Changes in Cerebrospinal Fluid Balance of TNF and TNF Receptors in Naïve Multiple Sclerosis Patients: Early Involvement in Compartmentalised Intrathecal Inflammation

Magliozzi, Roberta; Pezzini, Francesco; Pucci, Mairi; Rossi, Stefania; Facchiano, Francesco; Marastoni, Damiano; Montagnana, Martina; Lippi, Giuseppe; Reynolds, Richard; Calabrese, Massimiliano

doi:10.3390/cells10071712

Cited by 17 publications

(12 citation statements)

References 37 publications

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“…Although sTNFR-II has been previously shown to be elevated in ALS, to date, there are no comprehensive studies analyzing its role on the rate of disease progression [ 57 ]. Previous work suggests that under pathological conditions associated with chronic inflammation such as multiple sclerosis, type 2 diabetes and/or cardiovascular disease, TNF-RII is detached from the cell surface through activation of the tumor necrosis factor-alpha converting enzyme (TACE), thus promoting the aberrant immune and noxious response of mononuclear cells [ 58 , 59 , 60 , 61 , 62 , 63 ]. Furthermore, results from our study strongly suggest that higher plasma levels of sTNFR-II, together with the concurrent hyperactivation of AMPK signaling contribute to reduced production of leptin in ALS-affected adipocytes.…”

Section: Discussionmentioning

confidence: 99%

Distinct Plasma Immune Profile in ALS Implicates sTNFR-II in pAMPK/Leptin Homeostasis

Picher-Martel

Boutej

Vézina

et al. 2023

IJMS

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Amyotrophic lateral sclerosis (ALS) is a clinically highly heterogeneous disease with a survival rate ranging from months to decades. Evidence suggests that a systemic deregulation of immune response may play a role and affect disease progression. Here, we measured 62 different immune/metabolic mediators in plasma of sporadic ALS (sALS) patients. We show that, at the protein level, the majority of immune mediators including a metabolic sensor, leptin, were significantly decreased in the plasma of sALS patients and in two animal models of the disease. Next, we found that a subset of patients with rapidly progressing ALS develop a distinct plasma assess immune–metabolic molecular signature characterized by a differential increase in soluble tumor necrosis factor receptor II (sTNF-RII) and chemokine (C-C motif) ligand 16 (CCL16) and further decrease in the levels of leptin, mostly dysregulated in male patients. Consistent with in vivo findings, exposure of human adipocytes to sALS plasma and/or sTNF-RII alone, induced a significant deregulation in leptin production/homeostasis and was associated with a robust increase in AMP-activated protein kinase (AMPK) phosphorylation. Conversely, treatment with an AMPK inhibitor restored leptin production in human adipocytes. Together, this study provides evidence of a distinct plasma immune profile in sALS which affects adipocyte function and leptin signaling. Furthermore, our results suggest that targeting the sTNF-RII/AMPK/leptin pathway in adipocytes may help restore assess immune–metabolic homeostasis in ALS.

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Section: Discussionmentioning

confidence: 99%

Distinct Plasma Immune Profile in ALS Implicates sTNFR-II in pAMPK/Leptin Homeostasis

Picher-Martel

Boutej

Vézina

et al. 2023

IJMS

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“…Future studies shall assess additional markers of coagulation cascade activation in the CSF such as thrombin and prothrombin and relate the parameters of fibrin-derived autoimmunity to other prognostic markers of MS disease activity, such as cytokines, 28,32 chemokines related to B-cell activity, 9 and markers of neuroaxonal degeneration (e.g., neurofilament light chain 33 ) to deepen the understanding of the interconnection of coagulation system and neuroimmunologic mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Analysis of CSF D-Dimer to Identify Intrathecal Fibrin-Driven Autoimmunity in Patients With Multiple Sclerosis

Schaller‐Paule

Yalachkov

Steinmetz

et al. 2022

Neurol Neuroimmunol Neuroinflamm

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Background and ObjectivesProteins of the coagulation system contribute to autoimmune inflammation in patients with multiple sclerosis (MS). On blood-brain barrier (BBB) disruption, fibrinogen enters the CNS and is rapidly converted to fibrin, unfolding pleiotropic autoimmune mechanisms. Fibrin accumulation leads to subsequent proteolytic degradation that results in D-dimer generation. The primary objective of this study was to determine intrathecal levels of D-dimer in CSF as a measure of intrathecal coagulation cascade activation and to evaluate its diagnostic utility in patients with MS in contrast to healthy subjects. Key secondary objectives included analysis of CSF D-dimer in differential diagnoses of MS and its relation to routine clinical markers of disease activity.MethodsPatients admitted for the assessment of suspected MS were prospectively recruited from October 2017 to December 2020. Blood plasma and citrated CSF samples were analyzed using a highly sensitive luminescent oxygen channeling immunoassay. Intrathecal generation of D-dimer was analyzed by adjusting for CSF/serum albumin (Qalb) and CSF/plasma D-dimer quotients (QD-dimer), and corresponding CSF fibrinogen levels were determined. Final diagnoses after full evaluation and clinical data were recorded.ResultsOf 187 patients, 113 patients received a diagnosis of MS or clinically/radiologically isolated syndrome. We found increased intrathecal CSF D-dimer generation levels (QD-dimer/Qalb-index) for patients with relapsing-remitting MS (RRMS; n = 71, median 4.7, interquartile range [IQR] 2.5–8.0) when compared with those for disease controls (n = 22, median 2.6, IQR 2.1–4.8, p = 0.031). Absolute CSF D-dimer values correlated with CSF fibrinogen levels (r = 0.463; p < 0 .001) and CSF leukocytes (r = 0.273; p = 0.003) and were elevated in MS patients with contrast enhancement (CE) compared with MS patients without CE on MRI (n = 48, median 6 ng/mL, and IQR 3–15.25 vs n = 41, median 4 ng/mL, and IQR 2–7; p = 0.026). Exploratory subgroup analyses indicated a correlation of intrathecal inflammatory activity and CSF D-dimer levels.DiscussionD-dimer in CSF can be reliably determined and correlates with markers of CNS inflammation and CSF fibrinogen levels. Adjusted for BBB dysfunction, CSF D-dimer may allow the identification of intrathecal coagulation cascade activation in patients with MS.Classification of EvidenceThis study provides Class I evidence that CSF D-dimer levels are elevated in patients with RRMS.

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“…Increasing evidence from in vitro and in vivo studies points to a crucial role of TNF signalling in mediating both WM and GM pathology. 25 – 28 CSF TNF levels in progressive MS patients have been linked to altered synaptic transmission, with exacerbation of glutamatergic transmission and neuronal damage when incubating CSF with corticostriatal slices. 29 , 30 Recently, persistent expression of CSF TNF along with IFN gamma has been described as a potent inducer of meningeal inflammation and subpial demyelination in the myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) model.…”

Section: Discussionmentioning

confidence: 99%

CSF TNF and osteopontin levels correlate with the response to dimethyl fumarate in early multiple sclerosis

Marastoni

Pisani

Schiavi

et al. 2022

Ther Adv Neurol Disord

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Background: Disease activity in the first years after a diagnosis of relapsing-remitting multiple sclerosis (RRMS) is a negative prognostic factor for long-term disability. Markers of both clinical and radiological responses to disease-modifying therapies (DMTs) are advocated. Objective: The objective of this study is to estimate the value of cerebrospinal fluid (CSF) inflammatory markers at the time of diagnosis in predicting the disease activity in treatment-naïve multiple sclerosis (MS) patients exposed to dimethyl fumarate (DMF). Methods: In total, 48 RRMS patients (31 females/17 males) treated with DMF after the diagnosis were included in this 2-year longitudinal study. All patients underwent a CSF examination, regular clinical and 3T magnetic resonance imaging (MRI) scans that included the assessment of white matter (WM) lesions, cortical lesions (CLs) and global cortical thickness. CSF levels of 10 pro-inflammatory markers – CXCL13 [chemokine (C-X-C motif) ligand 13 or B lymphocyte chemoattractant], CXCL12 (stromal cell-derived factor or C-X-C motif chemokine 12), tumour necrosis factor (TNF), APRIL (a proliferation-inducing ligand, or tumour necrosis factor ligand superfamily member 13), LIGHT (tumour necrosis factor ligand superfamily member 14 or tumour necrosis factor superfamily member 14), interferon (IFN) gamma, interleukin 12 (IL-12), osteopontin, sCD163 [soluble-CD163 (cluster of differentiation 163)] and Chitinase3-like1 – were assessed using immune-assay multiplex techniques. The combined three-domain status of ‘no evidence of disease activity’ (NEDA-3) was defined by no relapses, no disability worsening and no MRI activity, including CLs. Results: Twenty patients (42%) reached the NEDA-3 status; patients with disease activity showed higher CSF TNF ( p = 0.009), osteopontin ( p = 0.005), CXCL12 ( p = 0.037), CXCL13 ( p = 0.040) and IFN gamma levels ( p = 0.019) compared with NEDA-3 patients. After applying a random forest approach, TNF and osteopontin revealed the most important variables associated with the NEDA-3 status. Six molecules that emerged at the random forest approach were added in a multivariate regression model with demographic, clinical and MRI measures of WM and grey matter damage as independent variables. TNF levels confirmed to be associated with the absence of disease activity: odds ratio (OR) = 0.25, CI% = 0.04–0.77. Conclusion: CSF inflammatory markers may provide prognostic information in predicting disease activity in the first years after DMF initiation. CSF TNF levels are a possible candidate in predicting treatment response, in addition to clinical, demographic and MRI variables.

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Changes in Cerebrospinal Fluid Balance of TNF and TNF Receptors in Naïve Multiple Sclerosis Patients: Early Involvement in Compartmentalised Intrathecal Inflammation

Cited by 17 publications

References 37 publications

Distinct Plasma Immune Profile in ALS Implicates sTNFR-II in pAMPK/Leptin Homeostasis

Distinct Plasma Immune Profile in ALS Implicates sTNFR-II in pAMPK/Leptin Homeostasis

Analysis of CSF D-Dimer to Identify Intrathecal Fibrin-Driven Autoimmunity in Patients With Multiple Sclerosis

CSF TNF and osteopontin levels correlate with the response to dimethyl fumarate in early multiple sclerosis

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