Defining the CSF Cytokine and Chemokine Signature of Neurosarcoidosis
Georgios Mangioris1, Sean Pittock2, Binxia Yang1, Allen Aksamit2, Divyanshu Dubey2, Eoin Flanagan2, Sebastian Lopez-Chiriboga2, Andrew McKeon2, John Mills1, Ivana Vodopivec3, W. Tobin2, Michel Toledano2, Anastasia Zekeridou2
1Department of Laboratory Medicine and Pathology, 2Department of Neurology, Mayo Clinic, 3F. Hoffmann-La Roche Ltd
Objective:

To describe the cytokine/chemokine profile in cerebrospinal fluid (CSF) of patients with neurosarcoidosis.

Background:

Studies investigating cytokines/chemokines in neurosarcoidosis patients’ CSF reported elevations of IL-2, IL-6, IL-8/CXCL8, IL-10, BAFF, CXCL10, IFN-gamma, and TNF-alpha. These studies have evaluated a restricted number of analytes in relatively small numbers of disease and control patient samples.

Design/Methods:

We performed a systematic analytical validation of a multiplexed automated CSF cytokine/chemokine immunoassay system with 17 analytes (IL1b, IL2, IL4, IL5, IL6, IL8/CXCL8, IL10, IL12p70, IL13, IL17A, GM-CSF, TNF-alpha, IFN-gamma, CXCL9, CXCL10, CXCL13, BAFF) and comprehensive stability assessment. We tested CSF of patients with probable or definite CNS neurosarcoidosis evaluated at Mayo Clinic (01/2011-02/2023). Evidence of active disease (symptomatic patients with gadolinium enhancement or inflammatory CSF) and immunotherapies were documented. CSF from patients with non-inflammatory disorders were used as controls. Comparisons were made with the Wilcoxon rank-sum test.

Results:

CSF cytokines/chemokines were stable at 4oC for at least 30 days, except for IL1b, IL2, IL10, and CXCL10. Thirty-two neurosarcoidosis patients were studied (59.4% female; median age 59 years [range, 19-81]); control patients were 38.2% female (median age 74 years [21-87]). Gadolinium enhancement was present in 31 (96.9%) and CSF was inflammatory in 28 (87.5%). IL-6, BAFF, CXCL9, CXCL10, CXCL13, GM-CSF, IFN-gamma, and TNF-alpha levels were significantly elevated in CSF from neurosarcoidosis patients compared with controls (p<0.0001). In addition, IL-2 (p=0.0002), IL-8/CXCL8 (p=0.0008), IL-10 (p=0.0005) and IL-13 (p=0.0018) also exhibited significantly higher levels in the neurosarcoidosis group.

Conclusions:

Neurosarcoidosis is associated with significant CSF elevation of cytokines and chemokines associated with Th1 response, B-cell, follicular T-cell, and macrophage activation. Although use of TNF-alpha inhibitors improved outcomes, some patients do not have a complete response or develop neutralizing antibodies.  Cytokine/chemokine signatures may guide differential diagnosis and provide novel targets for treatment.

10.1212/WNL.0000000000205790