Effect of Rituximab on the Peripheral Blood and Cerebrospinal Fluid B Cells in Patients With Primary Progressive Multiple Sclerosis

Monson, Nancy; Cravens, Petra D.; Frohman, Elliot M.; Hawker, Kathleen; Racke, Michael K.

doi:10.1001/archneur.62.2.258

Cited by 188 publications

(110 citation statements)

References 22 publications

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“…However, little is currently known about the immunopathological relevance of focused B cell responses within the CNS compartment in MS, and the target antigens or tissues of antibodies produced by cePC remain to be determined. Such knowledge could provide fundamental insights into the immunological mechanisms underlying one of the most frequent neurological disorders and may provide additional understanding of the beneficial mechanisms mediated by novel therapeutic strategies leading to decreased B lymphocyte counts in the CSF of MS patients [20][21][22].…”

Section: Introductionmentioning

confidence: 99%

Clonally expanded plasma cells in the cerebrospinal fluid of MS patients produce myelin‐specific antibodies

et al. 2008

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Clonally expanded plasma cells (cePC) and their presumed products, oligoclonal immunoglobulin G bands (OCB), are characteristic findings in the cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS). While cePC and OCB strongly suggest an involvement of B cell-dependent immune mechanisms in the pathogenesis of MS, their actual pathological relevance and target antigens remain unknown. To further understand the potential role played by cePC, we generated a panel of monoclonal antibodies (MS-mAb) from CSF-derived cePC from four patients with early or definite MS. Single-cell RT-PCR of correctly paired heavy and light chain immunoglobulin genes from individual cePC ensured the subsequent resurrection of their original antigen specificity. Immunofluorescence stainings of MS lesion tissue with MS-mAb revealed myelin reactivity in the cePC repertoire of all four patients and intracellular filament reactivity in one patient. While myelin staining by MS-mAb was only rarely detectable in non-MS CNS white matter tissue, it was greatly enhanced at the edge of demyelinating lesions in MS brain tissue. Our findings provide conclusive evidence for the presence of an antigen-driven B cell response in the CSF of MS patients directed against epitopes present in areas of myelin degradation.

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Section: Introductionmentioning

confidence: 99%

Clonally expanded plasma cells in the cerebrospinal fluid of MS patients produce myelin‐specific antibodies

et al. 2008

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“…The effect of these drugs on Bcell depletion does not appear to affect significantly the abnormal antibodies (IgG), OCB number and pattern, or antibody synthesis rates in the CSF of treated patients [88][89][90]. Together with the rapid onset of action, these findings suggest that the benefit of B-cell depletion targets antibody-independent functions of B cells.…”

Section: B-cell Depletion In Msmentioning

confidence: 89%

Neuroinflammation: Ways in Which the Immune System Affects the Brain

et al. 2015

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Neuroinflammation is the response of the central nervous system (CNS) to disturbed homeostasis and typifies all neurological diseases. The main reactive components of the CNS include microglial cells and infiltrating myeloid cells, astrocytes, oligodendrocytes, and the blood-brain b a r r i e r , c y t o k i n e s , a n d c y t o k i n e s i g n a l i n g . Neuroinflammatory responses may be helpful or harmful, as mechanisms associated with neuroinflammation are involved in normal brain development, as well as in neuropathological processes. This review examines the roles of various cell types that contribute to the immune dysregulation associated with neuroinflammation. Microglia enter the CNS very early in embryonic development and, as such, play an essential role in both the healthy and diseased brain. B-cell diversity contributes to CNS disease through both antibody-dependent and antibody-independent mechanisms. The influences of these B-cell mechanisms on other cell types, including myeloid cells and T cells, are reviewed in relationship to antibody-mediated CNS disorders, paraneoplastic neurological diseases, and multiple sclerosis. New insights into neuroinflammation offer exciting opportunities to investigate potential therapeutic targets for debilitating CNS diseases.

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“…Targeting the mechanism(s) that allows these self-reactive B cells to reside in the CNS of recently diagnosed MS patients may prove to be a potent immunotherapeutic strategy. In fact, Rituximab, a B cell depleting monoclonal antibody therapy, has been reported to have efficacy in patients with MS (Monson et al, 2005b;Stuve et al, 2005) (www.medicalnewstoday.com/medicalnews.php?newsid=51006), which is likely due to a decreased frequency of potentially autoreactive B cells.…”

Section: Discussionmentioning

confidence: 99%

Antigen specificity of clonally expanded and receptor edited cerebrospinal fluid B cells from patients with relapsing remitting MS

Lambracht-Washington

O’Connor

Cameron

et al. 2007

Journal of Neuroimmunology

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We re-engineered the immunoglobulin rearrangements from clonally expanded CSF B cells of three Multiple Sclerosis patients as Fab fragments, and used three methods to test for their Ag-specificity. Nine out of ten Fab fragments were reactive to Myelin Basic Protein (MBP). The one Fab that did not react to MBP was a product of receptor editing. Two of the nine MBP-reactive Fabs were also reactive to GFAP and CNPase, indicating that these clones were polyreactive. Targeting the mechanisms that allows these self-reactive B cells to reside in the CSF of MS patients may prove to be a potent immunotherapeutic strategy.

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Effect of Rituximab on the Peripheral Blood and Cerebrospinal Fluid B Cells in Patients With Primary Progressive Multiple Sclerosis

Cited by 188 publications

References 22 publications

Clonally expanded plasma cells in the cerebrospinal fluid of MS patients produce myelin‐specific antibodies

Clonally expanded plasma cells in the cerebrospinal fluid of MS patients produce myelin‐specific antibodies

Neuroinflammation: Ways in Which the Immune System Affects the Brain

Antigen specificity of clonally expanded and receptor edited cerebrospinal fluid B cells from patients with relapsing remitting MS

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