Author Of 1 Presentation
P0337 - Extensive healthy donor age/gender adjustments and propensity score matching reveal physiology of multiple sclerosis through immunophenotyping (ID 466)
Abstract
Background
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 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 diseases (OIND) controls to identify MS-specific changes.
Objectives
1. To define physiological age/gender-related changes in blood and CSF cells. 2) To define/validate cellular abnormalities in blood and CSF of untreated MS. 3. To compare the effects of low-efficacy and high-efficacy drugs on MS-related cellular abnormalities.
Methods
1240 prospectively acquired paired CSF/blood samples were collected from 588 subjects, representing HDs, MS patients, and various controls. Samples were blinded during processing, stained with a 12-color antibody panel, and run by flow cytometry. All p-values were adjusted for multiple comparisons. HDs and untreated MS patients were compared in independent training and validation cohorts. Propensity score matching was completed between untreated and treated MS patients to account for differences in age, gender, and disability.
Results
Both CSF and blood of HDs have changes in immune cell populations with age, although the changes are more pronounced in blood than CSF. Different MS subtypes have similar immunological changes, where immune cell populations are constantly recruited to the CSF from the periphery. All MS drugs decrease CSF inflammation; low efficacy drugs tend to normalize it, meanwhile, high efficacy drugs overshoot CSF HD range.
Conclusions
Age-related changes suggest decreased immunosurveillance of CNS by activated, HLA-DR+ T cells associated with natural aging. MS is an immunologically single disease evolving in time. At early stage of the disease, peripherally activated innate and adaptive immune cells migrate into CSF to form MS lesions. T cells and NK cells are depleted from blood as they accumulate, together with B cells, in the CSF. Eventually, these immune cells remain in CNS tissue as compartmentalized inflammation. High efficacy treatments exert a stronger inhibitory effect on recently activated HLA-DR+ T cells, which may underlie their greater efficacy. High efficacy treatments also overshoot CSF immune cell depletion beyond physiological levels, likely disrupting natural immune surveillance of CNS tissue.