Memory B cells from a subset of treatment‐naïve relapsing‐remitting multiple sclerosis patients elicit CD4<sup>+</sup> T‐cell proliferation and IFN‐γ production in response to myelin basic protein and myelin oligodendrocyte glycoprotein

Harp, Christopher; Ireland, Sara; Davis, Laurie S.; Remington, Gina; Cassidy, Bonnie; Cravens, Petra D.; Stüve, Olaf; Lovett-Racke, Amy E.; Eagar, Todd N.; Greenberg, Benjamin; Racke, Michael K.; Cowell, Lindsay G.; Karandikar, Nitin J.; Frohman, Elliot M.; Monson, Nancy

doi:10.1002/eji.201040516

Cited by 107 publications

(97 citation statements)

References 69 publications

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“…Antigen-experienced (memory) B cells differentiate into antibody-secreting plasma cells and/or plasmablasts, serve as highly selective antigen-presenting cells (APCs) (1,2), and regulate numerous effector functions of T and B cells (3). In the demyelinating disorder multiple sclerosis (MS), autoimmunity may be triggered by B cells that undergo antigen-dependent maturation within specialized lymphoid follicle-like structures in the meningeal and Virchow-Robin spaces of the CNS (4).…”

Section: Introductionmentioning

confidence: 99%

B cell exchange across the blood-brain barrier in multiple sclerosis

Büdingen¹,

Kuo²,

Sirota³

et al. 2012

J. Clin. Invest.

214

216

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In multiple sclerosis (MS) pathogenic B cells likely act on both sides of the blood-brain barrier (BBB). However, it is unclear whether antigen-experienced B cells are shared between the CNS and the peripheral blood (PB) compartments. We applied deep repertoire sequencing of IgG heavy chain variable region genes (IgG-VH) in paired cerebrospinal fluid and PB samples from patients with MS and other neurological diseases to identify related B cells that are common to both compartments. For the first time to our knowledge, we found that a restricted pool of clonally related B cells participated in robust bidirectional exchange across the BBB. Some clusters of related IgG-VH appeared to have undergone active diversification primarily in the CNS, while others have undergone active diversification in the periphery or in both compartments in parallel. B cells are strong candidates for autoimmune effector cells in MS, and these findings suggest that CNS-directed autoimmunity may be triggered and supported on both sides of the BBB. These data also provide a powerful approach to identify and monitor B cells in the PB that correspond to clonally amplified populations in the CNS in MS and other inflammatory states.

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Section: Introductionmentioning

confidence: 99%

B cell exchange across the blood-brain barrier in multiple sclerosis

Büdingen¹,

Kuo²,

Sirota³

et al. 2012

J. Clin. Invest.

214

216

View full text Add to dashboard Cite

show abstract

“…Despite the evidence for B cells' role in the development and regulation of the autoimmune inflammatory response in MS (22), little is known about the IFN-b's effects on B cell functions. We have characterized in this study the in vitro and in vivo IFN-b-1b's effect on the human B cells' stimulatory capacity toward T cells and cytokine secretion in the context of the autoimmune response in RR MS.…”

mentioning

confidence: 99%

B Cells as a Therapeutic Target for IFN-β in Relapsing–Remitting Multiple Sclerosis

Ramgolam

Sha

Marcus

et al. 2011

The Journal of Immunology

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IFN-β-1b is a first-line immunomodulatory therapy for relapsing–remitting multiple sclerosis (RR MS). However, its effects on B cells have not been characterized. In vitro studies of B cells derived from RR MS patients revealed that IFN-β-1b decreases B cells’ stimulatory capacity, as detected by inhibition of the Ag-specific T cell proliferative response upon Ag presentation by IFN-β-1b–treated B cells. Our study has identified that IFN-β-1b inhibited B cells’ stimulatory capacity in RR MS patients and healthy controls through the suppression of CD40 and CD80 expression, whereas the MHC class I and II expression was not changed. IFN-β-1b in vitro treatment inhibited B cell secretion of IL-1β and IL-23 and induced IL-12 and IL-27. Supernatants transferred from IFN-β-1b–treated B cells inhibited Th17 cell differentiation, as they suppressed gene expression of the retinoic acid-related orphan nuclear hormone receptor C and IL-17A and secretion of IL-17A. In addition, IFN-β-1b induced B cells’ IL-10 secretion, which may mediate their regulatory effect. Studies of B cells derived from RR MS patients treated with recombinant s.c. injected IFN-β-1b revealed that they induced a significantly lower proliferative response in allogenic MLR than the B cells from untreated patients. Further confirming the IFN-β-1b in vitro-induced changes in B cell cytokine secretion, B cells derived from the IFN-β-1b–treated patients secreted significantly lower levels of IL-1β and IL-23 and higher levels of IL-12 and IL-27 in comparison with the B cells derived from untreated patients. We conclude that IFN-β-1b exerts its therapeutic effects in part by targeting B cells’ functions that contribute to the autoimmune pathogenesis of RR MS.

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“…Little is known about regulatory B cells in humans and whether they are changed by B cell targeting therapies (23,24). IL-10-producing B cells were found to be reduced in MS (23), but it is unknown whether these were naive or memory B cells (23,25).…”

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confidence: 99%

CD20+ B Cell Depletion Alters T Cell Homing

Kap

Driel

Laman

et al. 2014

The Journal of Immunology

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Depleting mAbs against the pan B cell marker CD20 are remarkably effective in the treatment of autoimmune-mediated inflammatory disorders, but the underlying mechanisms are poorly defined. The primary objective of this study was to find a mechanistic explanation for the remarkable clinical effect of the anti-CD20 mAbs in a representative nonhuman primate autoimmune-mediated inflammatory disorder model, experimental autoimmune encephalomyelitis (EAE) in common marmosets, allowing detailed analysis of secondary lymphoid organs (SLO). We observed that the depletion of CD20+ B cells creates a less immunostimulatory environment in the SLO reflected by reduced expression of MHC class II, CD40, CD83, and CD80/CD86. APCs isolated from SLO of B cell–depleted EAE monkeys were also less responsive to mitogenic stimulation. The depleted B cell areas were replenished by T cells, of which the majority expressed CD127 (IL-7R) and CCR7. Such effects were not detected in EAE marmosets treated with mAb against BLyS or APRIL, where B cell depletion via withdrawal of essential survival cytokines was not associated with a marked clinical effect. We propose that at least part of the efficacy of anti-CD20 mAb therapy is attributable to the sustained CCR7 expression on T cells within SLO, limiting their release into the circulation.

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Memory B cells from a subset of treatment‐naïve relapsing‐remitting multiple sclerosis patients elicit CD4⁺ T‐cell proliferation and IFN‐γ production in response to myelin basic protein and myelin oligodendrocyte glycoprotein

Cited by 107 publications

References 69 publications

B cell exchange across the blood-brain barrier in multiple sclerosis

B cell exchange across the blood-brain barrier in multiple sclerosis

B Cells as a Therapeutic Target for IFN-β in Relapsing–Remitting Multiple Sclerosis

CD20+ B Cell Depletion Alters T Cell Homing

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Memory B cells from a subset of treatment‐naïve relapsing‐remitting multiple sclerosis patients elicit CD4+ T‐cell proliferation and IFN‐γ production in response to myelin basic protein and myelin oligodendrocyte glycoprotein

Cited by 107 publications

References 69 publications

B cell exchange across the blood-brain barrier in multiple sclerosis

B cell exchange across the blood-brain barrier in multiple sclerosis

B Cells as a Therapeutic Target for IFN-β in Relapsing–Remitting Multiple Sclerosis

CD20+ B Cell Depletion Alters T Cell Homing

Contact Info

Product

Resources

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Memory B cells from a subset of treatment‐naïve relapsing‐remitting multiple sclerosis patients elicit CD4⁺ T‐cell proliferation and IFN‐γ production in response to myelin basic protein and myelin oligodendrocyte glycoprotein