title: MRI phenotypes with high neurodegeneration are associated with peripheral blood B-cell changes.
abstract: Little is known about the mechanisms leading to neurodegeneration in multiple sclerosis (MS) and the role of peripheral blood cells in this neurodegenerative component. We aimed to correlate brain radiological phenotypes defined by high and low neurodegeneration with gene expression profiling of peripheral blood mononuclear cells (PBMC) from MS patients. Magnetic resonance imaging (MRI) scans from 64 patients with relapsing-remitting MS (RRMS) were classified into radiological phenotypes characterized by low (N = 27) and high (N = 37) neurodegeneration according to the number of contrast-enhancing lesions, the relative volume of non-enhancing black holes on T1-weighted images, and the brain parenchymal fraction. Gene expression profiling was determined in PBMC using microarrays, and validation of selected genes was performed by polymerase chain reaction (PCR). B-cell immunophenotyping was conducted by flow cytometry. Microarray analysis revealed the B-cell specific genes FCRL1, FCRL2, FCRL5 (Fc receptor-like 1, 2 and 5 respectively), and CD22 as the top differentially expressed genes between patients with high and low neurodegeneration. Levels for these genes were significantly down-regulated in PBMC from patients with MRI phenotypes characterized by high neurodegeneration and microarray findings were validated by PCR. In patients with high neurodegeneration, immunophenotyping showed a significant increase in the expression of the B-cell activation markers CD80 in naïve B cells (CD45+/CD19+/CD27-/IgD+), unswitched memory B cells (CD45+/CD19+/CD27+/IgD+), and switched memory B cells (CD45+/CD19+/CD27+/IgD-), and CD86 in naïve and switched memory B cells. These results suggest that RRMS patients with radiological phenotypes showing high neurodegeneration have changes in B cells characterized by down-regulation of B-cell-specific genes and increased activation status.
authors.affiliation: Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), manuel.comabella@vhir.org.
authors.forename: Manuel
authors.initials: M
authors.lastname: Comabella
authors.affiliation: Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR).
authors.forename: Ester
authors.initials: E
authors.lastname: Cantó
authors.affiliation: Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR).
authors.forename: Ramil
authors.initials: R
authors.lastname: Nurtdinov
authors.affiliation: Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR).
authors.forename: Jordi
authors.initials: J
authors.lastname: Río
authors.affiliation: Department of Neurology and Department of Immunology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigacion Sanitaria, Madrid, Spain.
authors.forename: Luisa M
authors.initials: LM
authors.lastname: Villar
authors.affiliation: Department of Neurology and Department of Immunology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigacion Sanitaria, Madrid, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Picón
authors.affiliation: Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR).
authors.forename: Joaquín
authors.initials: J
authors.lastname: Castilló
authors.affiliation: Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR).
authors.forename: Nicolás
authors.initials: N
authors.lastname: Fissolo
authors.affiliation: Unitat de RM, Servei de Radiologia, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Aymerich
authors.affiliation: Unitat de RM, Servei de Radiologia, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Auger
authors.affiliation: Unitat de RM, Servei de Radiologia, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Alex
authors.initials: A
authors.lastname: Rovira
authors.affiliation: Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR).
authors.forename: Xavier
authors.initials: X
authors.lastname: Montalban
mesh_terms: D000328:Adult; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D016130:Immunophenotyping; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011961:Receptors, Fc / Q000235:genetics*; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000235:genetics*
chemical_list: C497867:CD22 protein, human; D011961:Receptors, Fc; D051918:Sialic Acid Binding Ig-like Lectin 2