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

2006 ◽  
Vol 12 (1) ◽  
pp. 2-12 ◽  
Author(s):  
E Fainardi ◽  
R Rizzo ◽  
L Melchiorri ◽  
M Castellazzi ◽  
E Paolino ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Disease Activity ◽  
Neurological Disorders ◽  
Serum Levels ◽  
Enzyme Linked Immunosorbent Assay ◽  
Serum Concentrations ◽  
Intrathecal Synthesis ◽  
Soluble Hla ◽  
Elisa Technique ◽  
Magnetic Resonance Imaging Mri

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.

CSF levels of soluble HLA-G and Fas molecules are inversely associated to MRI evidence of disease activity in patients with relapsing—remitting multiple sclerosis

2008 ◽  
Vol 14 (4) ◽  
pp. 446-454 ◽  
Author(s):  
E. Fainardi ◽  
R. Rizzo ◽  
L. Melchiorri ◽  
M. Stignani ◽  
M. Castellazzi ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Disease Activity ◽  
Neurological Disorders ◽  
Human Leukocyte ◽  
Inverse Correlation ◽  
Enzyme Linked Immunosorbent Assay ◽  
Relapsing Remitting ◽  
Soluble Hla ◽  
Csf Levels ◽  
Magnetic Resonance Imaging Mri

Cerebrospinal fluid (CSF) concentrations of soluble human leukocyte antigen class I (HLA-I) (sHLA-I), HLA-G (sHLA-G) and anti-apoptotic Fas (sFas) molecules were measured by enzyme linked immunosorbent assay technique in 65 relapsing—remitting (RR) MS patients classified according to clinical and magnetic resonance imaging (MRI) evidence of disease activity. Sixty-four patients with other inflammatory neurological disorders (OIND) and 64 subjects with noninflammatory neurological disorders (NIND) served as controls. CSF concentrations were higher in RRMS and in OIND than in NIND patients for sHLA-I ( P < 0.02), greater in RRMS than in OIND and in NIND for sHLA-G ( P < 0.001 and P < 0.01, respectively) and lower in RRMS than in OIND and in NIND for sFas ( P < 0.001 and P < 0.02, respectively). An increase in CSF levels was identified in MRI active RRMS for sHLA-I ( P < 0.01) and in MRI stable RRMS for sHLA-G ( P < 0.01), whereas CSF values of sFas were decreased in RRMS without Gd-enhancing lesions ( P < 0.02). In MS patients with no evidence of MRI disease activity, a trend towards an inverse correlation was found between CSF concentrations of sHLA-G and sHLA-I and between CSF levels of sHLA-G and sFas. Our results indicate that enhanced CSF levels of sHLA-I antigens most likely represent an indirect manifestation of intrathecal immune activation taking place in neuroinflammation. Conversely, reciprocal fluctuations in CSF sHLA-G and sFas levels observed when MRI disease activity resolved suggest that sHLA-G could play an immunomodulatory role in MS through Fas/FasL-mediated mechanisms. Multiple Sclerosis 2008; 14: 446—454. http://msj.sagepub.com

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

2006 ◽  
Vol 12 (3) ◽  
pp. 294-301 ◽  
Author(s):  
E Fainardi ◽  
M Castellazzi ◽  
T Bellini ◽  
M C Manfrinato ◽  
E Baldi ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
Matrix Metalloproteinase ◽  
Disease Activity ◽  
Neurological Disorders ◽  
Serum Levels ◽  
Matrix Metalloproteinase 9 ◽  
Active Matrix ◽  
Magnetic Resonance Imaging Mri ◽  
Metalloproteinase 9

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.

Epstein-Barr virus-specific antibody response in cerebrospinal fluid and serum of patients with multiple sclerosis

2010 ◽  
Vol 16 (7) ◽  
pp. 883-887 ◽  
Author(s):  
Massimiliano Castellazzi ◽  
Carmine Tamborino ◽  
Alice Cani ◽  
Elena Negri ◽  
Eleonora Baldi ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
Neurological Disorders ◽  
Epstein Barr Virus ◽  
Serum Levels ◽  
Nuclear Antigen ◽  
Enzyme Linked Immunosorbent Assay ◽  
Barr Virus ◽  
Epstein Barr ◽  
Multiple Sclerosis Patients

Cerebrospinal fluid and serum levels and intrathecal synthesis of anti-Epstein—Barr virus (EBV) IgG were measured by enzyme-linked immunosorbent assay in 80 relapsing—remitting multiple sclerosis patients grouped according to clinical and magnetic resonance imaging (MRI) evidence of disease activity. Eighty patients with other inflammatory neurological disorders (OIND) and 80 patients with non-inflammatory neurological disorders (NIND) served as neurological controls. Cerebrospinal fluid concentrations were higher in OIND than in multiple sclerosis ( p < 0.0001) and NIND ( p < 0.01) for anti-viral-capsid-antigen (anti-VCA) IgG, in multiple sclerosis than in NIND ( p < 0.01) and in OIND than in NIND ( p < 0.05) for anti-EBV nuclear antigen-1 (EBNA-1) IgG. Serum levels were more elevated in OIND than in multiple sclerosis ( p < 0.05) and in MRI inactive than in MRI active multiple sclerosis ( p < 0.0001) for anti-VCA IgG, and in multiple sclerosis than in OIND and NIND ( p < 0.01) for anti-EBNA-1 IgG. Serum titres of anti-VCA and anti-EBNA-1 IgG were also positively ( p < 0.05) and inversely ( p < 0.001) correlated, respectively, with the Expanded Disability Status Scale. An intrathecal IgG production of anti-VCA and anti-EBNA-1 IgG, as indicated by Antibody Index, was present only in a limited number of multiple sclerosis patients and controls (range from 1.3 to 6.3%). These findings do not support a direct pathogenetic role of EBV-targeted humoral immune response in multiple sclerosis.

scholarly journals Human Herpesvirus 6 and 7 Reactivation and Disease Activity in Multiple Sclerosis

Medicina ◽  
2011 ◽  
Vol 47 (10) ◽  
pp. 75 ◽  
Author(s):  
Zaiga Nora-Krukle ◽  
Svetlana Chapenko ◽  
Inara Logina ◽  
Andrejs Millers ◽  
Ardis Platkajis ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Disease Activity ◽  
Human Herpesvirus ◽  
Interleukin 12 ◽  
Enzyme Linked Immunosorbent Assay ◽  
Serum Concentrations ◽  
Human Herpesvirus 6 ◽  
Chain Reaction ◽  
Tnf Α ◽  
Herpesvirus 6

Recent studies have focused on the associations between human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7), and multiple sclerosis (MS). The aim of this study was to investigate the associations between HHV-6 and HHV-7 reactivation and MS disease activity, and interleukin 12 (IL-12) and tumor necrosis factor α (TNF-α) production. Material and Methods. The frequency of plasma viremia by nested polymerase chain reaction and transcription of viral mRNA in peripheral blood mononuclear cells by reverse transcriptasepolymerase chain reaction (RT-PCR) of 14 relapsing/remitting (RR) and 14 secondary progressive (SP) MS patients were studied in comparison with clinical manifestation of the disease. Serum concentrations of cytokines IL-12 and TNF-α were analyzed by enzyme-linked immunosorbent assay. Results. Plasma samples from 25 of the 28 MS patients with estimated latent/persistent HHV-6 and/or HHV-7 infection were examined during relapse and remission/relative remission. HHV-6 reactivation was found in 4 of the 7 RRMS and 4 of the 7 SPMS patients, and HHV-7 reactivation was identified in 3 of the 7 RRMS and 1 of the 7 SPMS patients (all in relapse). In 2 of the 3 RRMS patients without viremia in relapse, HHV-6 mRNA transcription was detected. In RRMS and SPMS patients with active HHV-6 and HHV-7 infection in relapse, the serum concentrations of IL-12 and TNF-α were significantly higher than in those with latent virus infection. Conclusions. HHV-6 and HHV-7 reactivation could be implicated in the exacerbation of MS via activation of Th1 lymphocyte subsets.

Intrathecal synthesis of matrix metalloproteinase-9 in patients with multiple sclerosis: implication for pathogenesis

2002 ◽  
Vol 8 (3) ◽  
pp. 222-228 ◽  
Author(s):  
G M Liuzzi ◽  
M Trojano ◽  
M Fanelli ◽  
C Avolio ◽  
A Fasano ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Matrix Metalloproteinase ◽  
Neurological Diseases ◽  
Inverse Correlation ◽  
Serum Levels ◽  
Matrix Metalloproteinase 9 ◽  
Enzyme Linked Immunosorbent Assay ◽  
Intrathecal Synthesis ◽  
Healthy Donors ◽  
Metalloproteinase 9

Matrix metalloproteinase-9 (MMP-9) was detected by zymography and enzyme-linked immunosorbent assay (ELISA) in matched serum and cerebrospinal fluid (CSF) samples from patients with neurological diseases. Patients with relapsing-remitting multiple sclerosis (RR-MS) had serum and CSF MMP-9 levels comparable to those from patients with inflammatory neurological diseases (INDs), but higher than patients with non-inflammatory neurological diseases (NINDs) and healthy donors (HDs). MMP-9 increased in active RR-MS in comparison with inactive RR-MS implying that MMP-9 in MS is related with clinical disease activity. A correlation between the CSF/serum albumin (QAlb) and CSF/serum MMP-9 (QMMP-9) was observed in IND and NIND but not in RR-MS patients, indicating that CSF MMP-9 levels in NIND and IND patients could be influenced by serum MMP-9 and blood-brain barrier (BBB) permeability properties. MS patients had higher values of QMMP-9:QAlb (MMP-9 index) than IND and NIND patients suggesting that in MS the increase in CSF MMP-9 could be due to intrathecal synthesis of MMP-9. A significant inverse correlation was found between MMP-9 and its endogenous inhibitor TIMP-1 in RR-MS indicating that in MS patients both the increase in MMP-9 and the decrease in TIMP-1 serum levels could contribute to BBB disruption and T-lymphocyte entry into the CNS.

Molecular detection of Parachlamydia-like organisms in cerebrospinal fluid of patients with multiple sclerosis

2008 ◽  
Vol 14 (4) ◽  
pp. 564-566 ◽  
Author(s):  
C Contini ◽  
S Seraceni ◽  
R Cultrera ◽  
M Castellazzi ◽  
E Granieri ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
Disease Activity ◽  
Neurological Disorders ◽  
Chlamydia Pneumoniae ◽  
Molecular Detection ◽  
Resonance Imaging ◽  
Relapsing Remitting ◽  
Polymerase Chain ◽  
Magnetic Resonance Imaging Mri

The presence of Chlamydia-like organism DNA was investigated by polymerase chain reaction (PCR) in cerebrospinal fluid (CSF) samples from 27 patients previously found positive for Chlamydia pneumoniae DNA: 12 with multiple sclerosis (MS), grouped according to clinical and magnetic resonance imaging (MRI) evidence of disease activity, 8 with other inflammatory neurological disorders and 7 with non-inflammatory neurological disorders. PCR evidence of Chlamydia-like organisms in CSF was observed only in two relapsing–remitting MS patients with clinical and MRI disease activity. These findings suggest a possible association between C. pneumoniae and Chlamydia-like organism brain infections as a cofactor in MS development.

TIMP-1 resistant matrix metalloproteinase-9 is the predominant serum active isoform associated with MRI activity in patients with multiple sclerosis

2015 ◽  
Vol 21 (9) ◽  
pp. 1121-1130 ◽  
Author(s):  
Alessandro Trentini ◽  
Maria C Manfrinato ◽  
Massimiliano Castellazzi ◽  
Carmine Tamborino ◽  
Gloria Roversi ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Matrix Metalloproteinase ◽  
Disease Activity ◽  
Serum Levels ◽  
Matrix Metalloproteinase 9 ◽  
Relapsing Remitting ◽  
Magnetic Resonance Imaging Mri ◽  
Specific Tissue ◽  
Metalloproteinase 9 ◽  
Ms Pathogenesis

Background: The activity of matrix metalloproteinase-9 (MMP-9) depends on two isoforms, an 82 kDa active MMP-9 modulated by its specific tissue inhibitor (TIMP-1), and a 65 kDa TIMP-1 resistant active MMP-9. The relevance of these two enzymatic isoforms in multiple sclerosis (MS) is still unknown. Objective: To investigate the contribution of the TIMP-1 modulated and resistant active MMP-9 isoforms to MS pathogenesis. Methods: We measured the serum levels of the 82 kDa and TIMP-1 resistant active MMP-9 isoforms by activity assay systems in 86 relapsing–remitting MS (RRMS) patients, categorized according to clinical and magnetic resonance imaging (MRI) evidence of disease activity, and in 70 inflammatory (OIND) and 69 non-inflammatory (NIND) controls. Results: Serum levels of TIMP-1 resistant MMP-9 were more elevated in MS patients than in OIND and NIND ( p < 0.05, p < 0.02, respectively). Conversely, 82 kDa active MMP-9 was higher in NIND than in the OIND and MS patients ( p < 0.01 and p < 0.00001, respectively). MRI-active patients had higher levels of TIMP-1 resistant MMP-9 and 82 kDa active MMP-9, than did those with MRI inactive MS ( p < 0.01 and p < 0.05, respectively). Conclusion: Our findings suggested that the TIMP-1 resistant MMP-9 seem to be the predominantly active isoform contributing to MS disease activity.

α-Linolenic acid is associated with MRI activity in a prospective cohort of multiple sclerosis patients

2018 ◽  
Vol 25 (7) ◽  
pp. 987-993 ◽  
Author(s):  
Kjetil Bjornevik ◽  
Kjell-Morten Myhr ◽  
Antonie Beiske ◽  
Kristian S Bjerve ◽  
Trygve Holmøy ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Disease Activity ◽  
Linolenic Acid ◽  
Statistical Significance ◽  
Serum Levels ◽  
T2 Lesions ◽  
Random Intercept ◽  
Magnetic Resonance Imaging Mri ◽  
Multiple Sclerosis Patients

Background: The plant-based ω-3 fatty acid α-linolenic acid (ALA) has been associated with lower MS risk. It is currently unknown whether ALA affects disease activity. Objective: To investigate the association between ALA levels and disease activity. Methods: We conducted a cohort study including 87 multiple sclerosis (MS)-patients who originally participated in a randomized trial of ω-3 fatty acids (the OFAMS study). We measured serum levels of ALA during follow-up and used random intercept logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CIs) for the association between ALA levels, new magnetic resonance imaging (MRI) lesions, Expanded Disability Status Scale (EDSS) progression and new relapses adjusting for age at inclusion, sex, and use of interferon beta-1a. Results: In continuous (per 1-SD increase) multivariable-adjusted analyses, higher ALA levels were significantly associated with lower odds of new T2-lesions (OR: 0.59, 95% CI: 0.37–0.95) during follow-up. The effect estimates were similar for new T1Gd + lesions (OR: 0.73, 95% CI: 0.48–1.11), EDSS-progression (OR: 0.62, 95% CI: 0.34–1.16) and new relapses (OR: 0.49, 95% CI: 0.22–1.10), but these estimates did not reach statistical significance. Further adjustment for vitamin D and tobacco use did not materially change the results. Conclusion: We found that higher levels of ALA were associated with lower disease activity in MS-patients.

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