Therapeutic perspectives on the metabolism of lymphocytes in patients with rheumatoid arthritis and systemic lupus erythematosus

References

• Yin Y, Sc C, Xu Z, et al. Normalization of CD4+ T cell metabolism reverses lupus. Sci Transl Med. 2015;7:274ra18.
   PubMed Web of Science ®Google Scholar
• Sundrud MS, Koralov SB, Feuerer M, et al. Halofuginone inhibits TH17 cell differentiation by activating the amino acid starvation response. Science. 2009;324:1334–1338.
   PubMed Web of Science ®Google Scholar
• Apostolidis SA, Rodríguez-Rodríguez N, Suárez-Fueyo A, et al. Phosphatase PP2A is requisite for the function of regulatory T cells. Nat Immunol. 2016;17:556–564.
   PubMed Web of Science ®Google Scholar
• Kono M, Yoshida N, Maeda K, et al. Transcriptional factor ICER promotes glutaminolysis and the generation of Th17 cells. Proc Natl Acad Sci USA. 2018;115:2478–2483.
   PubMed Web of Science ®Google Scholar
• O’Neill LA, Kishton RJ, Rathmell J, et al., A guide to immunometabolism for immunologists. Nat Rev Immunol. 2016;16(9): 553–565. .
   PubMed Web of Science ®Google Scholar
• Sn L, Xz D, GJ D, et al. Altered pattern of TCR/CD3- mediated protein-tyrosyl phosphorylation in T cells from patients with systemiclupus erythematosus. deficient expression of the T cell receptor zeta chain. J Clin Invest. 1998;101:1448–1457.
   PubMed Web of Science ®Google Scholar
• Nambiar MP, Enyedy EJ, Warke VG, et al. T cell signaling abnormalities in systemic lupus erythematosus are associated with increased mutations/polymorphisms and splice variants of T cell receptor zeta chain messenger RNA. Arthritis Rheum. 2001;44:1336–1350.
   PubMed Web of Science ®Google Scholar
• Enyedy EJ, Nambiar MP, Liossis SN, et al. Fc epsilon receptor type I gamma chain replaces the deˆcient T cell receptor zeta chain in T cells of patients with systemic lupus erythematosus. Arthritis Rheum. 2001;44:1114–1121.
   PubMed Web of Science ®Google Scholar
• Crispƒn JC, Kyttaris VC, Juang YT, et al. Systemic lupus erythematosus: new molecular targets. Ann Rheu Dis. 2007;66:65–69.
   PubMed Web of Science ®Google Scholar
• Chi H. Regulation and function of mTOR signalling in T cell fate decisions. Nat Rev Immunol. 2012;12:325–338.
   PubMed Web of Science ®Google Scholar
• Wahl DR, Petersen B, Warner R, et al. Characterization of the metabolic phenotype of chronically activated lymphocytes. Lupus. 2010;19(13):1492–1501. .
   PubMed Web of Science ®Google Scholar
• Murray PJ, Rathmell J, Pearce E, et al. SnapShot: immunometabolism. Cell Metabol. 2015;22(1):190–190.e1. .
   PubMed Web of Science ®Google Scholar
• Delgoffe GM, Pollizzi KN, Waickman AT, et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol. 2011;12:295–303.
   PubMed Web of Science ®Google Scholar
• Finlay D, Cantrell DA. Metabolism, migration and memory in cytotoxic T cells. Nat Rev Immunol. 2011;11:109–117.
   PubMed Web of Science ®Google Scholar
• Wahl DR, Petersen B, Warner R, et al. Characterization of the metabolic phenotype of chronically activated lymphocytes. Lupus. 2010;19:1492–1501.
   PubMed Web of Science ®Google Scholar
• Gergely P Jr, Grossman C, Niland B, et al., Mitochondrial hyperpolarization and ATP depletion in patients with systemic lupus erythematosus. Arthritis Rheum. 2002;46(1): 175–190. .
   PubMed Web of Science ®Google Scholar
• Katsuyama T, Li H, Comte D, et al. Splicing factor SRSF1 controls T cell hyperactivity and systemic autoimmunity. J Clin Invest. 2019;129:5411–5423.
   PubMed Web of Science ®Google Scholar
• Katsuyama T, Martin-Delgado IJ, Krishfield SM, et al. Splicing factor SRSF1 controls T cell homeostasis and its decreased levels are linked to lymphopenia in systemic lupus erythematosus. Rheumatology (Oxford). 2020;59:2146–2155.
   PubMed Web of Science ®Google Scholar
• Zheng X, Tsou PS, Sawalha AH, et al. Increased expression of EZH2 is mediated by higher glycolysis and mTORC1 activation in lupus CD4+ T Cells. Immunometabolism. 2020;2(2):e200013.
   PubMedGoogle Scholar
• Koga T, Hedrich CM, Mizui M, et al. CaMK4-dependent activation of AKT/mTOR and CREM-α underlies autoimmunityassociated Th17 imbalance. J Clin Invest. 2014;124:2234–2245.
   PubMed Web of Science ®Google Scholar
• Perl A, Hanczko R, Zhi-Wei Lai ZW, et al. Comprehensive metabolome analyses reveal N-acetylcysteine-responsive accumulation of kynurenine in systemic lupus erythematosus: implications for activation of the mechanistic target of rapamycin. Metabolomics. 2015;11:1157–1174.
   PubMed Web of Science ®Google Scholar
• Psarelis S, Nikiphorou E. Coexistence of SLE, tuberous sclerosis and aggressive natural killer-cell leukaemia: coincidence or correlated?. Lupus. 2017;26(1):107–108.
   PubMed Web of Science ®Google Scholar
• Olde Bekkink M, Ahmed-Ousenkova YM, Netea MG, et al. Coexistence of systemic lupus erythematosus, tuberous sclerosis and aggressive natural killer-cell leukaemia: coincidence or correlated?. Lupus. 2016;25(7):766–771. .
   PubMed Web of Science ®Google Scholar
• Carrasco Cubero C, Bejarano Moguel V, Fernández Gil MÁ, et al. Coincidence of tuberous sclerosis and systemic lupus erythematosus-a case report. Reumatol Clin. 2016;12:219–222.
   PubMed Web of Science ®Google Scholar
• Singh N, Birkenbach M, Caza T, et al. Tuberous sclerosis and fulminant lupus in a young woman. J Clin Rheumatol. 2013;19:134–137.
   PubMed Web of Science ®Google Scholar
• Frauwirth KA, Riley JL, Harris MH, et al. The CD28 signaling pathway regulates glucose metabolism. Immunity. 2002;16:769e77.
   Web of Science ®Google Scholar
• Zhang CX, Wang HY, Yin L, et al. Immunometabolism in the pathogenesis of systemic lupus erythematosus. J Transl Autoimmun. 2020;3:100046.
   PubMedGoogle Scholar
• Wang R, Dillon CP, Shi LZ, et al. The transcription factor myc controls metabolic reprogramming upon T lymphocyte activation. Immunity. 2011;35(6):871–882. .
   PubMed Web of Science ®Google Scholar
• Shi LZ, Wang R, Huang G, et al. HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and treg cells. J Exp Med. 2011;208:1367–1376.
   PubMed Web of Science ®Google Scholar
• Shehade H, Acolty V, Moser M, et al. Cutting edge: hypoxia-inducible factor 1 negatively regulates Th1 function. J Immunol. 2015;195:1372–1376.
   PubMed Web of Science ®Google Scholar
• Jacobs SR, Herman CE, Maciver NJ, et al. Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and indepndent pathways. J Immunol. 2008;180:4476–4486.
   PubMed Web of Science ®Google Scholar
• Macintyre AN, Gerriets VA, Nicholset AG, et al. The glucose transporter glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab. 2014;20:61–72.
   PubMed Web of Science ®Google Scholar
• Cretenet G, Clerc I, Matias M, et al. Cell surface glut 1 levels distinguish human CD4 and CD8 T lymphocyte subsets with distinct effector functions. Sci Rep. 2016;6:24129.
   PubMed Web of Science ®Google Scholar
• Koga T, Sato T, Furukawa K, et al. Promotion of calcium/calmodulin-dependent protein kinase 4 by GLUT1-dependent glycolysis in systemic lupus erythematosus. Arthritis Rheum. 2019;71:766e72.
   Web of Science ®Google Scholar
• Guma M, Tiziani S, Firestein GS, et al. Metabolomics in rheumatic diseases: desperately seeking biomarkers. Nat Rev Rheumatol. 2016;12:269–281.
   PubMed Web of Science ®Google Scholar
• Zeng H, Cohen S, Guy C, et al. mTORC1 and mTORC2 kinase signaling and glucose metabolism drive follicular helper T cell differentiation. Immunity. 2016;45(3):540–554. .
   PubMed Web of Science ®Google Scholar
• Gerriets VA, Kishton RJ, Nichols AG, et al. Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation. J Clin Invest. 2015;125:194–207.
   PubMed Web of Science ®Google Scholar
• Yin Y, Sc C, Xu Z, et al. Glucose oxidation is critical for CD4+ T cell activation in a mouse model of systemic lupus erythematosus. J Immunol. 2016;196:80–90.
   PubMed Web of Science ®Google Scholar
• Sinclair LV, Rolf J, Emslie E, et al. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat Immunol. 2013;14:500–508.
   PubMed Web of Science ®Google Scholar
• Wolfson RL, Chantranupong L, Saxton RA, et al. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science. 2016;351:43–48.
   PubMed Web of Science ®Google Scholar
• Nakajima H, Kunimoto H. TET2 as an epigenetic master regulator for normal and malignant hematopoiesis. Cancer Sci. 2014;105:1093–1099.
   PubMed Web of Science ®Google Scholar
• Nakaya M, Xiao Y, Zhou X, et al. Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity. 2014;40:692olde5.
   Web of Science ®Google Scholar
• Xu T, Stewart KM, Wang X, et al. Metabolic control of TH17 and induced treg cell balance by an epigenetic mechanism. Nature. 2017;548:228–233.
   PubMed Web of Science ®Google Scholar
• Johnson MO, M Wolf MM, MZ M, et al. Distinct regulation of Th17 and Th1 cell differentiation by glutaminase-dependent metabolism. Cell. 2018;175:1780–1795.
   PubMed Web of Science ®Google Scholar
• Mezrich JD, Fechner JH, Zhang X, et al. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol. 2010;185:3190–3198.
   PubMed Web of Science ®Google Scholar
• Buck MD, O’Sullivan D, Pearce EL, et al. T cell metabolism drives immunity. J Exp Med. 2015;212:1345–1360.
   PubMed Web of Science ®Google Scholar
• Cobbold SP, Adams E, Farquhar CA, et al. Infectious tolerance via the consumption of essential amino acids and mTOR signaling. Proc Natl Acad Sci USA. 2009;106:12055–12060.
   PubMed Web of Science ®Google Scholar
• Widner B, Sepp N, Kowald E, et al. Degradation of tryptophan in patients with systemic lupus erythematosus. Adv Exp Med Biol. 1999;467:571e7.
   Web of Science ®Google Scholar
• Yan R, Jiang H, Gu S, et al. Fecal metabolites were altered, identified as biomarkers and correlated with disease activity in patients with systemic lupus erythematosus in a GC-MS-based metabolomics study. Front Immunol. 2020;11:2138.
   PubMed Web of Science ®Google Scholar
• Pertovaara M, Hasan T, Raitala A, et al. Indoleamine 2,3-dioxygenase activity is increased in patients with systemic lupus erythematosus and predicts disease activation in the sunny season. Clin. Exp Immunol. 2007;150:274–278.
   PubMed Web of Science ®Google Scholar
• Haghikia A, Jörg S, Duscha A, et al. Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine. Immunity. 2015;43(4):817–829. .
   PubMed Web of Science ®Google Scholar
• Qian X, Yang Z, Mao E, et al. Regulation of fatty acid synthesis in immune cells. Scand. J Immunol. 2018;88:e12713.
   PubMed Web of Science ®Google Scholar
• Van den Bossche J, Van der Windt GJW. Fatty acid oxidation in macrophages and T cells: time for reassessment. Cell Metabol. 2018;28:538–540.
   PubMed Web of Science ®Google Scholar
• Berod L, Friedrich C, Nandan A, et al. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat. Med. 2014;20:1327–1333.
   PubMed Web of Science ®Google Scholar
• Young KE, Flaherty S, Woodman KM, et al. Fatty acid synthase regulates the pathogenicity of Th17 cells. J Leukoc Biol. 2017;102(5):1229–1235. .
   Web of Science ®Google Scholar
• McDonald G, Deepak S, Miguel L, et al. Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients. J Clin Invest. 2014;124:712–724.
   PubMed Web of Science ®Google Scholar
• Krishnan S, Nambiar MP, Warke VG, et al. Alterations in lipid raft composition and dynamics contribute to abnormal T cell responses in systemic lupus erythematosus. J Immunol. 2004;172:7821–7831.
   PubMed Web of Science ®Google Scholar
• McDonald G, Deepak S, Miguel L, et al. Normalizing glycosphingolipids restores function in CD4. T cells from lupus patients. J Clin Invest. 2014;124:712–724.
   PubMed Web of Science ®Google Scholar
• Waddington KE, Jury EC, Pineda-Torra I, et al. Liver X receptors in immune cell function in humans. Biochem Soc Trans. 2015;43:752–757.
   PubMed Web of Science ®Google Scholar
• Zhang L, Eddy A, Teng YT, et al. An immunological renal disease in transgenic mice that overexpress Fli-1, a member of the ets family of transcription factor genes. Mol Cell Biol. 1995;15:6961–6970.
   PubMed Web of Science ®Google Scholar
• Zhang XK, Gallant S, Molano I, et al. Decreased expression of the Ets family transcription factor Fli-1 markedly prolongs survival and significantly reduces renal disease in MRL/lpr mice. J Immunol. 2004;173:6481–6489.
   PubMed Web of Science ®Google Scholar
• Mathenia J, Reyes-Cortes E, Williams S, et al. Impact of Fli-1 transcription factor on autoantibody and lupus nephritis in NZM2410 mice. Clin Exp Immunol. 2010;162:362–371.
   PubMed Web of Science ®Google Scholar
• Richard EM, Thiyagarajan T, Bunni MA, et al. Reducing FLI1 levels in the MRL/lpr lupus mouse model impacts T cell function by modulating glycosphingolipid metabolism. PLOS ONE. 2013;8(9):e75175. .
   PubMed Web of Science ®Google Scholar
• Iwata S, Mikami Y, Sun HW, et al. The Transcription Factor T-bet Limits Amplification of Type I IFN Transcriptome and Circuitry in T Helper 1 Cells. Immunity. 2017;46(6):983–991.e4.
   Google Scholar
• Iwata S, Zhang M, Hao H, et al. Enhanced fatty acid synthesis leads to subset imbalance and IFN-γ overproduction in T helper 1 cells. Front Immunol. 2020;11:593103.
   PubMed Web of Science ®Google Scholar
• Caro-Maldonado A, Wang R, Nichols AG, et al. Metabolic reprogramming is required for antibody production that is suppressed in anergic but exaggerated in chronically BAFF-exposed B cells. J Immunol. 2014;192(8):3626–3636. .
   PubMed Web of Science ®Google Scholar
• Wu T, Qin X, Kurepa Z, et al. Shared signaling networks active in B cells isolated from genetically distinct mouse models of lupus. J Clin Invest. 2007;117:2186–2196.
   PubMed Web of Science ®Google Scholar
• Zeng Q, Zhang H, Qin J, et al. Rapamycin inhibits BAFF-stimulated cell proliferation and survival by suppressing mTOR-mediated PP2A-Erk 1/2 signaling pathway in normal and neoplastic B-lymphoid cells. Cell Mol Life Sci. 2015;72:4867–4884.
   PubMed Web of Science ®Google Scholar
• Zheng L, Anne D. BAFF and selection of autoreactive B cells. Trends Immunol. 2011;32:388–394.
   PubMed Web of Science ®Google Scholar
• Gayed M, Gordon C. Novel treatments for systemic lupus erythematosus. Curr Opin Invest Drugs. 2010;11:1256–1264.
   PubMedGoogle Scholar
• Zeng Q, Zhang H, Qin J, et al. Rapamycin inhibits BAFF-stimulated cell proliferation and survival by suppressing mTOR-mediated PP2A-Erk1/2 signaling pathway in normal and neoplastic B-lymphoid cells. Cell Mol Life Sci. 2015 Dec;72(24):4867–4884. .
   PubMed Web of Science ®Google Scholar
• Torigoe M, Iwata S, Nakayamada S, et al. Metabolic reprogramming commits differentiation of human CD27 + IgD + B Cells to plasmablasts or CD27−IgD– cells. J Immunol. 2017;199(2):425–434. .
   PubMed Web of Science ®Google Scholar
• Lee SY, Moon SJ, Kim EK, et al. Metformin suppresses systemic autoimmunity in roquin(san/-san) mice through inhibiting B cell differentiation into plasma cells via regulation of AMPK/mTOR/STAT3. J Immunol. 2017;198:2661e70.
   Web of Science ®Google Scholar
• Zhang M, Iwata S, Hajime M, et al., Methionine commits cells to differentiate into plasmablasts through epigenetic regulation of BTB and CNC homolog 2 by the Methyltransferase EZH2. Arthritis Rheumatol. 2020;72(7): 1143–1153. .
   PubMed Web of Science ®Google Scholar
• Lam WY, Becker AM, Kennerly KM, et al. Mitochondrial pyruvate import promotes long-term survival of antibody-secreting plasma cells. Immunity. 2016;45(1):60–73. .
   PubMed Web of Science ®Google Scholar
• Yang Z, Fujii H, Mohan SV, et al. Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells. J Exp Med. 2013;210(10):2119–2134. .
   PubMed Web of Science ®Google Scholar
• Weyand CM, Goronzy JJ. Immunometabolism in the development of rheumatoid arthritis. Immunol Rev. 2020;294(1):177–187.
   PubMed Web of Science ®Google Scholar
• Yang Z, Matteson EL, Goronzy JJ, et al. T-cell metabolism in autoimmune disease. Arthritis Res Ther. 2015;17(1):29. .
   PubMedGoogle Scholar
• Weyand CM, Zeisbrich M, Goronzy JJ, et al. Metabolic signatures of T-cells and macrophages in rheumatoid arthritis. Curr Opin Immunol. 2017;46:112–120.
   PubMed Web of Science ®Google Scholar
• Petrasca A, Jj P, Ansboro S, et al. Targeting bioenergetics prevents CD4 T cell-mediated activation of synovial fibroblasts in rheumatoid arthritis. Rheumatology. 2020:
   Web of Science ®Google Scholar
• Biniecka M, Canavan M, McGarry T, et al. Dysregulated bioenergetics: a key regulator of joint inflammation. Ann Rheum Dis. 2016;75(12):2192–2200. .
   PubMed Web of Science ®Google Scholar
• Treuhaft PS, Dj M. Synovial fluid pH, lactate, oxygen and carbon dioxide partial pressure in various joint diseases. Arthritis Rheum. 1971;14:475–484.
   PubMed Web of Science ®Google Scholar
• Pucino V, Certo M, Bulusu V, et al. Lactate buildup at the site of chronic inflammation promotes disease by inducing CD4+ T Cell metabolic rewiring. Cell Metab. 2019;30(6):1055–1074. . e1058.
   PubMed Web of Science ®Google Scholar
• Haas R, Smith J, Rocher-Ros V, et al. Lactate regulates metabolic and pro-inflammatory circuits in control of T Cell migration and effector functions. PLoS Biol. 2015;13(7):e1002202. .
   PubMed Web of Science ®Google Scholar
• Shen Y, Wen Z, Li Y, et al. Metabolic control of the scaffold protein TKS5 in tissue-invasive, proinflammatory T cells. Nat Immunol. 2017;18(9):1025–1034. .
   PubMed Web of Science ®Google Scholar
• Weyand CM, Shen Y, Goronzy JJ, et al. Redox-sensitive signaling in inflammatory T cells and in autoimmune disease. Free Radic Biol Med. 2018;125:36–43.
   PubMed Web of Science ®Google Scholar
• Garcia D, Shaw RJ. AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Mol Cell. 2017;66(6):789–800.
   PubMed Web of Science ®Google Scholar
• Wen Z, Jin K, Shen Y, et al. N-myristoyltransferase deficiency impairs activation of kinase AMPK and promotes synovial tissue inflammation. Nat Immunol. 2019;20(3):313–325. .
   PubMed Web of Science ®Google Scholar
• Cantaert T, Kolln J, Timmer T, et al. B lymphocyte autoimmunity in rheumatoid synovitis is independent of ectopic lymphoid neogenesis. J Immunol. 2008;181(1):785–794. .
   PubMed Web of Science ®Google Scholar
• Zhang F, Wei K, Slowikowski K, et al. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat Immunol. 2019;20(7):928–942. .
   PubMed Web of Science ®Google Scholar
• Iwata S, Zhang M, Hajime M, et al. Pathological role of activated mTOR in CXCR3+ memory B cells of rheumatoid arthritis. Rheumatology (Oxford). 2021 Mar 9:keab229. DOI:https://doi.org/10.1093/rheumatology/keab229.
   Google Scholar
• Dolhain RJ, An VDH, Nt TH, et al. Shift toward T lymphocytes with a T helper 1 cytokine-secretion profile in the joints of patients with rheumatoid arthritis. Arthritis Rheum. 1996;39(12):1961–1969. .
   PubMedGoogle Scholar
• Chemin K, Gerstner C, Malmstrom V, et al. Effector functions of CD4+ T Cells at the site of local autoimmune inflammation-lessons from rheumatoidArthritis. Front Immunol. 2019;10:353.
   PubMed Web of Science ®Google Scholar
• Lee EJ, Lilja S, Li X, et al. Bulk and single cell transcriptomic data indicate that a dichotomy between inflammatory pathways in peripheral blood and arthritic joints complicates biomarker discovery. Cytokine. 2019;127:154960.
   PubMed Web of Science ®Google Scholar
• James EA, Rieck M, Pieper J, et al. Citrullinespecific Th1 cells are increased in rheumatoid arthritis and their frequency is influenced by disease duration and therapy. Arthritis Rheumatol. 2014;66(7):1712–1722. .
   PubMed Web of Science ®Google Scholar
• Ota Y, Niiro H, Ota S, et al. Generation mechanism of RANKL+ effector memory B cells: relevance to the pathogenesis of rheumatoid arthritis. Arthritis Res Ther. 2016;18(1):67. .
   PubMedGoogle Scholar
• Iwata S, Nakayamada S, Fukuyo S, et al. Activation of Syk in peripheral blood B cells in patients with rheumatoid arthritis: a potential target for abatacept therapy. Arthritis Rheumatol. 2015;67(1):63–73. .
   PubMed Web of Science ®Google Scholar
• Davis RE, Ngo VN, Lenz G, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature. 2010;463(7277):88–92. .
   PubMed Web of Science ®Google Scholar
• Srinivasan L, Sasaki Y, Calado DP, et al. PI3 kinase signals BCR-dependent mature B cell survival. Cell. 2009 Oct 30;139(3):573–586. .
   PubMed Web of Science ®Google Scholar
• Lam KP, Kühn R, Rajewsky K, et al. In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell. 1997;90(6):1073–1083. .
   PubMed Web of Science ®Google Scholar
• Scharer CD, Blalock EL, Mi T, et al. Epigenetic programming underpins B cell dysfunction in human SLE. Nat Immunol. 2019;20(8):1071–1082. .
   PubMed Web of Science ®Google Scholar
• Pernis AB, Ivashkiv LB. ‘-Omics’ shed light on B Cells in lupus. Nat Immunol. 2019;20(8):946–948.
   PubMed Web of Science ®Google Scholar
• He X, Smeets RL, Koenen HJPM, et al. Mycophenolic acid-mediated suppression of human CD4+ T cells: more than mere guanine nucleotide deprivation. Am J Transplant. 2011 Mar;11(3):439–449. .
   PubMed Web of Science ®Google Scholar
• Torigoe M, Sakata K, Ishii A, et al. Hydroxychloroquine efficiently suppresses inflammatory responses of human class-switched memory B cells via toll-like receptor 9 inhibition. Clin Immunol. 2018 Oct;195:1–7. .
   PubMed Web of Science ®Google Scholar
• Asberg A, Midtvedt K, Voytovich MH, et al. Calcineurin inhibitor effects on glucose metabolism and endothelial function following renal transplantation. Clin Transplant. Aug-Sep 2009;23(4):511–518. .
   PubMed Web of Science ®Google Scholar
• Eriksson P, Wallin P, Sjowall C, et al. Clinical experience of sirolimus regarding efficacy and safety in systemic lupus erythematosus. Front Pharmacol. 2019;10:82.
   PubMed Web of Science ®Google Scholar
• Zhang C, Chan CCY, Cheung KF, et al. Effect of mycophenolate and rapamycin on renal fibrosis in lupus nephritis. Clin Sci (Lond). 2019;133:1721–1744.
   PubMed Web of Science ®Google Scholar
• Lai ZW, Kelly R, Winans T, et al. Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial. Lancet. 2018;391:1186e96.
   Web of Science ®Google Scholar
• Viollet B, Guigas B, Sanz Garcia N, et al. Cellular and molecular mechanisms of metformin: an overview. Clin Sci. 2012;122(6):253e70. .
   Web of Science ®Google Scholar
• Batandier C, Guigas B, Detaille D, et al. The ROS production induced by a reverseelectron flux at respiratory-chain complex 1 is hampered by metformin. J Bioenerg Biomembr. 2006 Feb;38:33e42. .
   Web of Science ®Google Scholar
• Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108(8):1167e74.
   Web of Science ®Google Scholar
• Wang H, Li T, Chen S, et al. Neutrophil extracellular trap mitochondrial DNA and its autoantibody in systemic lupus erythematosus and a proof-of-concept trial of metformin. Arthritis Rheum. 2015;67:3190e200.
   Web of Science ®Google Scholar
• Sun F, Wang HJ, Liu Z, et al. Safety and efficacy of metformin in systemic lupus erythematosus: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Rheumatol. 2020;2(4):E210–216.
   Google Scholar
• Sun F, Geng S, Wang H, et al. Effects of metformin on disease flares in patients with systemic lupus erythematosus: post hoc analyses from two randomised trials. Lupus Sci Med. 2020;7(1):e000429.
   PubMed Web of Science ®Google Scholar