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

Ramgolam, Vinod S.; Sha, Yi‐Gao; Marcus, Karen L.; Choudhary, Neelima; Troiani, Luigi; Chopra, Manisha; Marković-Pleše, Silva

doi:10.4049/jimmunol.1000271

Cited by 80 publications

(77 citation statements)

References 39 publications

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“…Only a few studies have thus far addressed this point and most have investigated the ability of highly purified B cells from MS patients to present antigens and subsequently regulate T-cell responses [28,29]. In contrast, we studied whether IFN-β therapy would regulate the maturation and differentiation of B cells into Ig-secreting cells in response to TLR7 or TLR9 stimulation.…”

Section: Discussionmentioning

confidence: 99%

IFN‐β therapy modulates B‐cell and monocyte crosstalk via TLR7 in multiple sclerosis patients

et al. 2013

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The implication of B lymphocytes in the immunopathology of multiple sclerosis (MS) is increasingly recognized. Here we investigated the response of B cells to IFN-β, a first-line therapy for relapsing-remitting MS patients, upon stimulation with TLR. IFN-β restored the frequency of TLR7-induced IgM and IgG-secreting cells in MS patients to the levels found in healthy donors, showing a specific deficiency in the TLR7 pathway. However, no difference was observed in the TLR9 response. Furthermore, in MS-derived PBMCs, TLR7-mediated production of IL-6 and the ex vivo expression of B-cell-activating factor of the TNF family, two crucial cytokines for B-cell differentiation and survival, were induced by IFN-β. Depletion of monocytes, which are key producers of both IL-6 and B-cellactivating factor of the TNF family, showed that TLR7-mediated B-cell differentiation into Ig-secreting cells is strongly dependent on the cross-talk between B cells and monocytes. Accordingly, impaired expression of TLR7 mRNA was observed in PBMCs and monocytes isolated from MS-affected individuals as compared with those from healthy donors, which was rescued by IFN-β therapy. Collectively, our data unveil a novel TLR7-regulated mechanism in in vivo IFN-β-stimulated whole leukocytes that could be exploited to define new TLR7-based strategies for the treatment of MS.Keywords: B cell r IFN-β r Monocyte r Multiple sclerosis r TLR Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionGrowing evidence is accumulating on the central role that B lymphocytes play in the immunopathology of multiple sclerosis (MS) [1,2]. For example, oligoclonal IgG bands, found in the cerebrospinal fluid of more than 90% of patients with MS, indicate an intrathecal Ab production [3]. The presence of clonally Correspondence: Dr. Eliana Marina Coccia e-mail: eliana.coccia@iss.it expanded B cells, plasma cells, complement and myelin-specific Abs in chronic MS lesions also suggested an intrathecal, Agdriven humoral immune response in the central nervous system of MS sufferers [4][5][6]. In addition, B-cell follicle-like structures are detectable in the meninges of MS patients [7,8]. More recently, B-cell depleting therapies, such as Rituximab (that targets the B lymphocyte surface antigen CD20 [9][10][11]), together with * These authors contributed equally to this work. Eur. J. Immunol. 2013Immunol. . 43: 1963Immunol. -1972 Ocrelizumab and Ofatumumab (two other humanized anti-CD20 monoclonal Abs), are proving their efficacy at various stages of clinical development [12]. All together these findings contribute to the compelling evidence that B cells and the humoral immune response are implicated in the pathogenesis of MS and suggest the therapeutic implications that all this may have for the treatment of this disease. B lymphocytes play an essential role in bridging innate and adaptive immunity. To differentiate into specialized cells capable of communicating with helper T cells and undergo Ab divers...

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Section: Discussionmentioning

confidence: 99%

IFN‐β therapy modulates B‐cell and monocyte crosstalk via TLR7 in multiple sclerosis patients

et al. 2013

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“…Our previous studies on DCs and B cells (15,19) and current experiments on CD4 + T cells have revealed that the IFN-b in vitro treatment induces SOCS1 and SOCS3 expression.…”

Section: Ifn-b-1a Treatment Of Rrms Patients Induced Ifnar1 Signalingmentioning

confidence: 99%

“…Following our previous studies reporting on the IFN-b-mediated inhibition of Th17 cell differentiation via its effect on the Th17 polarizing cytokines secreted by DCs (19) and B cells (15) (Fig. 1D).…”

Section: Ifn-b-1a Inhibits Th17 Cytokine Secretionmentioning

confidence: 99%

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The Role of Endogenous IFN-β in the Regulation of Th17 Responses in Patients with Relapsing-Remitting Multiple Sclerosis

Tao

Zhang

Chopra

et al. 2014

The Journal of Immunology

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IFN-β has been used as a first-line therapy for relapsing-remitting multiple sclerosis (RRMS). Because only a few studies have addressed the role of endogenous IFN-β in the pathogenesis of the disease, our objective was to characterize its role in the transcriptional regulation of pathogenic Th17 cytokines in patients with RRMS. In vitro studies have demonstrated that IFN-β inhibits IL-17A, IL-17F, IL-21, IL-22, and IFN-γ secretion in CD4+ lymphocytes through the induction of suppressor of cytokine secretion 1 and suppressor of cytokine secretion 3. We found that patients with RRMS have increased serum and cerebrospinal fluid Th17 (IL-17A and IL-17F) cytokine levels in comparison with the control subjects, suggesting that deficient endogenous IFN-β secretion or signaling can contribute to the dysregulation of those pathogenic cytokines in CD4+ cells. We identified that the endogenous IFN-β from serum of RRMS patients induced a significantly lower IFN-inducible gene expression in comparison with healthy controls. In addition, in vitro studies have revealed deficient endogenous and exogenous IFN-β signaling in the CD4+ cells derived from patients with MS. Interestingly, upon inhibition of the endogenous IFN-β signaling by silencing IFN regulatory factor (IRF) 7 gene expression, the resting CD4+ T cells secreted significantly higher level of IL-17A, IL-17F, IL-21, IL-22, and IL-9, suggesting that endogenous IFN-β suppresses the secretion of these pathogenic cytokines. In vivo recombinant IFN-β–1a treatment induced IFNAR1 and its downstream signaling molecules’ gene expression, suggesting that treatment reconstitutes a deficient endogenous IFN-β regulation of the CD4+ T cells’ pathogenic cytokine production in patients with MS.

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“…Indeed, a study on human patients treated with IFN-demonstrated that their B cells showed a lower proliferative response in vitro than B cells from untreated patients. In vitro IFN-treatment of B cells shifted their cytokine profile and induced IL-10 secretion (Ramgolam, Sha et al 2011). …”

Section: Induction and Expansion Of Breg Cells By Chemical Drugs Usedmentioning

confidence: 99%

Regulatory B Cells - Implications in Autoimmune and Allergic Disorders

Sattler¹,

Vlugt²,

Hussaarts³

et al. 2012

Recent Advances in Immunology to Target Cancer, Inflammation and Infections

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

Cited by 80 publications

References 39 publications

IFN‐β therapy modulates B‐cell and monocyte crosstalk via TLR7 in multiple sclerosis patients

IFN‐β therapy modulates B‐cell and monocyte crosstalk via TLR7 in multiple sclerosis patients

The Role of Endogenous IFN-β in the Regulation of Th17 Responses in Patients with Relapsing-Remitting Multiple Sclerosis

Regulatory B Cells - Implications in Autoimmune and Allergic Disorders

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