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B Cells in the CNS at Postmortem Are Associated With Worse Outcome and Cell Types in Multiple Sclerosis
Marcello Moccia1, Lukas Haider1, Arman Eshaghi1
1From the Queen Square MS Centre (M.M., L.H., A.E., S.H.P.v.d.P., A.P., C.A.M.W.-K., O.C.), Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, University College London, United Kingdom; Multiple Sclerosis Clinical Care and Research Unit (M.M., V.B.M.), Department of Neurosciences, Federico II University, Naples, Italy; Department of Biomedical Imaging and Image Guided Therapy (L.H.), Medical University of Vienna, Austria; Translational Imaging Group F.B., UCL Institute of Healthcare Engineering, University College London, United Kingdom; Department of Radiology and Nuclear Medicine (F.B.), VU University Medical Center, Amsterdam, the Netherlands; and National Institute for Health Research (O.C.), University College London Hospitals Biomedical Research Centre, United Kingdom.
Background And Objectives:
To define the clinical and pathologic correlations of compartmentalized perivascular B cells in postmortem progressive multiple sclerosis (MS) brains.
Methods:
Brain slices were acquired from 11 people with secondary progressive (SP) MS, 5 people with primary progressive (PP) MS, and 4 controls. Brain slices were immunostained for B lymphocytes (CD20), T lymphocytes (CD3), cytotoxic T lymphocytes (CD8), neuronal neurofilaments (NF200), myelin (SMI94), macrophages/microglia (CD68 and IBA1), astrocytes (glial fibrillary acidic protein [GFAP]), and mitochondria (voltage-dependent anion channel and cytochrome c oxidase subunit 4). Differences in CD20 immunostaining intensity between disease groups and associations between CD20 immunostaining intensity and both clinical variables and other immunostaining intensities were explored with linear mixed regression models and Cox regression models, as appropriate.
Results:
CD20 immunostaining intensity was higher in PPMS (Coeff = 0.410; 95% confidence interval [CI] = 0.046, 0.774; p = 0.027) and SPMS (Coeff = 0.302; 95% CI = 0.020, 0.585; p = 0.036) compared with controls. CD20 immunostaining intensity was higher in cerebellar, spinal cord, and pyramidal onset (Coeff = 0.274; 95% CI = 0.039, 0.510; p = 0.022) compared with optic neuritis and sensory onset. Higher CD20 immunostaining intensity was associated with younger age at onset (hazard ratio [HR] = 1.033; 95% CI = 1.013, 1.053; p = 0.001), SP conversion (HR = 1.056; 95% CI = 1.022, 1.091; p = 0.001), wheelchair dependence (HR = 1.472; 95% CI = 1.108, 1.954; p = 0.008), and death (HR = 1.684; 95% CI = 1.238, 2.291; p = 0.001). Higher immunostaining intensity for CD20 was associated with higher immunostaining intensity for CD3 (Coeff = 0.114; 95% CI = 0.005, 0.224; p = 0.040), CD8 (Coeff = 0.275; 95% CI = 0.200, 0.350; p < 0.001), CD68 (Coeff = 0.084; 95% CI = 0.023, 0.144; p = 0.006), GFAP (Coeff = 0.002; 95% CI = 0.001, 0.004; p = 0.030), and damaged mitochondria (Coeff = 3.902; 95% CI = 0.891, 6.914; p = 0.011).
Discussion:
Perivascular B cells were associated with worse clinical outcomes and CNS-compartmentalized inflammation. Our findings further support the concept of targeting compartmentalized B-cell inflammation in progressive MS.
