{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,9]],"date-time":"2026-11-09T06:01:41Z","timestamp":1794204101793,"version":"4.8.0"},"reference-count":80,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,1,23]],"date-time":"2020-01-23T00:00:00Z","timestamp":1579737600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,1,23]],"date-time":"2020-01-23T00:00:00Z","timestamp":1579737600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Supported by Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale (INSERM), Sorbonne Universit\u00e9, Universit\u00e9 Paris Descartes and CSL Behring, France"},{"name":"Raman-Charpak fellowship from Indo-French Center for Promotion of Advanced Research"},{"name":"fellowship from La Fondation pour la Recherche M\u00e9dicale"},{"name":"fellowship from CEFIPRA"},{"name":"fellowship from University Grant Commission, India"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Autophagy plays an important role in the regulation of autoimmune and autoinflammatory responses of the immune cells. Defective autophagy process is associated with various autoimmune and inflammatory diseases. Moreover, in many of these diseases, the therapeutic use of normal immunoglobulin G or intravenous immunoglobulin (IVIG), a pooled normal IgG preparation, is well documented. Therefore, we explored if IVIG immunotherapy exerts therapeutic benefits via induction of autophagy in the immune cells. Here we show that IVIG induces autophagy in peripheral blood mononuclear cells (PBMCs). Further dissection of this process revealed that IVIG-induced autophagy is restricted to inflammatory cells like monocytes, dendritic cells, and M1 macrophages but not in cells associated with Th2 immune response like M2 macrophages. IVIG induces autophagy by activating AMP-dependent protein kinase, beclin-1, class III phosphoinositide 3-kinase and p38 mitogen-activated protein kinase and by inhibiting mammalian target of rapamycin. Mechanistically, IVIG-induced autophagy is F(ab\u2032)<jats:sub>2<\/jats:sub>-dependent but sialylation independent, and requires endocytosis of IgG by innate cells. Inhibition of autophagy compromised the ability of IVIG to suppress the inflammatory cytokines in innate immune cells. Moreover, IVIG therapy in inflammatory myopathies such as dermatomyositis, antisynthetase syndrome and immune-mediated necrotizing myopathy induced autophagy in PBMCs and reduced inflammatory cytokines in the circulation, thus validating the translational importance of these results. Our data provide insight on how circulating normal immunoglobulins maintain immune homeostasis and explain in part the mechanism by which IVIG therapy benefits patients with autoimmune and inflammatory diseases.<\/jats:p>","DOI":"10.1038\/s41419-020-2249-y","type":"journal-article","created":{"date-parts":[[2020,1,23]],"date-time":"2020-01-23T09:07:07Z","timestamp":1579770427000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Intravenous immunoglobulin mediates anti-inflammatory effects in peripheral blood mononuclear cells by inducing autophagy"],"prefix":"10.1038","volume":"11","author":[{"given":"Mrinmoy","family":"Das","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anupama","family":"Karnam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Stephen-Victor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Gilardin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bharat","family":"Bhatt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Varun","family":"Kumar Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naresh","family":"Rambabu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veerupaxagouda","family":"Patil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxime","family":"Lecerf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian","family":"K\u00e4sermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Bruneval","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kithiganahalli","family":"Narayanaswamy Balaji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Benveniste","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srini V.","family":"Kaveri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0498-9808","authenticated-orcid":false,"given":"Jagadeesh","family":"Bayry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,1,23]]},"reference":[{"key":"2249_CR1","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1146\/annurev-genet-102808-114910","volume":"43","author":"C He","year":"2009","unstructured":"He, C. & Klionsky, D. J. Regulation mechanisms and signaling pathways of autophagy. Annu. Rev. Genet. 43, 67\u201393 (2009).","journal-title":"Annu. Rev. Genet."},{"key":"2249_CR2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/15548627.2015.1100356","volume":"12","author":"DJ Klionsky","year":"2016","unstructured":"Klionsky, D. J. et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12, 1\u2013222 (2016).","journal-title":"Autophagy"},{"key":"2249_CR3","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1038\/cr.2010.82","volume":"20","author":"M Mehrpour","year":"2010","unstructured":"Mehrpour, M., Esclatine, A., Beau, I. & Codogno, P. Overview of macroautophagy regulation in mammalian cells. Cell Res. 20, 748\u2013762 (2010).","journal-title":"Cell Res."},{"key":"2249_CR4","doi-asserted-by":"publisher","first-page":"88","DOI":"10.3389\/fimmu.2013.00088","volume":"4","author":"A Bhattacharya","year":"2013","unstructured":"Bhattacharya, A. & Eissa, N. T. Autophagy and autoimmunity crosstalks. Front. Immunol. 4, 88 (2013).","journal-title":"Front. Immunol."},{"key":"2249_CR5","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1084\/jem.20061303","volume":"204","author":"HH Pua","year":"2007","unstructured":"Pua, H. H., Dzhagalov, I., Chuck, M., Mizushima, N. & He, Y. W. A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J. Exp. Med. 204, 25\u201331 (2007).","journal-title":"J. Exp. Med."},{"key":"2249_CR6","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1038\/nrrheum.2016.92","volume":"12","author":"JS Rockel","year":"2016","unstructured":"Rockel, J. S. & Kapoor, M. Autophagy: controlling cell fate in rheumatic diseases. Nat. Rev. Rheumatol. 12, 517\u2013531 (2016).","journal-title":"Nat. Rev. Rheumatol."},{"key":"2249_CR7","doi-asserted-by":"publisher","first-page":"1113","DOI":"10.4161\/auto.20275","volume":"8","author":"F Gros","year":"2012","unstructured":"Gros, F. et al. Macroautophagy is deregulated in murine and human lupus T lymphocytes. Autophagy 8, 1113\u20131123 (2012).","journal-title":"Autophagy"},{"key":"2249_CR8","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1038\/ng1954","volume":"39","author":"J Hampe","year":"2007","unstructured":"Hampe, J. et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat. Genet. 39, 207\u2013211 (2007).","journal-title":"Nat. Genet."},{"key":"2249_CR9","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1038\/ng2032","volume":"39","author":"JD Rioux","year":"2007","unstructured":"Rioux, J. D. et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat. Genet. 39, 596\u2013604 (2007).","journal-title":"Nat. Genet."},{"key":"2249_CR10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002406","volume":"7","author":"PS Ramos","year":"2011","unstructured":"Ramos, P. S. et al. A comprehensive analysis of shared loci between systemic lupus erythematosus (SLE) and sixteen autoimmune diseases reveals limited genetic overlap. PLoS Genet. 7, e1002406 (2011).","journal-title":"PLoS Genet."},{"key":"2249_CR11","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1136\/annrheumdis-2012-201671","volume":"72","author":"NY Lin","year":"2013","unstructured":"Lin, N. Y. et al. Autophagy regulates TNF\u03b1-mediated joint destruction in experimental arthritis. Ann. Rheum. Dis. 72, 761\u2013768 (2013).","journal-title":"Ann. Rheum. Dis."},{"key":"2249_CR12","doi-asserted-by":"publisher","first-page":"152","DOI":"10.4161\/auto.5.2.7348","volume":"5","author":"M Alirezaei","year":"2009","unstructured":"Alirezaei, M. et al. Elevated ATG5 expression in autoimmune demyelination and multiple sclerosis. Autophagy 5, 152\u2013158 (2009).","journal-title":"Autophagy"},{"key":"2249_CR13","doi-asserted-by":"publisher","first-page":"1377","DOI":"10.2353\/ajpath.2010.100050","volume":"177","author":"A Nogalska","year":"2010","unstructured":"Nogalska, A., D\u2019Agostino, C., Terracciano, C., Engel, W. K. & Askanas, V. Impaired autophagy in sporadic inclusion-body myositis and in endoplasmic reticulum stress-provoked cultured human muscle fibers. Am. J. Pathol. 177, 1377\u20131387 (2010).","journal-title":"Am. J. Pathol."},{"key":"2249_CR14","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-019-1500-x","volume":"10","author":"VR Villella","year":"2019","unstructured":"Villella, V. R. et al. Autophagy suppresses the pathogenic immune response to dietary antigens in cystic fibrosis. Cell Death Dis. 10, 258 (2019).","journal-title":"Cell Death Dis."},{"key":"2249_CR15","doi-asserted-by":"publisher","first-page":"1512","DOI":"10.3389\/fimmu.2018.01512","volume":"9","author":"H Yin","year":"2018","unstructured":"Yin, H. et al. The therapeutic and pathogenic role of autophagy in autoimmune diseases. Front. Immunol. 9, 1512 (2018).","journal-title":"Front. Immunol."},{"key":"2249_CR16","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.jaut.2018.08.009","volume":"94","author":"SR Bonam","year":"2018","unstructured":"Bonam, S. R., Wang, F. & Muller, S. Autophagy: a new concept in autoimmunity regulation and a novel therapeutic option. J. Autoimmun. 94, 16\u201332 (2018).","journal-title":"J. Autoimmun."},{"key":"2249_CR17","doi-asserted-by":"publisher","first-page":"2015","DOI":"10.1056\/NEJMra1009433","volume":"367","author":"EW Gelfand","year":"2012","unstructured":"Gelfand, E. W. Intravenous immune globulin in autoimmune and inflammatory diseases. N. Engl. J. Med. 367, 2015\u20132025 (2012).","journal-title":"N. Engl. J. Med."},{"key":"2249_CR18","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1038\/nrrheum.2011.61","volume":"7","author":"J Bayry","year":"2011","unstructured":"Bayry, J., Negi, V. S. & Kaveri, S. V. Intravenous immunoglobulin therapy in rheumatic diseases. Nat. Rev. Rheumatol. 7, 349\u2013359 (2011).","journal-title":"Nat. Rev. Rheumatol."},{"key":"2249_CR19","doi-asserted-by":"publisher","first-page":"S1","DOI":"10.1016\/j.jaci.2016.09.023","volume":"139","author":"EE Perez","year":"2017","unstructured":"Perez, E. E. et al. Update on the use of immunoglobulin in human disease: a review of evidence. J. Allergy Clin. Immunol. 139, S1\u2013S46 (2017).","journal-title":"J. Allergy Clin. Immunol."},{"key":"2249_CR20","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1038\/nrneurol.2014.253","volume":"11","author":"JD Lunemann","year":"2015","unstructured":"Lunemann, J. D., Nimmerjahn, F. & Dalakas, M. C. Intravenous immunoglobulin in neurology\u2014mode of action and clinical efficacy. Nat. Rev. Neurol. 11, 80\u201389 (2015).","journal-title":"Nat. Rev. Neurol."},{"key":"2249_CR21","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1093\/intimm\/dxx039","volume":"29","author":"C Galeotti","year":"2017","unstructured":"Galeotti, C., Kaveri, S. V. & Bayry, J. IVIG-mediated effector functions in autoimmune and inflammatory diseases. Int. Immunol. 29, 491\u2013498 (2017).","journal-title":"Int. Immunol."},{"key":"2249_CR22","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1016\/j.autrev.2008.04.012","volume":"7","author":"JF Seite","year":"2008","unstructured":"Seite, J. F., Shoenfeld, Y., Youinou, P. & Hillion, S. What is the contents of the magic draft IVIg? Autoimmun. Rev. 7, 435\u2013439 (2008).","journal-title":"Autoimmun. Rev."},{"key":"2249_CR23","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1002\/art.38910","volume":"67","author":"JF Seite","year":"2015","unstructured":"Seite, J. F., Hillion, S., Harbonnier, T. & Pers, J. O. Review: intravenous immunoglobulin and B cells: when the product regulates the producer. Arthritis Rheumatol. 67, 595\u2013603 (2015).","journal-title":"Arthritis Rheumatol."},{"key":"2249_CR24","doi-asserted-by":"publisher","first-page":"789","DOI":"10.1016\/j.it.2017.08.008","volume":"38","author":"MS Maddur","year":"2017","unstructured":"Maddur, M. S., Kaveri, S. V. & Bayry, J. Circulating normal IgG as stimulator of regulatory T cells: lessons from intravenous immunoglobulin. Trends Immunol. 38, 789\u2013792 (2017).","journal-title":"Trends Immunol."},{"key":"2249_CR25","doi-asserted-by":"publisher","first-page":"5720","DOI":"10.1093\/emboj\/19.21.5720","volume":"19","author":"Y Kabeya","year":"2000","unstructured":"Kabeya, Y. et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 19, 5720\u20135728 (2000).","journal-title":"EMBO J."},{"key":"2249_CR26","doi-asserted-by":"publisher","first-page":"E2385","DOI":"10.1073\/pnas.1505292112","volume":"112","author":"BM Fiebiger","year":"2015","unstructured":"Fiebiger, B. M., Maamary, J., Pincetic, A. & Ravetch, J. V. Protection in antibody- and T cell-mediated autoimmune diseases by antiinflammatory IgG Fcs requires type II FcRs. Proc. Natl Acad. Sci. USA 112, E2385\u2013E2394 (2015).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2249_CR27","doi-asserted-by":"publisher","first-page":"1444","DOI":"10.1002\/eji.201344230","volume":"44","author":"I Schwab","year":"2014","unstructured":"Schwab, I. et al. Broad requirement for terminal sialic acid residues and Fc\u03b3RIIB for the preventive and therapeutic activity of intravenous immunoglobulins in vivo. Eur. J. Immunol. 44, 1444\u20131453 (2014).","journal-title":"Eur. J. Immunol."},{"key":"2249_CR28","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1016\/j.jaci.2013.09.029","volume":"133","author":"AH Massoud","year":"2014","unstructured":"Massoud, A. H. et al. Dendritic cell immunoreceptor: a novel receptor for intravenous immunoglobulin mediates induction of regulatory T cells. J. Allergy Clin. Immunol. 133, 853\u2013863 (2014). e855.","journal-title":"J. Allergy Clin. Immunol."},{"key":"2249_CR29","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1002\/eji.201847774","volume":"49","author":"S Bozza","year":"2019","unstructured":"Bozza, S., Kasermann, F., Kaveri, S. V., Romani, L. & Bayry, J. Intravenous immunoglobulin protects from experimental allergic bronchopulmonary aspergillosis via a sialylation-dependent mechanism. Eur. J. Immunol. 49, 195\u2013198 (2019).","journal-title":"Eur. J. Immunol."},{"key":"2249_CR30","doi-asserted-by":"publisher","first-page":"2059","DOI":"10.1002\/eji.201444440","volume":"44","author":"S Othy","year":"2014","unstructured":"Othy, S. et al. Sialylation may be dispensable for reciprocal modulation of helper T cells by intravenous immunoglobulin. Eur. J. Immunol. 44, 2059\u20132063 (2014).","journal-title":"Eur. J. Immunol."},{"key":"2249_CR31","doi-asserted-by":"publisher","first-page":"3709","DOI":"10.1182\/blood-2014-05-576835","volume":"124","author":"SQ Nagelkerke","year":"2014","unstructured":"Nagelkerke, S. Q. et al. Inhibition of Fc\u03b3R-mediated phagocytosis by IVIg is independent of IgG-Fc sialylation and Fc\u03b3RIIb in human macrophages. Blood 124, 3709\u20133718 (2014).","journal-title":"Blood"},{"key":"2249_CR32","doi-asserted-by":"publisher","first-page":"5031","DOI":"10.4049\/jimmunol.1301611","volume":"192","author":"IK Campbell","year":"2014","unstructured":"Campbell, I. K. et al. Therapeutic effect of IVIG on inflammatory arthritis in mice is dependent on the Fc portion and independent of sialylation or basophils. J. Immunol. 192, 5031\u20135038 (2014).","journal-title":"J. Immunol."},{"key":"2249_CR33","doi-asserted-by":"publisher","first-page":"1799","DOI":"10.1111\/j.1537-2995.2011.03517.x","volume":"52","author":"D Leontyev","year":"2012","unstructured":"Leontyev, D. et al. Sialylation-independent mechanism involved in the amelioration of murine immune thrombocytopenia using intravenous gammaglobulin. Transfusion 52, 1799\u20131805 (2012).","journal-title":"Transfusion"},{"key":"2249_CR34","doi-asserted-by":"publisher","first-page":"3253","DOI":"10.1182\/blood-2007-03-077057","volume":"110","author":"T Tha-In","year":"2007","unstructured":"Tha-In, T. et al. Intravenous immunoglobulins suppress T-cell priming by modulating the bidirectional interaction between dendritic cells and natural killer cells. Blood 110, 3253\u20133262 (2007).","journal-title":"Blood"},{"key":"2249_CR35","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1016\/j.clim.2011.12.014","volume":"142","author":"P Trepanier","year":"2012","unstructured":"Trepanier, P., Aubin, E. & Bazin, R. IVIg-mediated inhibition of antigen presentation: predominant role of naturally occurring cationic IgG. Clin. Immunol. 142, 383\u2013389 (2012).","journal-title":"Clin. Immunol."},{"key":"2249_CR36","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1111\/j.1432-1033.1997.0240a.x","volume":"243","author":"EF Blommaart","year":"1997","unstructured":"Blommaart, E. F., Krause, U., Schellens, J. P., Vreeling-Sindelarova, H. & Meijer, A. J. The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes. Eur. J. Biochem. 243, 240\u2013246 (1997).","journal-title":"Eur. J. Biochem."},{"key":"2249_CR37","doi-asserted-by":"publisher","first-page":"778","DOI":"10.1038\/nri2849","volume":"10","author":"MR Ehrenstein","year":"2010","unstructured":"Ehrenstein, M. R. & Notley, C. A. The importance of natural IgM: scavenger, protector and regulator. Nat. Rev. Immunol. 10, 778\u2013786 (2010).","journal-title":"Nat. Rev. Immunol."},{"key":"2249_CR38","doi-asserted-by":"publisher","first-page":"939","DOI":"10.4049\/jimmunol.1102107","volume":"188","author":"SV Kaveri","year":"2012","unstructured":"Kaveri, S. V., Silverman, G. J. & Bayry, J. Natural IgM in immune equilibrium and harnessing their therapeutic potential. J. Immunol. 188, 939\u2013945 (2012).","journal-title":"J. Immunol."},{"key":"2249_CR39","doi-asserted-by":"publisher","first-page":"13","DOI":"10.4049\/jimmunol.1400844","volume":"194","author":"S Panda","year":"2015","unstructured":"Panda, S. & Ding, J. L. Natural antibodies bridge innate and adaptive immunity. J. Immunol. 194, 13\u201320 (2015).","journal-title":"J. Immunol."},{"key":"2249_CR40","doi-asserted-by":"publisher","first-page":"4144","DOI":"10.4049\/jimmunol.1201946","volume":"189","author":"C Peral de Castro","year":"2012","unstructured":"Peral de Castro, C. et al. Autophagy regulates IL-23 secretion and innate T cell responses through effects on IL-1 secretion. J. Immunol. 189, 4144\u20134153 (2012).","journal-title":"J. Immunol."},{"key":"2249_CR41","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1016\/j.immuni.2007.07.022","volume":"27","author":"J Harris","year":"2007","unstructured":"Harris, J. et al. T helper 2 cytokines inhibit autophagic control of intracellular Mycobacterium tuberculosis. Immunity 27, 505\u2013517 (2007).","journal-title":"Immunity"},{"key":"2249_CR42","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1016\/j.molimm.2010.10.020","volume":"48","author":"HJ Park","year":"2011","unstructured":"Park, H. J. et al. IL-10 inhibits the starvation induced autophagy in macrophages via class I phosphatidylinositol 3-kinase (PI3K) pathway. Mol. Immunol. 48, 720\u2013727 (2011).","journal-title":"Mol. Immunol."},{"key":"2249_CR43","doi-asserted-by":"publisher","first-page":"1388","DOI":"10.1016\/j.jaci.2016.12.978","volume":"140","author":"A Fischer","year":"2017","unstructured":"Fischer, A. et al. Autoimmune and inflammatory manifestations occur frequently in patients with primary immunodeficiencies. J. Allergy Clin. Immunol. 140, 1388\u20131393 (2017). e1388.","journal-title":"J. Allergy Clin. Immunol."},{"key":"2249_CR44","doi-asserted-by":"publisher","first-page":"352","DOI":"10.2119\/molmed.2010.00049","volume":"16","author":"T Laragione","year":"2010","unstructured":"Laragione, T. & Gulko, P. S. mTOR regulates the invasive properties of synovial fibroblasts in rheumatoid arthritis. Mol. Med. 16, 352\u2013358 (2010).","journal-title":"Mol. Med."},{"key":"2249_CR45","doi-asserted-by":"publisher","first-page":"2294","DOI":"10.1002\/art.27504","volume":"62","author":"D Cejka","year":"2010","unstructured":"Cejka, D. et al. Mammalian target of rapamycin signaling is crucial for joint destruction in experimental arthritis and is activated in osteoclasts from patients with rheumatoid arthritis. Arthritis Rheum. 62, 2294\u20132302 (2010).","journal-title":"Arthritis Rheum."},{"key":"2249_CR46","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1177\/0961203307081401","volume":"16","author":"A Ramos-Barron","year":"2007","unstructured":"Ramos-Barron, A. et al. Prevention of murine lupus disease in (NZBxNZW)F1 mice by sirolimus treatment. Lupus 16, 775\u2013781 (2007).","journal-title":"Lupus"},{"key":"2249_CR47","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0074450","volume":"8","author":"N Prevel","year":"2013","unstructured":"Prevel, N., Allenbach, Y., Klatzmann, D., Salomon, B. & Benveniste, O. Beneficial role of rapamycin in experimental autoimmune myositis. PLoS ONE 8, e74450 (2013).","journal-title":"PLoS ONE"},{"key":"2249_CR48","doi-asserted-by":"publisher","first-page":"3497","DOI":"10.1002\/art.11346","volume":"48","author":"J Bayry","year":"2003","unstructured":"Bayry, J. et al. Intravenous immunoglobulin abrogates dendritic cell differentiation induced by interferon-\u03b1 present in serum from patients with systemic lupus erythematosus. Arthritis Rheum. 48, 3497\u20133502 (2003).","journal-title":"Arthritis Rheum."},{"key":"2249_CR49","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1038\/nm1416","volume":"12","author":"V Siragam","year":"2006","unstructured":"Siragam, V. et al. Intravenous immunoglobulin ameliorates ITP via activating Fc gamma receptors on dendritic cells. Nat. Med. 12, 688\u2013692 (2006).","journal-title":"Nat. Med."},{"key":"2249_CR50","doi-asserted-by":"publisher","first-page":"5037","DOI":"10.1182\/blood-2007-07-099549","volume":"111","author":"A Smed-Sorensen","year":"2008","unstructured":"Smed-Sorensen, A. et al. IgG regulates the CD1 expression profile and lipid antigen-presenting function in human dendritic cells via Fc\u03b3RIIa. Blood 111, 5037\u20135046 (2008).","journal-title":"Blood"},{"key":"2249_CR51","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1189\/jlb.3VMA0315-078R","volume":"98","author":"LK Kozicky","year":"2015","unstructured":"Kozicky, L. K. et al. Intravenous immunoglobulin skews macrophages to an anti-inflammatory, IL-10-producing activation state. J. Leukoc. Biol. 98, 983\u2013994 (2015).","journal-title":"J. Leukoc. Biol."},{"key":"2249_CR52","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2013.326","volume":"4","author":"DY Fann","year":"2013","unstructured":"Fann, D. Y. et al. Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke. Cell Death Dis. 4, e790 (2013).","journal-title":"Cell Death Dis."},{"key":"2249_CR53","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1165\/rcmb.2015-0012OC","volume":"53","author":"AA Tarique","year":"2015","unstructured":"Tarique, A. A. et al. Phenotypic, functional, and plasticity features of classical and alternatively activated human macrophages. Am. J. Respir. Cell Mol. Biol. 53, 676\u2013688 (2015).","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"2249_CR54","doi-asserted-by":"publisher","first-page":"292","DOI":"10.4161\/auto.6.2.11128","volume":"6","author":"JL Webber","year":"2010","unstructured":"Webber, J. L. Regulation of autophagy by p38alpha MAPK. Autophagy 6, 292\u2013293 (2010).","journal-title":"Autophagy"},{"key":"2249_CR55","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1248\/bpb.33.545","volume":"33","author":"DS Kim","year":"2010","unstructured":"Kim, D. S. et al. p38 Mitogen-activated protein kinase is involved in endoplasmic reticulum stress-induced cell death and autophagy in human gingival fibroblasts. Biol. Pharm. Bull. 33, 545\u2013549 (2010).","journal-title":"Biol. Pharm. Bull."},{"key":"2249_CR56","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1038\/ncb2152","volume":"13","author":"J Kim","year":"2011","unstructured":"Kim, J., Kundu, M., Viollet, B. & Guan, K. L. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell. Biol. 13, 132\u2013141 (2011).","journal-title":"Nat. Cell. Biol."},{"key":"2249_CR57","doi-asserted-by":"publisher","first-page":"4788","DOI":"10.1073\/pnas.1100844108","volume":"108","author":"L Shang","year":"2011","unstructured":"Shang, L. et al. Nutrient starvation elicits an acute autophagic response mediated by Ulk1 dephosphorylation and its subsequent dissociation from AMPK. Proc. Natl Acad. Sci. USA 108, 4788\u20134793 (2011).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"2249_CR58","doi-asserted-by":"publisher","first-page":"1708","DOI":"10.1016\/j.bcp.2010.08.009","volume":"80","author":"A Bai","year":"2010","unstructured":"Bai, A. et al. AMPK agonist downregulates innate and adaptive immune responses in TNBS-induced murine acute and relapsing colitis. Biochem. Pharmacol. 80, 1708\u20131717 (2010).","journal-title":"Biochem. Pharmacol."},{"key":"2249_CR59","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.bbrc.2009.05.106","volume":"386","author":"N Nath","year":"2009","unstructured":"Nath, N. et al. Loss of AMPK exacerbates experimental autoimmune encephalomyelitis disease severity. Biochem. Biophys. Res. Commun. 386, 16\u201320 (2009).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2249_CR60","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1038\/nature10134","volume":"475","author":"RM Anthony","year":"2011","unstructured":"Anthony, R. M., Kobayashi, T., Wermeling, F. & Ravetch, J. V. Intravenous gammaglobulin suppresses inflammation through a novel T(H)2 pathway. Nature 475, 110\u2013113 (2011).","journal-title":"Nature"},{"key":"2249_CR61","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1093\/intimm\/dxf099","volume":"14","author":"Y Shoenfeld","year":"2002","unstructured":"Shoenfeld, Y. et al. Efficacy of IVIG affinity-purified anti-double-stranded DNA anti-idiotypic antibodies in the treatment of an experimental murine model of systemic lupus erythematosus. Int. Immunol. 14, 1303\u20131311 (2002).","journal-title":"Int. Immunol."},{"key":"2249_CR62","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1016\/j.jaci.2010.12.1102","volume":"127","author":"MS Maddur","year":"2011","unstructured":"Maddur, M. S. et al. Inhibition of differentiation, amplification, and function of human TH17 cells by intravenous immunoglobulin. J. Allergy Clin. Immunol. 127, 823\u2013830 (2011). e821\u2013827.","journal-title":"J. Allergy Clin. Immunol."},{"key":"2249_CR63","doi-asserted-by":"publisher","first-page":"1419","DOI":"10.1182\/blood-2012-11-468264","volume":"122","author":"J Trinath","year":"2013","unstructured":"Trinath, J. et al. Intravenous immunoglobulin expands regulatory T cells via induction of cyclooxygenase-2-dependent prostaglandin E2 in human dendritic cells. Blood 122, 1419\u20131427 (2013).","journal-title":"Blood"},{"key":"2249_CR64","doi-asserted-by":"publisher","first-page":"4535","DOI":"10.4049\/jimmunol.1201965","volume":"190","author":"S Othy","year":"2013","unstructured":"Othy, S. et al. Intravenous gammaglobulin inhibits encephalitogenic potential of pathogenic T cells and interferes with their trafficking to the central nervous system, implicating sphingosine-1 phosphate receptor 1-mammalian target of rapamycin axis. J. Immunol. 190, 4535\u20134541 (2013).","journal-title":"J. Immunol."},{"key":"2249_CR65","doi-asserted-by":"crossref","first-page":"2713","DOI":"10.1002\/art.38082","volume":"65","author":"AE Wiedeman","year":"2013","unstructured":"Wiedeman, A. E. et al. Contrasting mechanisms of interferon-\u03b1 inhibition by intravenous immunoglobulin after induction by immune complexes versus Toll-like receptor agonists. Arthritis Rheum. 65, 2713\u20132723 (2013).","journal-title":"Arthritis Rheum."},{"key":"2249_CR66","doi-asserted-by":"publisher","first-page":"275","DOI":"10.3389\/fimmu.2017.00275","volume":"8","author":"C Saha","year":"2017","unstructured":"Saha, C. et al. Monomeric immunoglobulin A from plasma inhibits human Th17 responses in vitro independent of Fc\u03b1RI and DC-SIGN. Front. Immunol. 8, 275 (2017).","journal-title":"Front. Immunol."},{"key":"2249_CR67","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-01404-0","volume":"7","author":"C Schneider","year":"2017","unstructured":"Schneider, C. et al. IVIG regulates the survival of human but not mouse neutrophils. Sci. Rep. 7, 1296 (2017).","journal-title":"Sci. Rep."},{"key":"2249_CR68","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1016\/j.jaci.2018.10.064","volume":"144","author":"C Galeotti","year":"2019","unstructured":"Galeotti, C. et al. Intravenous immunoglobulin induces IL-4 in human basophils by signaling through surface-bound IgE. J. Allergy Clin. Immunol. 144, 524\u2013535 (2019). e528.","journal-title":"J. Allergy Clin. Immunol."},{"key":"2249_CR69","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1111\/j.1365-2249.1991.tb05631.x","volume":"83","author":"F Rossi","year":"1991","unstructured":"Rossi, F., Jayne, D. R., Lockwood, C. M. & Kazatchkine, M. D. Anti-idiotypes against anti-neutrophil cytoplasmic antigen autoantibodies in normal human polyspecific IgG for therapeutic use and in the remission sera of patients with systemic vasculitis. Clin. Exp. Immunol. 83, 298\u2013303 (1991).","journal-title":"Clin. Exp. Immunol."},{"key":"2249_CR70","doi-asserted-by":"publisher","first-page":"1993","DOI":"10.1056\/NEJM199312303292704","volume":"329","author":"MC Dalakas","year":"1993","unstructured":"Dalakas, M. C. et al. A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis. N. Engl. J. Med. 329, 1993\u20132000 (1993).","journal-title":"N. Engl. J. Med."},{"key":"2249_CR71","doi-asserted-by":"publisher","first-page":"1729","DOI":"10.1172\/JCI117520","volume":"94","author":"M Basta","year":"1994","unstructured":"Basta, M. & Dalakas, M. C. High-dose intravenous immunoglobulin exerts its beneficial effect in patients with dermatomyositis by blocking endomysial deposition of activated complement fragments. J. Clin. Invest. 94, 1729\u20131735 (1994).","journal-title":"J. Clin. Invest."},{"key":"2249_CR72","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/j.cyto.2009.02.013","volume":"46","author":"A Tournadre","year":"2009","unstructured":"Tournadre, A. et al. Th1 and Th17 balance in inflammatory myopathies: interaction with dendritic cells and possible link with response to high-dose immunoglobulins. Cytokine 46, 297\u2013301 (2009).","journal-title":"Cytokine"},{"key":"2249_CR73","doi-asserted-by":"publisher","first-page":"450","DOI":"10.3899\/jrheum.111123","volume":"39","author":"J Bayry","year":"2012","unstructured":"Bayry, J., Mouthon, L. & Kaveri, S. V. Intravenous immunoglobulin expands regulatory T cells in autoimmune rheumatic disease. J. Rheumatol. 39, 450\u2013451 (2012).","journal-title":"J. Rheumatol."},{"key":"2249_CR74","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1182\/blood-2003-05-1530","volume":"103","author":"HU Lutz","year":"2004","unstructured":"Lutz, H. U. et al. Intravenously applied IgG stimulates complement attenuation in a complement-dependent autoimmune disease at the amplifying C3 convertase level. Blood 103, 465\u2013472 (2004).","journal-title":"Blood"},{"key":"2249_CR75","doi-asserted-by":"publisher","DOI":"10.1038\/srep05672","volume":"4","author":"M Sharma","year":"2014","unstructured":"Sharma, M. et al. Intravenous immunoglobulin-induced IL-33 is insufficient to mediate basophil expansion in autoimmune patients. Sci. Rep. 4, 5672 (2014).","journal-title":"Sci. Rep."},{"key":"2249_CR76","doi-asserted-by":"publisher","first-page":"1887","DOI":"10.1093\/brain\/awh518","volume":"128","author":"R Raju","year":"2005","unstructured":"Raju, R. & Dalakas, M. C. Gene expression profile in the muscles of patients with inflammatory myopathies: effect of therapy with IVIg and biological validation of clinically relevant genes. Brain 128, 1887\u20131896 (2005).","journal-title":"Brain"},{"key":"2249_CR77","doi-asserted-by":"publisher","first-page":"1167","DOI":"10.1093\/hmg\/dds524","volume":"22","author":"JK Ching","year":"2013","unstructured":"Ching, J. K. et al. mTOR dysfunction contributes to vacuolar pathology and weakness in valosin-containing protein associated inclusion body myopathy. Hum. Mol. Genet. 22, 1167\u20131179 (2013).","journal-title":"Hum. Mol. Genet."},{"key":"2249_CR78","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1007\/s00401-012-1073-6","volume":"125","author":"N Ramachandran","year":"2013","unstructured":"Ramachandran, N. et al. VMA21 deficiency prevents vacuolar ATPase assembly and causes autophagic vacuolar myopathy. Acta Neuropathol. 125, 439\u2013457 (2013).","journal-title":"Acta Neuropathol."},{"key":"2249_CR79","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1038\/s42003-019-0392-8","volume":"2","author":"S Mukherjee","year":"2019","unstructured":"Mukherjee, S., Karnam, A., Das, M., Babu, S. P. S. & Bayry, J. Wuchereria bancrofti filaria activates human dendritic cells and polarizes T helper 1 and regulatory T cells via toll-like receptor 4. Commun. Biol. 2, 169 (2019).","journal-title":"Commun. Biol."},{"key":"2249_CR80","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1046\/j.1523-1755.1999.00592.x","volume":"56","author":"C Chalumeau","year":"1999","unstructured":"Chalumeau, C. et al. Kidney cortex cells derived from SV40 transgenic mice retain intrinsic properties of polarized proximal tubule cells. Kidney Int. 56, 559\u2013570 (1999).","journal-title":"Kidney Int."}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-020-2249-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-020-2249-y","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-020-2249-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,30]],"date-time":"2024-07-30T15:19:53Z","timestamp":1722352793000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-020-2249-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,23]]},"references-count":80,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,1]]}},"alternative-id":["2249"],"URL":"https:\/\/doi.org\/10.1038\/s41419-020-2249-y","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,23]]},"assertion":[{"value":"26 September 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 January 2020","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 January 2020","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 January 2020","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"50"}}