Elevated and dysregulated bone morphogenic proteins in immune cells of patients with relapsing–remitting multiple sclerosis

Mausner-Fainberg, Karin; Urshansky, Nataly; Regev, Keren; Auriel, Eitan; Karni, Arnon

doi:10.1016/j.jneuroim.2013.09.004

Cited by 20 publications

(12 citation statements)

References 40 publications

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“…BAMBI was initially described as a pan‐TGFβ superfamily inhibitor that, in addition to its modulatory activity on TGFβ signaling, regulates activin and BMP activities . In this regard, different BMPs and activin A can be produced by activated CD4+ cells and can regulate Treg cell/Th17 cell differentiation in vitro . BAMBI also potentiates Wnt‐β catenin signaling , and this pathway acts as a negative regulator of Treg cell function .…”

Section: Discussionmentioning

confidence: 99%

Bone Morphogenetic Protein and Activin Membrane–Bound Inhibitor, a Transforming Growth Factor β Rheostat That Controls Murine Treg Cell/Th17 Cell Differentiation and the Development of Autoimmune Arthritis by Reducing Interleukin‐2 Signaling

Postigo

Iglesias

Álvarez

et al. 2016

Arthritis & Rheumatology

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Objective Transforming growth factor β (TGFβ) plays a prominent role in the establishment of immunologic tolerance, and mice lacking TGFβ1 die of multiorgan inflammation early in life. TGFβ controls the differentiation of CD4+ lymphocytes into Treg cells or proinflammatory Th17 cells. Although this dual capacity is modulated by the presence of additional cytokines around the activated cells, TGFβ also dissociates Th17/Treg cell differentiation in a dose‐dependent manner by mechanisms still unknown. The purpose of this study was to explore the contribution of bone morphogenetic protein and activin membrane–bound inhibitor (BAMBI) to the modulation of TGFβ activity during the differentiation of CD4+ cells and in the control of immunologic tolerance in mice with collagen‐induced arthritis (CIA). Methods The in vitro and in vivo Treg cell and Th17 cell differentiation and the development of CIA were compared in wild‐type mice and BAMBI‐deficient mice. Results BAMBI was induced after activation by TGFβ and fixed the appropriate intensity level of TGFβ signaling in CD4+ cells. Its deficiency protected mice against the development of CIA by a Treg cell– and TGFβ‐dependent mechanism. Mechanistically, BAMBI was found to regulate CD25 expression and interleukin‐2 (IL‐2) signaling in Treg cells and in IL‐2– and/or TGFβ‐activated CD4+ cells and modulated Treg cell and Th17 cell differentiation both in vitro and in vivo. Conclusion Taken together, the results indicate that BAMBI is a component of a rheostat‐like mechanism that, through the control of TGFβ and IL‐2 signaling strength, regulates the differentiation of CD4+ lymphocytes and the development of autoimmune arthritis.

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Section: Discussionmentioning

confidence: 99%

Bone Morphogenetic Protein and Activin Membrane–Bound Inhibitor, a Transforming Growth Factor β Rheostat That Controls Murine Treg Cell/Th17 Cell Differentiation and the Development of Autoimmune Arthritis by Reducing Interleukin‐2 Signaling

Postigo

Iglesias

Álvarez

et al. 2016

Arthritis & Rheumatology

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“…BMP4 and BMP5 are expressed at the lesions in post-mortem brain tissues from MS patients, and BMP5 expression is augmented in MS patients compared to healthy controls [110] (Table 2). T cellderived BMP2, BMP4, and BMP5 are increased in peripheral blood mononuclear cells from MS patients [111]. The BMP signaling regulates myelination and demyelination through oligodendrogenesis [11,12].…”

Section: Multiple Sclerosismentioning

confidence: 99%

The role of TGF-β superfamily signaling in neurological disorders

Kashima¹,

Hata²

2018

ABBS

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The TGF-β superfamily signaling is involved in a variety of biological processes during embryogenesis and in adult tissue homeostasis. Faulty regulation of the signaling pathway that transduces the TGF-β superfamily signals accordingly leads to a number of ailments, such as cancer and cardiovascular, metabolic, urinary, intestinal, skeletal, and immune diseases. In recent years, a number of studies have elucidated the essential roles of TGF-βs and BMPs during neuronal development in the maintenance of appropriate innervation and neuronal activity. The new advancement implicates significant roles of the aberrant TGF-β superfamily signaling in the pathogenesis of neurological disorders. In this review, we compile a number of reports implicating the deregulation of TGF-β/BMP signaling pathways in the pathogenesis of cognitive and neurodegenerative disorders in animal models and patients. We apologize in advance that the review falls short of providing details of the role of TGF-β/BMP signaling or mechanisms underlying the pathogenesis of neurological disorders. The goal of this article is to reveal a gap in our knowledge regarding the association between TGF-β/BMP signaling pathways and neuronal tissue homeostasis and development and facilitate the research with a potential to develop new therapies for neurological ailments by modulating the pathways.

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“…For example, injected neuronal precursor cells ameliorate the pathologies of experimental autoimmune encephalomyelitis (EAE), an animal model of MS, in a BMP4-dependent manner [30]. Furthermore, T cell secretion of BMP2, BMP4 and BMP5 is elevated in MS patients [31]. Although BMP5 expression is increased in mesenchymal stem cells from systemic lupus erythematosus (SLE) patients [32], BMP4 and BMP5 expression in synovial tissues from osteoarthritis and RA patients [33], and BMP2 and BMP6 expression in the arthritic synovium from RA and spondyloarthropathy patients [34] were decreased.…”

Section: Tgf-β Superfamily Members and Immunitymentioning

confidence: 99%

Reevaluation of Pluripotent Cytokine TGF-β3 in Immunity

Komai

Okamura

Inoue

et al. 2018

IJMS

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Transforming growth factor (TGF)-βs are pluripotent cytokines with stimulatory and inhibitory properties for multiple types of immune cells. Analyses of genetic knockouts of each isoform of TGF-β have revealed differing expression patterns and distinct roles for the three mammalian isoforms of TGF-β. Considerable effort has been focused on understanding the molecular mechanisms of TGF-β1-mediated immune regulation, given its pivotal role in prohibiting systemic autoimmune disease. In recent years, functional similarities and differences between the TGF-β isoforms have delineated their distinct roles in the development of immunopathology and immune tolerance, with increased recent attention being focused on TGF-β3. In addition to the characteristic properties of each TGF-β isoform, recent progress has identified determinants of context-dependent functionality, including various cellular targets, cytokine concentrations, tissue microenvironments, and cytokine synergy, which combine to shape the physiological and pathophysiological roles of the TGF-βs in immunity. Controlling TGF-β production and signaling is being tested as a novel therapeutic strategy in multiple clinical trials for several human diseases. This review highlights advances in the understanding of the cellular sources, activation processes, contextual determinants, and immunological roles of TGF-β3 with comparisons to other TGF-β isoforms.

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Elevated and dysregulated bone morphogenic proteins in immune cells of patients with relapsing–remitting multiple sclerosis

Cited by 20 publications

References 40 publications

Bone Morphogenetic Protein and Activin Membrane–Bound Inhibitor, a Transforming Growth Factor β Rheostat That Controls Murine Treg Cell/Th17 Cell Differentiation and the Development of Autoimmune Arthritis by Reducing Interleukin‐2 Signaling

Bone Morphogenetic Protein and Activin Membrane–Bound Inhibitor, a Transforming Growth Factor β Rheostat That Controls Murine Treg Cell/Th17 Cell Differentiation and the Development of Autoimmune Arthritis by Reducing Interleukin‐2 Signaling

The role of TGF-β superfamily signaling in neurological disorders

Reevaluation of Pluripotent Cytokine TGF-β3 in Immunity

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Elevated and dysregulated bone morphogenic proteins in immune cells of patients with relapsing–remitting multiple sclerosis

Cited by 20 publications

References 40 publications

Bone Morphogenetic Protein and Activin Membrane–Bound Inhibitor, a Transforming Growth Factor β Rheostat That Controls Murine Treg Cell/Th17 Cell Differentiation and the Development of Autoimmune Arthritis by Reducing Interleukin‐2 Signaling

Bone Morphogenetic Protein and Activin Membrane–Bound Inhibitor, a Transforming Growth Factor β Rheostat That Controls Murine Treg Cell/Th17 Cell Differentiation and the Development of Autoimmune Arthritis by Reducing Interleukin‐2 Signaling

The role of TGF-&beta; superfamily signaling in neurological disorders

Reevaluation of Pluripotent Cytokine TGF-β3 in Immunity

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The role of TGF-β superfamily signaling in neurological disorders