of multiple sclerosis patients

Antibodies against myelin oligodendrocyte glycoprotein (MOG) mediate demyelination in experimental autoimmune encephalomyelitis (EAE) in different animal species and are implicated in the immunopathogenesis of multiple sclerosis (MS). In order to evaluate the anti-MOG response, we have analyzed the cerebrospinal fluids (CSFs) from 44 MS patients and 51 controls, 11 with other inflammatory neurological disorders (OIND) and 40 with non-inflammatory neurological disorders (NIND). The frequency of anti-MOG antibodies positive patients in the MS group (30%) was significantly higher compared to the NIND (8%, p=0.02), but not compared to the OIND group (55%, p=0.228). Interestingly, all six patients with neurosarcoidosis had MOG-specific antibodies in their CSF. Frequency of anti-MOG antibodies was similar in patients with clinically active and stable MS (32% and 26%, respectively; p=0.921). However, in clinically active MS patients, antibody titers were higher in comparison with patients with stable disease, although the difference did not reach the level of statistical significance ( p=0.06). These results further support the potential role of anti-MOG antibodies in the immunopathology of MS in the subset of patients with this disease. Furthermore, our findings suggest for the first time that anti-MOG antibodies could be an accessory diagnostic tool in neurosarcoidosis.

Clinical and MRI disease activity in multiple sclerosis are associated with reciprocal fluctuations in serum and cerebrospinal fluid levels of soluble HLA class I molecules

The goal of our study was to clarify the contribution of soluble human leukocyte antigens class I (sHLA-I) in multiple sclerosis (MS) immune dysregulation. We retrospectively evaluated by ELISA cerebrospinal fluid (CSF) and serum sHLA-I levels in 79 relapsing–remitting (RR), 26 secondary progressive (SP) and 15 primary progressive (PP) MS patients stratified according to clinical and Magnetic Resonance Imaging (MRI) evidence of disease activity. One hundred and nine patients with other inflammatory neurological disorders (OIND), 88 with noninflammatory neurological disorders (NIND) and 82 healthy donors were used as controls. An intrathecal synthesis of sHLA-I detected by a specific index was significantly more consistent in MS than in controls, with more pronounced values in MS patients with relapses and MRI enhancing brain lesions. A decrease in serum sHLA-I concentrations was observed in MS patients with demyelinating attacks, while an increase in CSF levels of sHLA-I was found in MS patients with lesional activity on MRI scans. This association between intrathecal synthesis and reciprocal fluctuations of CSF and serum levels of sHLA-I in clinically and MRI active MS seems to suggest a potential role for CSF and serum levels of sHLA-I as a sensitive marker of immune activation taking place both intrathecally and systemically in MS.