B cells from relapsing remitting multiple sclerosis patients support neuro-antigen-specific Th17 responses

Ireland, Sara; Guzman, Alyssa A.; Frohman, Elliot M.; Monson, Nancy

doi:10.1016/j.jneuroim.2015.11.022

Cited by 24 publications

(17 citation statements)

References 44 publications

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“…We have recently demonstrated that B cells from RRMS patients, but not healthy donors (HD), are hyper-responsive to CD40 stimulation as measured by proliferation (19, 20, 22, 30). Based on this data, we hypothesized that dysregulation of CD40 signaling contributes to the hyperactivity of B cells from RRMS patients.…”

Section: Discussionmentioning

confidence: 99%

CD40-Mediated NF-κB Activation in B Cells Is Increased in Multiple Sclerosis and Modulated by Therapeutics

Chen

Ireland

Remington

et al. 2016

The Journal of Immunology

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CD40 interacts with CD40 ligand and plays an essential role in immune regulation and homeostasis. Recent research findings, however, support a pathogenic role of CD40 in a number of autoimmune diseases. We previously showed that memory B cells from relapsing-remitting multiple sclerosis (RRMS) patients exhibited enhanced proliferation with CD40 stimulation compared to healthy donors. In this study, we used a multi-parameter phosflow approach to analyze the phosphorylation status of NFκB and three major MAP kinases (P38, ERK and JNK), the essential components of signaling pathways downstream of CD40 engagement in B cells from MS patients. We found that memory and naïve B cells from RRMS and secondary progressive MS (SPMS) patients exhibited a significantly elevated level of phosphorylated NFκB (p-P65) following CD40 stimulation compared to healthy donor controls. Combination therapy with interferon beta-1a (Avonex) and mycophenolate mofetil (Cellcept) modulated the hyper-phosphorylation of P65 in B cells of RRMS patients at levels similar to healthy donor controls. Lower disease activity after the combination therapy correlated with the reduced phosphorylation of P65 following CD40 stimulation in treated patients. In addition, glatiramer acetate (GA) treatment also significantly reduced CD40-mediated P65 phosphorylation in RRMS patients, suggesting that reducing CD40-mediated p-P65 induction may be a general mechanism by which some current therapies modulate MS disease.

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Section: Discussionmentioning

confidence: 99%

CD40-Mediated NF-κB Activation in B Cells Is Increased in Multiple Sclerosis and Modulated by Therapeutics

Chen

Ireland

Remington

et al. 2016

The Journal of Immunology

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“…One study shows that GM-CSF expression in MS patients is promoted by the IL-12/T-bet/Th1 axis, instead of IL-23 as observed in mouse EAE (273). Other publications report that B-cells are a major source of GM-CSF and specifically act in concert with Th17 cells (274, 276). In accord with these discrepant results, MS is shown to be a heterogeneous disease that can be driven by either Th1 or Th17 immunity (242), which also has implications for therapy as will be discussed in Section 4.3.1.…”

Section: T1-ifns the Th17 Response And Their Interactions In Autoimmmentioning

confidence: 99%

Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases

et al. 2017

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The classical paradigm of tuberculosis (TB) immunity, with a central protective role for Th1 responses and IFN-γ-stimulated cellular responses, has been challenged by unsatisfactory results of vaccine strategies aimed at enhancing Th1 immunity. Moreover, preclinical TB models have shown that increasing IFN-γ responses in the lungs is more damaging to the host than to the pathogen. Type 1 interferon signaling and altered Th17 responses have also been associated with active TB, but their functional roles in TB pathogenesis remain to be established. These two host responses have been studied in more detail in autoimmune diseases (AID) and show functional interactions that are of potential interest in TB immunity. In this review, we first identify the role of type 1 interferons and Th17 immunity in TB, followed by an overview of interactions between these responses observed in systemic AID. We discuss (i) the effects of GM-CSF-secreting Th17.1 cells and type 1 interferons on CCR2+ monocytes; (ii) convergence of IL-17 and type 1 interferon signaling on stimulating B-cell activating factor production and the central role of neutrophils in this process; and (iii) synergy between IL-17 and type 1 interferons in the generation and function of tertiary lymphoid structures and the associated follicular helper T-cell responses. Evaluation of these autoimmune-related pathways in TB pathogenesis provides a new perspective on recent developments in TB research.

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“…Monson summarized investigations using an assay system that directly tests B-T interactions ex vivo. B cells from MS patients, but not from healthy donors, were found to incite proliferation and IL-17 cytokine production by Th17 cells in response to neuroantigens and to support antigen-specific Th1 response (28). Since therapeutic B cell targeting is known to reduce Th17 response in MS patients, these observations could account, at least in part, for the beneficial effects observed.…”

Section: Therapeutic Avenuesmentioning

confidence: 93%

Developing Connections among B Lymphocytes and Deregulated Pathways in Autoimmunity

Zouali

Tsay

2016

Mol Med

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Immunologists have long investigated B lymphocytes as solely antibody-producing cells. With further studies, it became clear that B cells can exert a variety of functions within the immune system and beyond. As a result, B cells are considered promising targets for immunotherapy in a variety of disorders. Recently, experts in B cell biology and autoimmunity convened to discuss important stepping stones to decipher the complexity of B lymphocyte-mediated pathways in autoimmune diseases. Twenty-five years ago, the first report describing the clinical efficacy of depleting B lymphocytes in autoimmune diseases was published (1). This also marked organization of the first International Conference on B Cells and Autoimmunity, held in 2001 in Bergen, Norway. Since then, the credentials of B cells as essential players in autoimmune disease have been well established. For its sixth edition, this conference series settled along the shores of Sun Moon Lake in the heart of Taiwan on August 16-18, 2016, to view and discuss recent advances in different facets of B cell biology and put them in the perspective of understanding autoimmunity and designing effective immunointervention strategies. Following the tradition established in 2001, the conference was a forum where basic immunologists and their clinically trained colleagues met to discuss hot topics of autoimmunity research. Speakers from four continents discussed some of their new data and insights and brought considerable excitement to the conference in the refreshingly beautiful and elegant landscape of Sun Moon Lake and its indescribable charm. B L Y M P H O C Y T E S A N D A U T O I M M U N I T Y

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B cells from relapsing remitting multiple sclerosis patients support neuro-antigen-specific Th17 responses

Cited by 24 publications

References 44 publications

CD40-Mediated NF-κB Activation in B Cells Is Increased in Multiple Sclerosis and Modulated by Therapeutics

CD40-Mediated NF-κB Activation in B Cells Is Increased in Multiple Sclerosis and Modulated by Therapeutics

Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases

Developing Connections among B Lymphocytes and Deregulated Pathways in Autoimmunity

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