Extensive Healthy Donor Age/Gender Adjustments and Propensity Score Matching Reveal Physiology of Multiple Sclerosis Through Immunophenotyping

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.