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. 2024 Oct;96(4):704-714.
doi: 10.1002/ana.27024. Epub 2024 Jul 19.

Cerebrospinal Fluid Cytokine and Chemokine Profiles in Central Nervous System Sarcoidosis: Diagnostic and Immunopathologic Insights

Georgios Mangioris  1 , Sean J Pittock  1   2   3 , Binxia Yang  1 , James P Fryer  1 , William S Harmsen  3 , Divyanshu Dubey  1   2   3 , Eoin P Flanagan  1   2   3 , Sebastian A Lopez-Chiriboga  4 , Andrew McKeon  1   2   3 , John R Mills  1 , Ivana Vodopivec  5 , W Oliver Tobin  2   3 , Michel Toledano  2   3 , Allen J Aksamit  2 , Anastasia Zekeridou  1   2   3
Affiliations

Cerebrospinal Fluid Cytokine and Chemokine Profiles in Central Nervous System Sarcoidosis: Diagnostic and Immunopathologic Insights

Georgios Mangioris et al. Ann Neurol. 2024 Oct.

Abstract

Objective: To evaluate the cerebrospinal fluid (CSF) cytokine/chemokine profile of central nervous system (CNS) neurosarcoidosis (NS), and its utility in differential diagnosis, treatment, and prognostication.

Methods: In this case-control study, we validated 17 cytokines/chemokines (interleukin [IL]-1-beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-13, IL-17A, BAFF, IL-8/CXCL8, CXCL9, CXCL10, CXCL13, GM-CSF, interferon-gamma, and tumor necrosis factor [TNF]-alpha) in a multiplexed automated immunoassay system (ELLA; Bio-Techne, Minneapolis, MN, USA), and assessed them in CSF and serum of symptomatic patients with probable or definite CNS NS (01/2011-02/2023) with gadolinium enhancement and/or CSF pleocytosis. Patients with multiple sclerosis, primary CNS lymphoma, aquaporin-4 immunoglobulin G positivity, non-inflammatory disorders, and healthy individuals were used as controls.

Results: A total of 32 NS patients (59% women; median age, 59 years [19-81]) were included; concurrent sera were available in 12. CSF controls consisted of 26 multiple sclerosis, 8 primary CNS lymphoma, 84 aquaporin-4 immunoglobulin G positive, and 34 patients with non-inflammatory disorders. Gadolinium enhancement was present in 31 of 32 NS patients, and CSF pleocytosis in 27 of 32 (84%). CSF IL-2, IL-6, IL-10, IL-13, BAFF, IL-8/CXCL8, CXCL9, CXCL10, CXCL13, GM-CSF, interferon-gamma, and TNF-alpha levels were significantly higher in NS patients compared with non-inflammatory controls (p ≤ 0.02); elevations were more common in CSF than serum. Concurrent elevation of IL-6, CXCL9, CXCL10, GM-CSF, interferon-gamma, and TNF-alpha was present in 18 of 32 NS patients, but only in 1 control. Elevated IL-6, IL-10, IL-13, CXCL9, CXL10, GM-CSF, and TNF-alpha associated with measures of disease activity.

Interpretation: NS CSF cytokine/chemokine profiles suggest T cell (mainly T helper cell type 1), macrophage, and B-cell involvement. These signatures aid in NS diagnosis, indicate disease activity, and suggest therapeutic avenues. ANN NEUROL 2024;96:704-714.

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Conflict of interest statement

POTENTIAL CONFLICTS OF INTEREST

GM, BY, JPF, AJA, WSH, JRM, WOT, MT, DD report no relevant conflicts of interest.

SJP has received personal compensation for serving as a consultant and for serving on scientific advisory boards or data safety monitoring boards for Roche/Genentech; he also received research support from Roche/Genentech. EPF has served on advisory boards for Roche/Genentech, and he is a site principal investigator and a member of the steering committee for a clinical trial of satralizumab for relapsing myelin oligodendrocyte glycoprotein antibody-associated disease run by Roche/Genentech. SLC has served on advisory boards for Roche/Genentech. AMK has consulted for Roche/Genentech, without personal compensation. IV has received personal compensation for serving as an employee of F. Hoffmann-La Roche Ltd (Roche) and she has stock in Roche. AZ has received research funding from Roche and the Mayo Clinic Center for MS and Autoimmune Neurology relevant to this work. Roche/Genentech has funded this project.

Figures

Figure 1.
Figure 1.
Neurosarcoidosis patient selection.
Figure 2.
Figure 2.. CSF cytokine and chemokine concentrations in neurosarcoidosis and controls.
Boxplots of only analytes significantly elevated in neurosarcoidosis in comparison to non-inflammatory controls are presented. Significant differences between neurosarcoidosis and individual control groups (Wilcoxon’s rank sum test) are indicated by asterisks (*=P<0.05; **=P<0.01; ***= P<0.001).
Figure 3.
Figure 3.. Correlation of cerebrospinal fluid analytes in neurosarcoidosis patients.
Correlogram of Spearman’s rank correlation coefficient matrix of neurosarcoidosis patients CSF results.
Figure 4.
Figure 4.. Results of paired cerebrospinal fluid and serum.
Percentage of analyte elevations in neurosarcoidosis patients with paired cerebrospinal fluid and serum (N=12).
Figure 5.
Figure 5.. Clinical associations of elevated CSF analytes.
The analyte levels were treated as a binary variable (elevated versus non-elevated). Enhancement resolution refers to excellent response versus no or moderate response. (1) Wilcoxon’s rank-sum test; (2) Fisher’s exact test. BMI=body mass index; CSF=cerebrospinal fluid; OCB=oligoclonal bands; WBC=white blood cell count
See this image and copyright information in PMC

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