Recapitulation of B cell differentiation in the central nervous system of patients with multiple sclerosis

Abstract

Clonally expanded populations of B cells carrying somatic mutations of Ig variable (V) region genes have been detected in the CNS of subjects with multiple sclerosis (MS), suggesting that a process of B cell affinity maturation with ensuing production of potentially pathogenic autoantibodies may occur inside the CNS. Here, we have characterized the B cell subsets present in the cerebrospinal fluid (CSF) of MS patients and of individuals with other inflammatory neurological disorders by flow cytometry. CD19 ؉ CD38 high؉ CD77 ؉ , Ki67 ؉ , Bcl-2 ؊ centroblasts, i.e., a B cell subset found exclusively in secondary lymphoid organs, were detected in the CSF but not in paired peripheral blood from both patient groups. CD27 ؉ IgD ؊ memory B cells, i.e., cells with hypermutated IgV genes, were significantly increased in the CSF vs. paired peripheral blood and displayed up-regulation of the CD80 and CD86 costimulatory molecules and of CC chemokine receptor (CCR) 1, CCR2, and CCR4 in both patient groups. Lymphotoxin-␣, CXC ligand (CXCL) 12, and CXCL13, key mediators of lymphoid neogenesis, were present in the CSF from patients with MS and other inflammatory neurological disorders and were expressed in MS brain tissue, with selective localization in the outer layer of the capillary vessel wall. In conclusion, this study suggests that a compartmentalized B cell response occurs within the CNS during an ongoing inflammatory reaction, through a recapitulation of all stages of B cell differentiation observed in secondary lymphoid organs. The presence of lymphotoxin-␣, CXCL12, and CXCL13 in the CNS may provide favorable microenvironmental conditions for these events.A rich mononuclear cell infiltrate, comprised of macrophages, T cells, and, to a lesser extent, B cells, is typical of the multiple sclerosis (MS) lesion (1-3). So far, the majority of studies have addressed the characterization of T cells involved in the autoimmune attack to the CNS (1).A role of B cells in MS pathogenesis is suggested by the presence of oligoclonal Ig bands within the cerebrospinal fluid (CSF) that represent a hallmark of the disease (4). In addition, clonally expanded B cells accumulate in chronic MS lesions (5, 6) and in the CSF (7, 8) from MS patients. Finally, antimyelin Abs may be involved in demyelination (9) and may have prognostic value (10).Ectopic structures resembling classical lymphoid follicles (11, 12) may develop in the parenchyma of nonlymphoid tissues during the course of both autoimmune (13) and chronic infectious (14) diseases. Newly formed lymphoid follicles recently have been detected in the CNS from MS patients, indicating occurrence of lymphoid neogenesis supported by the CXL13 and CC chemokine ligand 21 chemokines (15).In this study, we characterize the B cell compartment within the CSF of subjects with MS and other inf lammatory neurological disorders (OIND) and demonstrate that a complete recapitulation of B cell differentiation occurs in the CSF, where favorable microenvironmental conditions have been identified. Materials...

Selective intrathecal enrichment of G1m1‐positive B cells in multiple sclerosis

“…Further characterization of the IgG1 ASCs in the CSF of MS patients showed that these cells express CD38, CD138, and HLA‐DR, together with dim levels of CD19 and high levels of CD27. This is in line with the results of a previous study characterizing intrathecal B cells,15 but contrasts another study that demonstrated increased numbers of CD19 – CD138 + plasma cells 16. Importantly, we show for the first time that the intrathecal IgG1 ASCs express high levels of Ki‐67, suggesting that the cells are newly derived and proliferate intrathecally.…”

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

“…Accumulation of innate and adaptive immune cells in the choroid plexus stroma in multiple sclerosis patients is associated with the appearance of increased numbers of memory/ effector T cells (Fig. 6) [51,68], B cells, and antibodyproducing cells in the CSF of these patients [26], suggesting that immune cells that invade the ventricles have to eventually pass the choroid plexus epithelium. Indeed, mimicking the increase of CNS danger signals by intracerebroventricular injection of TNF-α, besides eliciting an inflammatory response throughout the brain, leads to T cell accumulation in the choroid plexus stroma [169].…”

Screening Random Peptide Libraries with Subacute Sclerosing PanencephalitisBrain-Derived Recombinant Antibodies Identifies Multiple Epitopes in the C-Terminal Region of the Measles Virus Nucleocapsid Protein

“…In CNS infectious diseases, such as subacute sclerosing panencephalitis (SSPE), neurosyphilis, mumps meningitis, progressive rubella panencephalitis, cryptococcal meningitis, and varicella zoster virus vasculitis, the oligoclonal IgG is directed largely against the infectious agent that causes the disease (reviewed in reference 12). Increased CNS IgG synthesis is accompanied by an elevated number of CD19 ϩ B cells and the appearance of post-germinal center reaction plasmablast/plasma cells (4,6,18). We previously used laser capture microdissection and single-cell PCR to identify expanded clones among the CD38 ϩ B cells found within the parenchyma of SSPE brain (3).…”