Abstract
Neutrophils and monocytes encompassing the classical, intermediate, and nonclassical population constitute the majority of circulating myeloid cells in humans and represent the first line of innate immune defense. As such, changes in their relative and absolute amounts serve as sensitive markers of diverse inflammatory conditions. Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system, causing demyelination and axonal loss, affecting various neuron functions and often causing irreversible neurological disability. MS disease course is individually highly heterogeneous but can be classified as progressive (PMS) or relapsing-remitting (RRMS). Each MS course type may be further characterized as active or inactive, depending on the recent disability progression and/or current relapses. Data on specific alterations of the myeloid compartment in association with MS disease course are scarce and conflicting. In the current study, we systematically immunophenotyped blood myeloid leukocytes by flow cytometry in 15 healthy and 65 MS subjects. We found a highly significant expansion of granulocytes, CD15+ neutrophils, and classical and nonclassical monocytes in inactive RRMS (RRMSi) with concomitant shrinkage of the lymphocyte compartment, which did not correlate with biochemical readouts of systemic inflammation. Each of these leukocyte populations and the combined myeloid signature accurately differentiated RRMSi from other MS forms. Additionally, nonclassical monocyte proportions were particularly elevated in RRMSi individuals receiving disease-modifying therapy (DMT), such as natalizumab. Our results suggest that flow cytometry-based myeloid cell immunophenotyping in MS may help to identify RRMSi earlier and facilitate monitoring of DMT response.
Highlights
Multiple sclerosis (MS) is a chronic auto-inflammatory disease of the central nervous system (CNS) causing demyelination and axonal loss
The first step of our cytometry data analysis enabled identification of circulating lymphoid cells defined by expression of lineage (Lin+), that is, T (CD3), B (CD19), and NK (CD56) cell markers, and pan-granulocytes defined as lineage-negative (Lin−) and highly granular [high sideward scatter (SSChi)] cells (Supplementary Figure S1)
We first assessed the levels of monocyte subsets within the HLA-DR+ pan-monocyte population in healthy individuals and MS patients stratified by disease course type and disease activity (Figure 1)
Summary
Multiple sclerosis (MS) is a chronic auto-inflammatory disease of the central nervous system (CNS) causing demyelination and axonal loss. 50–80% of untreated RRMS patients will develop progressive disability worsening independent of relapses and similar to PPMS termed secondary PMS (SPMS) [1]. The current concept of MS pathology includes both inflammation, which is predominant in RRMS, and neurodegeneration, which is considered the key contributor to disability and development of PPMS and SPMS [1, 3]. PPMS and SPMS can be subsumed as PMS [4]. Either of these forms can be further classified as momentarily active or inactive, based on relapse frequencies and/or pace of disability progression measured by Expanded Disability Status Scale (EDSS) [1, 5]
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