CSF proteome in multiple sclerosis subtypes related to brain lesion transcriptomes

AbstractTo identify markers in the CSF of multiple sclerosis (MS) subtypes, we used a two-step proteomic approach: (i) Discovery proteomics compared 169 pooled CSF from MS subtypes and inflammatory/degenerative CNS diseases (NMO spectrum and Alzheimer disease) and healthy controls. (ii) Next, 299 proteins selected by comprehensive statistics were quantified in 170 individual CSF samples. (iii) Genes of the identified proteins were also screened among transcripts in 73 MS brain lesions compared to 25 control brains. F-test based feature selection resulted in 8 proteins differentiating the MS subtypes, and secondary progressive (SP)MS was the most different also from controls. Genes of 7 out these 8 proteins were present in MS brain lesions: GOLM was significantly differentially expressed in active, chronic active, inactive and remyelinating lesions, FRZB in active and chronic active lesions, and SELENBP1 in inactive lesions. Volcano maps of normalized proteins in the different disease groups also indicated the highest amount of altered proteins in SPMS. Apolipoprotein C-I, apolipoprotein A-II, augurin, receptor-type tyrosine-protein phosphatase gamma, and trypsin-1 were upregulated in the CSF of MS subtypes compared to controls. This CSF profile and associated brain lesion spectrum highlight non-inflammatory mechanisms in differentiating CNS diseases and MS subtypes and the uniqueness of SPMS.

Download Full-text

Intrathecal synthesis of IgM measured after a first demyelinating event suggestive of multiple sclerosis is associated with subsequent MRI brain lesion accrual

Multiple Sclerosis Journal ◽

10.1177/1352458511424589 ◽

2011 ◽

Vol 18 (5) ◽

pp. 587-591 ◽

Cited By ~ 17

Author(s):

Laurence Durante ◽

Wafaa Zaaraoui ◽

Audrey Rico ◽

Lydie Crespy ◽

Delphine Wybrecht ◽

...

Keyword(s):

Multiple Sclerosis ◽

Longitudinal Study ◽

Brain Lesion ◽

Rank Correlation ◽

Brain Lesions ◽

Subsequent Formation ◽

Intrathecal Synthesis ◽

Igg Synthesis ◽

Intrathecal Igg Synthesis

Background: Previous studies have demonstrated that intrathecal synthesis of IgM is observed in multiple sclerosis (MS) and correlates with a worse disease course. These results suggest that IgM participates in the formation of MS lesions. Objective: The aim of the present study was to assess the potential association between the level of intrathecal synthesis of IgM measured after a clinically isolated syndrome (CIS) and the subsequent formation of brain lesions. Methods: Fifty seven patients with a CIS and a high risk developing MS were enrolled in a longitudinal study. Examination of cerebrospinal fluid was performed after the CIS and included measures of intrathecal IgM and IgG synthesis. Patients were assessed with the same 1.5 Tesla magnetic resonance imaging (MRI) system at baseline and after a mean follow-up period of 49 months (range 36–60). Spearman Rank correlation was used to assess the potential correlations between levels of intrathecal immunoglobulin synthesis and MRI data. Results: The level of intrathecal IgM synthesis was correlated with the number of gadolinium-enhancing lesions at baseline ( p = 0.01) and with accrual of brain lesions during the follow-up period ( p = 0.02). By taking into account brain sub-regions, we demonstrated that the level of intrathecal IgM synthesis was only correlated with the increased number of lesions in the periventricular regions ( p = 0.004). The level of intrathecal IgG synthesis was not correlated with any MRI data. Conclusion: The present longitudinal study demonstrates that the level of intrathecal IgM synthesis measured after a CIS is associated with subsequent lesion accrual during the first years of MS. This result emphasizes the involvement of IgM in plaque formation.

Download Full-text

Association of the HLA-DRB1 alleles with characteristic MRI features of Asian multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458508097818 ◽

2008 ◽

Vol 14 (9) ◽

pp. 1181-1190 ◽

Cited By ~ 28

Author(s):

T Matsuoka ◽

T Matsushita ◽

M Osoegawa ◽

Y Kawano ◽

M Minohara ◽

...

Keyword(s):

Multiple Sclerosis ◽

Brain Lesion ◽

Japanese Patients ◽

Brain Lesions ◽

Oligoclonal Bands ◽

Factors Associated ◽

Logistic Analysis ◽

Asian Patients ◽

Mri Features ◽

Magnetic Resonance Imaging Mri

Background In Asian patients with multiple sclerosis (MS), a paucity of brain lesions and longitudinally extensive spinal cord lesions (LESCLs) extending three or more vertebral segments are characteristic findings on magnetic resonance imaging (MRI). We aimed to disclose possible factors contributing to the development of such MRI features. Method Genotyping of HLA-DRB1 and -DPB1 alleles was performed in 121 consecutive Japanese patients with clinically definite MS based on the Poser criteria and 125 healthy controls. Possible factors associated with MRI features were determined by multiple logistic analysis. Patients with MS were classified based on the presence or absence of brain lesions fulfilling the Barkhof criteria (Barkhof brain lesions) and LESCLs. Barkhof brain lesion–negative (−) patients had a markedly lower frequency of HLA-DRB1*0901 than controls ( Pcorr < 0.05), whereas the frequency of DRB1*1501 was increased in the Barkhof brain lesion–positive (+) group, although this increase was not significant after correction. No Barkhof(−)LESCL(+) patients carried DRB1*0901 ( Pcorr < 0.05), despite this being the most common allele in Japanese. The Barkhof(−)LESCL(−) group showed a significant increase in the frequency of DRB1*0405 compared with controls ( Pcorr < 0.05). None of the DPB1 alleles were significantly different among the groups. Using multiple logistic analysis, the absence of oligoclonal bands was positively associated with an absence of Barkhof brain lesions, whereas a higher EDSS score was positively associated with the presence of LESCLs; however, the presence of anti-aquaporin-4 antibodies was not associated with either feature. Conclusion The characteristic MRI features in Asians are partly related to distinct HLA-DRB1 gene alleles and an absence of oligoclonal bands.

Download Full-text

Proportion of alemtuzumab-treated patients converting from relapsing-remitting multiple sclerosis to secondary progressive multiple sclerosis over 6 years

Multiple Sclerosis Journal - Experimental Translational and Clinical ◽

10.1177/2055217320972137 ◽

2020 ◽

Vol 6 (4) ◽

pp. 205521732097213 ◽

Cited By ~ 1

Author(s):

Dana Horáková ◽

Aaron Boster ◽

Antonio Bertolotto ◽

Mark S Freedman ◽

Isabel Firmino* ◽

...

Keyword(s):

Multiple Sclerosis ◽

Brain Lesion ◽

Functional System ◽

Progressive Multiple Sclerosis ◽

Secondary Progressive ◽

Kaplan Meier ◽

Relapsing Remitting ◽

Core Study ◽

Few Data ◽

Post Hoc

Background Few data exist concerning conversion to secondary progressive MS in patients treated with disease-modifying therapies. Objective Determine the proportion of alemtuzumab-treated patients converting from relapsing-remitting to secondary progressive MS during the CARE-MS core and extension studies. Methods Patients ( N = 811) were analyzed post hoc for secondary progressive MS conversion. Optimal conversion definition: Expanded Disability Status Scale (EDSS) score ≥4, pyramidal functional system score ≥2, and confirmed progression over ≥3 months including confirmation within the functional system leading to progression, independent of relapse. Results Over 6.2 years median follow-up, 20 alemtuzumab-treated patients converted (Kaplan-Meier estimate, 2.7%; 95% confidence interval, 1.8%–4.2%). Sensitivity analysis accounting for dropouts showed similar results (3%), as did analyses using alternative definitions with different EDSS thresholds and/or confirmation periods, and analysis of core study subcutaneous interferon beta-1a-treated patients who received alemtuzumab in the extension. Patients converting to secondary progressive MS were older, and had higher EDSS scores and greater brain lesion volumes at baseline, but did not need additional alemtuzumab or other therapies. Conclusions The 6-year conversion rate to secondary progressive MS was low for alemtuzumab-treated patients, supporting further study of the role alemtuzumab may play in reducing risk of secondary progression. ClinicalTrials.gov identifiers: NCT00530348, NCT00548405, NCT00930553.

Download Full-text

Identification of galectin-3 as a possible antibody target for secondary progressive multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458516655217 ◽

2016 ◽

Vol 23 (3) ◽

pp. 382-394 ◽

Cited By ~ 13

Author(s):

Hideaki Nishihara ◽

Fumitaka Shimizu ◽

Takao Kitagawa ◽

Nanami Yamanaka ◽

Junko Akada ◽

...

Keyword(s):

Multiple Sclerosis ◽

Neurological Diseases ◽

Progressive Multiple Sclerosis ◽

Intercellular Adhesion Molecule ◽

Intercellular Adhesion Molecule 1 ◽

Protein Levels ◽

Secondary Progressive ◽

Proteomic Approach ◽

Galectin 3 ◽

Progressive Stage

Background: Recent studies have revealed that the disruption of the blood–brain barrier (BBB) might contribute to the induction of neurodegeneration in the progressive stage of multiple sclerosis (MS). Objective: We investigated a potential target for the serum auto-antibodies responsible for the BBB impairment in patients with secondary progressive MS (SPMS). Methods: We identified undetermined target antigens in human brain microvascular endothelial cells (BMECs) that reacted with auto-antibodies in sera from SPMS patients using a proteomic approach. In addition, we examined how the identified auto-antibodies compromise the BBB integrity. Results: We found that 10 of 11 SPMS sera had auto-antibodies against galectin-3, although the patients with other neurological diseases did not have these antibodies. Downregulation of galectin-3 led to elevated intercellular adhesion molecule-1 (ICAM-1) and phospho-nuclear factor-kappa (NFκ) B p65 expression in the BMECs. Exposure to SPMS patients’ sera also increased the protein levels of ICAM-1 and phospho-NFκB p65 in BMECs, but these effects induced by anti-galectin-3 immunoreactivity were canceled by the downregulation of galectin-3. Conclusion: Galectin-3 is a possible immunological target molecule of the pathogenic auto-antibodies and contributes to the persistent BBB breakdown in patients with SPMS. These antibodies may also serve as a novel biomarker for SPMS.

Download Full-text