Abstract

Quantifying cell subpopulations in biological fluids aids in diagnosis and understanding of the mechanisms of injury. Although much has been learned from cerebrospinal fluid (CSF) flow cytometry in neuroimmunological disorders, such as multiple sclerosis (MS), previous studies did not contain enough healthy donors (HD) to derive age- and gender-related normative data and sufficient heterogeneity of other inflammatory neurological disease (OIND) controls to identify MS specific changes.The goals of this blinded training and validation study of MS patients and embedded controls, representing 1,240 prospectively acquired paired CSF/blood samples from 588 subjects was (1) to define physiological age-/gender-related changes in CSF cells, (2) to define/validate cellular abnormalities in blood and CSF of untreated MS through disease duration (DD) and determine which are MS-specific, and (3) to compare effect(s) of low-efficacy (i.e., interferon-beta [IFN-beta] and glatiramer acetate [GA]) and high-efficacy drugs (i.e., natalizumab, daclizumab, and ocrelizumab) on MS-related cellular abnormalities using propensity score matching.Physiological gender differences are less pronounced in the CSF compared to blood, and age-related changes suggest decreased immunosurveillance of CNS by activated HLA-DR+T cells associated with natural aging. Results from patient samples support the concept of MS being immunologically single disease evolving in time. Initially, peripherally activated innate and adaptive immune cells migrate into CSF to form MS lesions. With progression, T cells (CD8+ > CD4+), NK cells, and myeloid dendritic cells are depleted from blood as they continue to accumulate, together with B cells, in the CSF and migrate to CNS tissue, forming compartmentalized inflammation. All MS drugs inhibit non-physiological accumulation of immune cells in the CSF. Although low-efficacy drugs tend to normalize it, high-efficacy drugs overshoot some aspects of CSF physiology, suggesting impairment of CNS immunosurveillance. Comparable inhibition of MS-related CSF abnormalities advocates changes within CNS parenchyma responsible for differences in drug efficacy on MS disability progression.Video summarizing all results may become useful educational tool.

Highlights

  • Neuroimmunological diseases of the central nervous system (CNS) are an expanding group of immune-mediated conditions that affect brain and spinal cord

  • Automated algorithms require identical assay parameters, practically achieved by performing only a single or highly limited assay run(s) on cryopreserved samples. This is problematic for cerebrospinal fluid (CSF) applications, as small numbers of CSF cells are poorly amenable to cryopreservation, and cryopreservation affects numbers/phenotype of activated immune cells in unpredictable ways

  • We believe that a key limitation for this effort is small numbers of available CSF cells even when we process >20 cc of CSF and perform immunophenotyping immediately

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Summary

Introduction

Neuroimmunological diseases of the central nervous system (CNS) are an expanding group of immune-mediated conditions that affect brain and spinal cord. The last decade brought exciting advances in antibody (Ab)-based diagnostic testing for some of these conditions [1, 2], the diagnosis of others is based on the combination of clinical suspicion, CNS imaging, and evaluation of cerebrospinal fluid (CSF). CSF flow cytometry remains a research test, not performed routinely by clinical laboratories. In 2014, we published our initial experience (i.e., first 221 subjects) with prospective blood and CSF immunophenotyping of untreated subjects who entered a natural history protocol: “Comprehensive Multimodal Analysis of Patients with Neuroimmunological Diseases of the CNS” (Clinicaltrials.gov identifier NCT00794352) [3]. This study identified new and validated previously published changes in immune compositions of blood vs CSF as well as changes between different neurological diseases

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