Istituto superiore di Sanità

Author Of 1 Presentation

Pathogenesis – Immunology Poster Presentation

P0969 - Imbalance of TNF and TNF receptors in the cerebrospinal fluid of naïve multiple sclerosis patients (ID 1602)

Speakers
Presentation Number
P0969
Presentation Topic
Pathogenesis – Immunology

Abstract

Background

Background: An imbalance in TNF signaling in the inflammatory milieu generated in the cortical subarachnoid space of the multiple sclerosis (MS) brain is thought to lead to increased cortical pathology.

Objectives

Objectives: To investigate the changes in TNF and its soluble receptors in CSF at the early stages of MS and how they associate with clinical outcome.

Methods

Methods: Protein levels of TNF, sTNFR1 and sTNFR2 were assayed in CSF collected from 122 naïve MS patients and 34 subjects with other neurological conditions at diagnosis. Potential correlations with other molecules of TNF family and other cytokines/chemokines were evaluated by using BioPlex System immunoassay and Ingenuity pathway analysis. TNF and TNFRs levels in CSF were correlated with clinical and imaging parameters at diagnosis (T0) and after 2 years of follow-up (T2).

Results

Results: Significant increased levels of TNF (fold change:7.739; p<0.001), sTNFR1 (fold change:1.693; p<0.001) and sTNFR2 (fold change:2.189; p<0.001) were detected in CSF of MS patients compared to the control group at T0, and were found especially high in patients with enhanced CSF inflammation. Increased TNF levels in CSF were significantly (p<0.01) associated with increased EDSS change (r=0.43), relapses (r=0.48) and new white matter lesions (r=0.49) at T2. Elevated CSF levels of sTNFR1 were associated with higher cortical lesion volume (r=0.41) at T0, as well as with new cortical lesions (r=0.56) and signs of disease activity (r= 0.61) at T2, whilst no correlation could be found between sTNFR2 levels inCSF and clinical or MRI features. By performing combined correlation and pathway analysis, CSF TNF signalling (encompassing elevated levels of BAFF, IFN-G, IL-1beta, IL-10, IL-8, IL-16, CCL21, haptoglobin and fibrinogen) was found predominantly related to interplay between innate and adaptive immune cell. CSF sTNFR1 pathway (encompassing high levels of CXCL13, TWEAK, LIGHT, IL35, osteopontin, pentraxin-3, sCD163 and chitinase-3-L1) was mainly related to dendritic cell maturation and acute immune response pathway. Finally, CSF sTNFR2 pathway (encompassing high CSF levels of IFN-B, IFN-L2, sIL-6Ra) was linked to Th cell differentiation and regulatory cytokine pathway.

Conclusions

Conclusions: CSF dysregulation of TNF and TNFRs pathways can be early identified in MS patients at time of diagnosis and associates with a specific clinical/MRI profile. This, in turn, could have a key role in predicting the disease outcome.

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