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      Ectonucleotidase-Mediated Suppression of Lupus Autoimmunity and Vascular Dysfunction

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          Abstract

          Objectives

          CD39 and CD73 are surface enzymes that jut into the extracellular space where they mediate the step-wise phosphohydrolysis of the autocrine and paracrine danger signals ATP and ADP into anti-inflammatory adenosine. Given the role of vascular and immune cells’ “purinergic halo” in maintaining homeostasis, we hypothesized that the ectonucleotidases CD39 and CD73 might play a protective role in lupus.

          Methods

          Lupus was modeled by intraperitoneal administration of pristane to three groups of mice: wild-type (WT), CD39 −/−, and CD73 −/−. After 36 weeks, autoantibodies, endothelial function, kidney disease, splenocyte activation/polarization, and neutrophil activation were characterized.

          Results

          As compared with WT mice, CD39 −/− mice developed exaggerated splenomegaly in response to pristane, while both groups of ectonucleotidase-deficient mice demonstrated heightened anti-ribonucleoprotein production. The administration of pristane to WT mice triggered only subtle dysfunction of the arterial endothelium; however, both CD39 −/− and CD73 −/− mice demonstrated striking endothelial dysfunction following induction of lupus, which could be reversed by superoxide dismutase. Activated B cells and plasma cells were expanded in CD73 −/− mice, while deficiency of either ectonucleotidase led to expansion of T H17 cells. CD39 −/− and CD73 −/− mice demonstrated exaggerated neutrophil extracellular trap release, while CD73 −/− mice additionally had higher levels of plasma cell-free DNA.

          Conclusion

          These data are the first to link ectonucleotidases with lupus autoimmunity and vascular disease. New therapeutic strategies may harness purinergic nucleotide dissipation or signaling to limit the damage inflicted upon organs and blood vessels by lupus.

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          Most cited references 54

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          Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma.

          Daratumumab targets CD38-expressing myeloma cells through a variety of immune-mediated mechanisms (complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis) and direct apoptosis with crosslinking. These mechanisms may also target nonplasma cells that express CD38, which prompted evaluation of daratumumab's effects on CD38-positive immune subpopulations. Peripheral blood (PB) and bone marrow (BM) from patients with relapsed/refractory myeloma from 2 daratumumab monotherapy studies were analyzed before and during therapy and at relapse. Regulatory B cells and myeloid-derived suppressor cells, previously shown to express CD38, were evaluated for immunosuppressive activity and daratumumab sensitivity in the myeloma setting. A novel subpopulation of regulatory T cells (Tregs) expressing CD38 was identified. These Tregs were more immunosuppressive in vitro than CD38-negative Tregs and were reduced in daratumumab-treated patients. In parallel, daratumumab induced robust increases in helper and cytotoxic T-cell absolute counts. In PB and BM, daratumumab induced significant increases in CD8(+):CD4(+) and CD8(+):Treg ratios, and increased memory T cells while decreasing naïve T cells. The majority of patients demonstrated these broad T-cell changes, although patients with a partial response or better showed greater maximum effector and helper T-cell increases, elevated antiviral and alloreactive functional responses, and significantly greater increases in T-cell clonality as measured by T-cell receptor (TCR) sequencing. Increased TCR clonality positively correlated with increased CD8(+) PB T-cell counts. Depletion of CD38(+) immunosuppressive cells, which is associated with an increase in T-helper cells, cytotoxic T cells, T-cell functional response, and TCR clonality, represents possible additional mechanisms of action for daratumumab and deserves further exploration.
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            Crucial Role for Ecto-5′-Nucleotidase (CD73) in Vascular Leakage during Hypoxia

            Extracellular adenosine has been widely implicated in adaptive responses to hypoxia. The generation of extracellular adenosine involves phosphohydrolysis of adenine nucleotide intermediates, and is regulated by the terminal enzymatic step catalyzed by ecto-5′-nucleotidase (CD73). Guided by previous work indicating that hypoxia-induced vascular leakage is, at least in part, controlled by adenosine, we generated mice with a targeted disruption of the third coding exon of Cd73 to test the hypothesis that CD73-generated extracellular adenosine functions in an innate protective pathway for hypoxia-induced vascular leakage. Cd73 −/− mice bred and gained weight normally, and appeared to have an intact immune system. However, vascular leakage was significantly increased in multiple organs, and after subjection to normobaric hypoxia (8% O2), Cd73 −/− mice manifested fulminant vascular leakage, particularly prevalent in the lung. Histological examination of lungs from hypoxic Cd73 −/− mice revealed perivascular interstitial edema associated with inflammatory infiltrates surrounding larger pulmonary vessels. Vascular leakage secondary to hypoxia was reversed in part by adenosine receptor agonists or reconstitution with soluble 5′-nucleotidase. Together, our studies identify CD73 as a critical mediator of vascular leakage in vivo.
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              A2A receptor signaling promotes peripheral tolerance by inducing T-cell anergy and the generation of adaptive regulatory T cells.

              Tissue-derived adenosine, acting via the adenosine A(2A) receptor (A(2A)R), is emerging as an important negative regulator of T-cell function. In this report, we demonstrate that A(2A)R stimulation not only inhibits the generation of adaptive effector T cells but also promotes the induction of adaptive regulatory T cells. In vitro, antigen recognition in the setting of A(2A)R engagement induces T-cell anergy, even in the presence of costimulation. T cells initially stimulated in the presence of an A(2A)R agonist fail to proliferate and produce interleukin-2 and interferon (IFN)-gamma when rechallenged in the absence of A(2A)R stimulation. Likewise, in an in vivo model of autoimmunity, tissue-derived adenosine promotes anergy and abrogates tissue destruction. Indeed, A(2A)R stimulation inhibits interleukin-6 expression while enhancing the production of transforming growth factor-beta. Accordingly, treating mice with A(2A)R agonists not only inhibits Th1 and Th17 effector cell generation but also promotes the generation of Foxp3(+) and LAG-3(+) regulatory T cells. In this regard, A(2A)R agonists fail to prevent autoimmunity by LAG-3(-/-) clonotypic T cells, implicating an important role for LAG-3 in adenosine-mediated peripheral tolerance. Overall, our findings demonstrate that extracellular adenosine stimulates the A(2A)R to promote long-term T-cell anergy and the generation of adaptive regulatory T cells.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                11 June 2018
                2018
                : 9
                Affiliations
                1Division of Rheumatology, Department of Internal Medicine, University of Michigan , Ann Arbor, MI, United States
                2Department of Pathology, University of Michigan , Ann Arbor, MI, United States
                3Division of Cardiology, Ann Arbor Veterans Administration Healthcare System , Ann Arbor, MI, United States
                4Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan , Ann Arbor, MI, United States
                5Department of Molecular and Integrative Physiology, University of Michigan , Ann Arbor, MI, United States
                Author notes

                Edited by: George C. Tsokos, Harvard Medical School, United States

                Reviewed by: Fabio Malavasi, Università degli Studi di Torino, Italy; Caroline Jefferies, Cedars-Sinai Medical Center, United States

                *Correspondence: Jason S. Knight, jsknight@ 123456umich.edu

                Specialty section: This article was submitted to Inflammation, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2018.01322
                6004379
                Copyright © 2018 Knight, Mazza, Yalavarthi, Sule, Ali, Hodgin, Kanthi and Pinsky.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 6, Tables: 0, Equations: 0, References: 68, Pages: 11, Words: 7441
                Funding
                Funded by: National Institutes of Health 10.13039/100000002
                Award ID: K08AR066569, K08HL131993, L30HL129373, R01HL127151, R01HL134846, R01NS087147
                Funded by: Burroughs Wellcome Fund 10.13039/100000861
                Funded by: Arthritis National Research Foundation 10.13039/100000964
                Funded by: Rheumatology Research Foundation 10.13039/100006260
                Categories
                Immunology
                Original Research

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