Contributions
Abstract: P951
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 12 Pathology
Background: The role of B-lymphocytes in the pathogenesis of multiple sclerosis (MS) is becoming clearer in recent years. B-cells are present in immune infiltrates in MS lesions, in the surrounding parenchyma, and in follicle-like structures in the leptomeningeal space of progressive MS patients. We aim to quantify B-cell levels in normal-appearing white and grey matter (NAWM and NAGM), and in WM and GM lesions of post-mortem MS tissue, and to evaluate associations of B-cells with age at death, and other pathological features of MS.
Methods: 71 histological cassettes from 14 post-mortem MS brains were immunostained and quantified by using Definiens software for neuronal structure (HE, NF200, SMI94), lymphocyte activity (CD20, CD3, CD8), microglia activation (CD68, IBA1), astrocyte reaction (GFAP), and mitochondrial activity (COX4, VDAC). We contoured the following regions-of-interest (ROIs) on digitized histological sections: NAWM, WM lesions, cortical NAGM, and cortical GM lesions. Spearman rank correlation was used to measure associations between age at death and CD20 and CD3 stains. Multilevel linear regression models with B-cell concentration (CD20) as dependent variable were used, including the hierarchical structure of data (cassettes nested within patients); covariates were age, gender, interval between death and fixation, and ROI size.
Results: Younger age at death was associated with higher CD20+ B-cell concentrations in NAWM
(rho=-0.360; p=0.012), NAGM (rho=0.340; p=0.019), and WM lesions (rho=-0.322; p=0.045).
CD20+ B-cells were associated with CD3+ T-cell levels in NAWM, (Coeff=0.516; p=0.013), NAGM (Coeff=5.425; p< 0.001), WM lesions (Coeff=0.554; p=0.003), and GM lesions (Coeff=8.162; p< 0.001). CD20+ B-cells were associated with mitochondrial activity in NAWM (Coeff=-6.703; p=0.022), and with atrocytes (Coeff=5.715; p=0.034), and microglia in WM lesions (Coeff=4.484; p< 0.001).
Conclusions: CD20+ B-lymphocytes, but not CD3+ T-cells, are associated with more aggressive MS, as reflected by a younger age at death. B- and CD3+ T-cell levels are associated in different brain compartments, and are associated with microglia/astrocyte activation in WM lesions. These results support the recent focus on medications targeting B-cells.
Disclosure:
Marcello Moccia has received grant from the ECTRIMS-MAGMNISM fellowship program, honoraria and travel support form Almirall, Coloplast, Genzyme, and Merck-Serono.
Steven van de Pavert has nothing to disclose.
Arman Eshaghi has nothing to disclose.
Jonas Pichat has nothing to disclose.
Marc Modat has received funding from the EPSRC (EP/H046410/1, EP/J020990/1, EP/K005278), the MRC (MR/J01107X/1), the EU-FP7 project VPH-DARE@IT (FP7-ICT-2011-9-601055), the NIHR Biomedical Research Unit (Dementia) at UCL, the National Institute for Health Research University College London Hospitals Biomedical Research Centre (NIHR BRC UCLH/UCL High Impact Initiative).
Alan Thompson has received honoraria and support for travel from Eisai and EXCEMED. He received support for travel from the International Progressive MS Alliance, as chair of their Scientific Steering Committee and the National MS Society (USA) as member of their Research Programs Advisory Committee. He receives an honorarium from SAGE Publishers as Editor-in-Chief of MSJ.
Frederik Barkhof has received funding from the Dutch MS Society, and honoraria from Bayer-Schering Pharma, Biogen-Idec, TEVA, Merck-Serono, Novartis, Roche, Synthon BV, Jansen Research, Genzyme, and IXICO.
Olga Ciccarelli has received research funding from UK MS Society, National MS Society, Rosetrees trust and NIHR UCLH BRC. OC serves as a consultant for Biogen, Novartis, Roche, Genzyme, Teva and GE healthcare.
Abstract: P951
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - 12 Pathology
Background: The role of B-lymphocytes in the pathogenesis of multiple sclerosis (MS) is becoming clearer in recent years. B-cells are present in immune infiltrates in MS lesions, in the surrounding parenchyma, and in follicle-like structures in the leptomeningeal space of progressive MS patients. We aim to quantify B-cell levels in normal-appearing white and grey matter (NAWM and NAGM), and in WM and GM lesions of post-mortem MS tissue, and to evaluate associations of B-cells with age at death, and other pathological features of MS.
Methods: 71 histological cassettes from 14 post-mortem MS brains were immunostained and quantified by using Definiens software for neuronal structure (HE, NF200, SMI94), lymphocyte activity (CD20, CD3, CD8), microglia activation (CD68, IBA1), astrocyte reaction (GFAP), and mitochondrial activity (COX4, VDAC). We contoured the following regions-of-interest (ROIs) on digitized histological sections: NAWM, WM lesions, cortical NAGM, and cortical GM lesions. Spearman rank correlation was used to measure associations between age at death and CD20 and CD3 stains. Multilevel linear regression models with B-cell concentration (CD20) as dependent variable were used, including the hierarchical structure of data (cassettes nested within patients); covariates were age, gender, interval between death and fixation, and ROI size.
Results: Younger age at death was associated with higher CD20+ B-cell concentrations in NAWM
(rho=-0.360; p=0.012), NAGM (rho=0.340; p=0.019), and WM lesions (rho=-0.322; p=0.045).
CD20+ B-cells were associated with CD3+ T-cell levels in NAWM, (Coeff=0.516; p=0.013), NAGM (Coeff=5.425; p< 0.001), WM lesions (Coeff=0.554; p=0.003), and GM lesions (Coeff=8.162; p< 0.001). CD20+ B-cells were associated with mitochondrial activity in NAWM (Coeff=-6.703; p=0.022), and with atrocytes (Coeff=5.715; p=0.034), and microglia in WM lesions (Coeff=4.484; p< 0.001).
Conclusions: CD20+ B-lymphocytes, but not CD3+ T-cells, are associated with more aggressive MS, as reflected by a younger age at death. B- and CD3+ T-cell levels are associated in different brain compartments, and are associated with microglia/astrocyte activation in WM lesions. These results support the recent focus on medications targeting B-cells.
Disclosure:
Marcello Moccia has received grant from the ECTRIMS-MAGMNISM fellowship program, honoraria and travel support form Almirall, Coloplast, Genzyme, and Merck-Serono.
Steven van de Pavert has nothing to disclose.
Arman Eshaghi has nothing to disclose.
Jonas Pichat has nothing to disclose.
Marc Modat has received funding from the EPSRC (EP/H046410/1, EP/J020990/1, EP/K005278), the MRC (MR/J01107X/1), the EU-FP7 project VPH-DARE@IT (FP7-ICT-2011-9-601055), the NIHR Biomedical Research Unit (Dementia) at UCL, the National Institute for Health Research University College London Hospitals Biomedical Research Centre (NIHR BRC UCLH/UCL High Impact Initiative).
Alan Thompson has received honoraria and support for travel from Eisai and EXCEMED. He received support for travel from the International Progressive MS Alliance, as chair of their Scientific Steering Committee and the National MS Society (USA) as member of their Research Programs Advisory Committee. He receives an honorarium from SAGE Publishers as Editor-in-Chief of MSJ.
Frederik Barkhof has received funding from the Dutch MS Society, and honoraria from Bayer-Schering Pharma, Biogen-Idec, TEVA, Merck-Serono, Novartis, Roche, Synthon BV, Jansen Research, Genzyme, and IXICO.
Olga Ciccarelli has received research funding from UK MS Society, National MS Society, Rosetrees trust and NIHR UCLH BRC. OC serves as a consultant for Biogen, Novartis, Roche, Genzyme, Teva and GE healthcare.