{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T16:52:43Z","timestamp":1787849563674,"version":"build-2784847793"},"reference-count":124,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,1,27]],"date-time":"2021-01-27T00:00:00Z","timestamp":1611705600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a broad spectrum of clinical presentations that can affect almost all organ systems. Lupus nephritis (LN) is a severe complication that affects approximately half of the systemic erythematosus lupus (SLE) patients, which significantly increases the morbidity and the mortality risk. LN is characterized by the accumulation of immune complexes, ultimately leading to renal failure. Aberrant activation of T cells plays a critical role in the pathogenesis of both SLE and LN and is involved in the production of inflammatory cytokines, the recruitment of inflammatory cells to the affected tissues and the co-stimulation of B cells. Calcineurin is a serine-threonine phosphatase that, as a consequence of the T cell hyperactivation, induces the production of inflammatory mediators. Moreover, calcineurin is also involved in the alterations of the podocyte phenotype, which contribute to proteinuria and kidney damage observed in LN patients. Therefore, calcineurin inhibitors have been postulated as a potential treatment strategy in LN, since they reduce T cell activation and promote podocyte cytoskeleton stabilization, both being key aspects in the development of LN. Here, we review the role of calcineurin in SLE and the latest findings about calcineurin inhibitors and their mechanisms of action in the treatment of LN.<\/jats:p>","DOI":"10.3390\/ijms22031263","type":"journal-article","created":{"date-parts":[[2021,1,27]],"date-time":"2021-01-27T20:21:51Z","timestamp":1611778911000},"page":"1263","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Calcineurin and Systemic Lupus Erythematosus: The Rationale for Using Calcineurin Inhibitors in the Treatment of Lupus Nephritis"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4451-9248","authenticated-orcid":false,"given":"Carlos","family":"Rafael-Vidal","sequence":"first","affiliation":[{"name":"Rheumatology &amp; Immuno-Mediated Diseases Research Group (IRIDIS), Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, 36201 Vigo, Spain"},{"name":"Rheumatology Department, University Hospital Complex of Vigo, 36201 Vigo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Altab\u00e1s","sequence":"additional","affiliation":[{"name":"Rheumatology &amp; Immuno-Mediated Diseases Research Group (IRIDIS), Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, 36201 Vigo, Spain"},{"name":"Rheumatology Department, University Hospital Complex of Vigo, 36201 Vigo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nair","family":"P\u00e9rez","sequence":"additional","affiliation":[{"name":"Rheumatology &amp; Immuno-Mediated Diseases Research Group (IRIDIS), Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, 36201 Vigo, Spain"},{"name":"Rheumatology Department, University Hospital Complex of Vigo, 36201 Vigo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Coral","family":"Mourino Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"Rheumatology &amp; Immuno-Mediated Diseases Research Group (IRIDIS), Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, 36201 Vigo, Spain"},{"name":"Rheumatology Department, University Hospital Complex of Vigo, 36201 Vigo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose M.","family":"Pego-Reigosa","sequence":"additional","affiliation":[{"name":"Rheumatology &amp; Immuno-Mediated Diseases Research Group (IRIDIS), Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, 36201 Vigo, Spain"},{"name":"Rheumatology Department, University Hospital Complex of Vigo, 36201 Vigo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5902-2699","authenticated-orcid":false,"given":"Samuel","family":"Garcia","sequence":"additional","affiliation":[{"name":"Rheumatology &amp; Immuno-Mediated Diseases Research Group (IRIDIS), Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, 36201 Vigo, Spain"},{"name":"Rheumatology Department, University Hospital Complex of Vigo, 36201 Vigo, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"106262","DOI":"10.1016\/j.intimp.2020.106262","article-title":"The epigenetic face of lupus: Focus on antigen-presenting cells","volume":"81","author":"Wardowska","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1038\/nrrheum.2016.186","article-title":"New insights into the immunopathogenesis of systemic lupus erythematosus","volume":"12","author":"Tsokos","year":"2016","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2220","DOI":"10.1172\/JCI78087","article-title":"T cell signaling abnormalities contribute to aberrant immune cell function and autoimmunity","volume":"125","author":"Moulton","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Katsuyama, T., Tsokos, G.C., and Moulton, V.R. (2018). Aberrant T cell signaling and subsets in systemic lupus erythematosus. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.01088"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/nrrheum.2010.60","article-title":"T cells as therapeutic targets in SLE","volume":"6","author":"Kyttaris","year":"2010","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1093\/ndt\/gfw289","article-title":"Pro: The use of calcineurin inhibitors in the treatment of lupus nephritis","volume":"31","author":"Mok","year":"2016","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Su, H., Wan, C., Song, A., Qiu, Y., Xiong, W., and Zhang, C. (2019). Renal Fibrosis: Mechanisms and Therapies, Springer.","DOI":"10.1007\/978-981-13-8871-2_29"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1007\/s11255-015-1201-z","article-title":"The effect of calcineurin inhibitors in the induction and maintenance treatment of lupus nephritis: A systematic review and meta-analysis","volume":"48","author":"Zhang","year":"2016","journal-title":"Int. Urol. Nephrol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2556","DOI":"10.1093\/rheumatology\/kez668","article-title":"EPISER2016 for the WGP. Prevalence of systemic lupus erythematosus in Spain: Higher than previously reported in other countries?","volume":"59","year":"2020","journal-title":"Rheumatology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1080\/1744666X.2017.1327352","article-title":"Epidemiology of systemic lupus erythematosus","volume":"13","year":"2017","journal-title":"Expert Rev. Clin. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1546-0096-10-21","article-title":"Monogenic forms of systemic lupus erythematosus: New insights into SLE pathogenesis","volume":"10","author":"Belot","year":"2012","journal-title":"Pediatr. Rheumatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"5902","DOI":"10.1038\/ncomms6902","article-title":"The HLA-DR\u03b21 amino acid positions 11-13-26 explain the majority of SLE-MHC associations","volume":"5","author":"Kim","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_13","first-page":"1003","article-title":"Cunninghame Graham DS. Mapping eQTLs with RNA-seq reveals novel susceptibility genes, non-coding RNAs and alternative-splicing events in systemic lupus erythematosus","volume":"26","author":"Odhams","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2392","DOI":"10.1093\/hmg\/ddy140","article-title":"A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus","volume":"27","author":"Patel","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1038\/ng.468","article-title":"A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus","volume":"41","author":"Gateva","year":"2009","journal-title":"Nat. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Lanata, C.M., Nititham, J., Taylor, K.E., Chung, S.A., Torgerson, D.G., Seldin, M.F., Pons-Estel, B.A., Tusi\u00e9-Luna, T., Tsao, B.P., and Morand, E.F. (2018). Genetic contributions to lupus nephritis in a multi-ethnic cohort of systemic lupus erythematous patients. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0199003"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.ajhg.2016.07.012","article-title":"Trans-ethnic Fine Mapping Highlights Kidney-Function Genes Linked to Salt Sensitivity","volume":"99","author":"Mahajan","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1038\/gene.2008.29","article-title":"Defective T-cell ERK signaling induces interferon-regulated gene expression and overexpression of methylation-sensitive genes similar to lupus patients","volume":"9","author":"Sawalha","year":"2008","journal-title":"Genes Immun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1007\/s12016-015-8497-4","article-title":"Epigenetics and Systemic Lupus Erythematosus: Unmet Needs","volume":"50","author":"Meroni","year":"2016","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.berh.2017.09.005","article-title":"Understanding the role of environmental factors in the development of systemic lupus erythematosus","volume":"31","author":"Parks","year":"2017","journal-title":"Best Pract. Res. Clin. Rheumatol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2550","DOI":"10.1002\/art.21955","article-title":"Mortality in systemic lupus erythematosus","volume":"54","author":"Bernatsky","year":"2006","journal-title":"Arthritis Rheum."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1093\/rheumatology\/kep012","article-title":"Renal damage is the most important predictor of mortality within the damage index: Data from LUMINA LXIV, a multiethnic US cohort","volume":"48","author":"Danila","year":"2009","journal-title":"Rheumatology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1111\/nep.13469","article-title":"Lupus nephritis: An update on treatments and pathogenesis","volume":"23","author":"Yap","year":"2018","journal-title":"Nephrology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2154","DOI":"10.1002\/art.38006","article-title":"Effect of renal disease on the standardized mortality ratio and life expectancy of patients with systemic lupus erythematosus","volume":"65","author":"Mok","year":"2013","journal-title":"Arthritis Rheum."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1002\/acr.22173","article-title":"Overall and cause-specific mortality in patients with systemic lupus erythematosus: A meta-analysis of observational studies","volume":"66","author":"Yurkovich","year":"2014","journal-title":"Arthritis Care Res."},{"key":"ref_26","first-page":"720","article-title":"Characterization of patients with lupus nephritis included in a large cohort from the Spanish society of rheumatology registry of patients with systemic lupus erythematosus (RELESSER)","volume":"95","author":"Freire","year":"2016","journal-title":"Medicine"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1093\/rheumatology\/kev311","article-title":"The frequency and outcome of lupus nephritis: Results from an international inception cohort study","volume":"55","author":"Hanly","year":"2015","journal-title":"Rheumatology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10157-015-1179-y","article-title":"Lupus nephritis: An update","volume":"20","author":"Imran","year":"2016","journal-title":"Clin. Exp. Nephrol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1007\/s00108-019-0574-y","article-title":"Lupus nephritis","volume":"60","author":"Schreiber","year":"2019","journal-title":"Internist"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1191\/0961203305lu2055oa","article-title":"Clinical presentation and monitoring of lupus nephritis","volume":"14","author":"Balow","year":"2005","journal-title":"Lupus"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/j.kint.2017.11.023","article-title":"Revision of the International Society of Nephrology\/Renal Pathology Society classification for lupus nephritis: Clarification of definitions, and modified National Institutes of Health activity and chronicity indices","volume":"93","author":"Bajema","year":"2018","journal-title":"Kidney Int."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"354","DOI":"10.2215\/CJN.05750515","article-title":"The native kidney biopsy: Update and evidence for best practice","volume":"11","author":"Hogan","year":"2016","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1136\/rmdopen-2020-001263","article-title":"Management of lupus nephritis: A systematic literature review informing the 2019 update of the joint EULAR and European Renal Association-European Dialysis and Transplant Association (EULAR\/ERA-EDTA) recommendations","volume":"6","author":"Kostopoulou","year":"2020","journal-title":"RMD Open"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1038\/ni1254","article-title":"Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages","volume":"6","author":"Harrington","year":"2005","journal-title":"Nat. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1038\/ni1261","article-title":"A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17","volume":"6","author":"Park","year":"2005","journal-title":"Nat. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1016\/j.immuni.2019.03.021","article-title":"The IL-17 Family of Cytokines in Health and Disease","volume":"50","author":"McGeachy","year":"2019","journal-title":"Immunity"},{"key":"ref_37","first-page":"1","article-title":"A pathogenic IFN\u03b1, BLyS and IL-17 axis in systemic lupus erythematosus patients","volume":"6","author":"Mozo","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"8761","DOI":"10.4049\/jimmunol.181.12.8761","article-title":"Expanded Double Negative T Cells in Patients with Systemic Lupus Erythematosus Produce IL-17 and Infiltrate the Kidneys","volume":"181","author":"Oukka","year":"2008","journal-title":"J. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1007\/s11739-011-0517-7","article-title":"The role of Th17 lymphocytes in the autoimmune and chronic inflammatory diseases","volume":"6","author":"Murdaca","year":"2011","journal-title":"Intern. Emerg. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1038\/ni.1741","article-title":"Interleukin 17 acts in synergy with B cell-activating factor to influence B cell biology and the pathophysiology of systemic lupus erythematosus","volume":"10","author":"Doreau","year":"2009","journal-title":"Nat. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1007\/s10875-009-9365-x","article-title":"Plasma IL-17A is increased in new-onset SLE patients and associated with disease activity","volume":"30","author":"Chen","year":"2010","journal-title":"J. Clin. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.clim.2008.01.019","article-title":"Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: Implications for Th17-mediated inflammation in auto-immunity","volume":"127","author":"Wong","year":"2008","journal-title":"Clin. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1083\/jcb.200606027","article-title":"Novel cell death program leads to neutrophil extracellular traps","volume":"176","author":"Fuchs","year":"2007","journal-title":"J. Cell Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1111\/j.1365-2249.2009.03944.x","article-title":"Interleukin-17 and systemic lupus erythematosus: Current concepts","volume":"157","author":"Nalbandian","year":"2009","journal-title":"Clin. Exp. Immunol."},{"key":"ref_45","first-page":"1067","article-title":"Tumour Necrosis Factor Alpha and its Soluble Receptors Parallel Clinical Disease and Autoimmune Activity in Systemic Lupus Erythematosus","volume":"35","author":"Steiner","year":"1996","journal-title":"Rheumatology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1093\/rheumatology\/ket428","article-title":"The association of cytokines with disease activity and damage scores in systemic lupus erythematosus patients","volume":"53","author":"McCarthy","year":"2014","journal-title":"Rheumatology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/j.cyto.2011.08.026","article-title":"The role of Tumor Necrosis Factor-alpha (TNF-\u03b1) in the pathogenesis of systemic lupus erythematosus","volume":"56","author":"Postal","year":"2011","journal-title":"Cytokine"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e000260","DOI":"10.1136\/lupus-2018-000260","article-title":"TNF-\u03b1 and plasma albumin as biomarkers of disease activity in systemic lupus erythematosus","volume":"5","author":"Idborg","year":"2018","journal-title":"Lupus Sci. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.3899\/jrheum.131025","article-title":"Increased interleukin 21 and follicular helper T-like cells and reduced interleukin 10+ B cells in patients with new-onset systemic lupus erythematosus","volume":"41","author":"Wang","year":"2014","journal-title":"J. Rheumatol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1038\/nm.1995","article-title":"Involvement of interleukin-21 in the epidermal hyperplasia of psoriasis","volume":"15","author":"Caruso","year":"2009","journal-title":"Nat. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2211","DOI":"10.4049\/jimmunol.181.3.2211","article-title":"Excessive Production of IFN-\u03b3 in Patients with Systemic Lupus Erythematosus and Its Contribution to Induction of B Lymphocyte Stimulator\/B Cell-Activating Factor\/TNF Ligand Superfamily-13B","volume":"181","author":"Harigai","year":"2008","journal-title":"J. Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/cmi.2014.58","article-title":"IL-21 acts as a promising therapeutic target in systemic lupus erythematosus by regulating plasma cell differentiation","volume":"12","author":"Deng","year":"2015","journal-title":"Cell. Mol. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1038\/s41577-018-0020-8","article-title":"Regulatory mechanisms in T cell receptor signalling","volume":"18","author":"Gaud","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1016\/S0021-9258(17)49904-2","article-title":"The structural basis of T-cell receptor (TCR) activation: An enduring enigma","volume":"295","author":"Mariuzza","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.tibs.2017.11.008","article-title":"TCR Signaling: Mechanisms of Initiation and Propagation","volume":"43","author":"Courtney","year":"2018","journal-title":"Trends Biochem. Sci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1146\/annurev.immunol.20.092601.111357","article-title":"Signal Transduction Mediated by the T Cell Antigen Receptor: The Role of Adapter Proteins","volume":"20","author":"Samelson","year":"2002","journal-title":"Annu. Rev. Immunol."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Mak, A., and Kow, N.Y. (2014). The pathology of T cells in systemic lupus erythematosus. J. Immunol. Res., 2014.","DOI":"10.1155\/2014\/419029"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1002\/1529-0131(200105)44:5<1114::AID-ANR192>3.0.CO;2-B","article-title":"Fc\u03b5 receptor type I \u03b3 chain replaces the deficient T cell receptor \u03b6 chain in T cells of patients with systemic lupus erythematosus","volume":"44","author":"Enyedy","year":"2001","journal-title":"Arthritis Rheum."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.smim.2006.03.011","article-title":"Autoimmunity in systemic lupus erythematosus: Integrating genes and biology","volume":"18","author":"Krishnan","year":"2006","journal-title":"Semin. Immunol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/S1471-4906(03)00100-5","article-title":"Rewiring the T-cell: Signaling defects and novel prospects for the treatment of SLE","volume":"24","author":"Tsokos","year":"2003","journal-title":"Trends Immunol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1046\/j.1365-2249.2002.01833.x","article-title":"Defective expression and tyrosine phosphorylation of the T cell receptor zeta chain in peripheral blood T cells from systemic lupus erythematosus patients","volume":"129","author":"Pang","year":"2002","journal-title":"Clin. Exp. Immunol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1948","DOI":"10.1002\/art.11072","article-title":"Reconstitution of deficient T cell receptor \u03b6 chain restores T cell signaling and augments T cell receptor\/CD3-induced interleukin-2 production in patients with systemic lupus erythematosus","volume":"48","author":"Nambiar","year":"2003","journal-title":"Arthritis Rheum."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"8145","DOI":"10.4049\/jimmunol.181.11.8145","article-title":"Differential Expression and Molecular Associations of Syk in Systemic Lupus Erythematosus T Cells","volume":"181","author":"Krishnan","year":"2008","journal-title":"J. Immunol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/S0167-5699(98)01395-4","article-title":"Immune cell signaling defects in lupus: Activation, anergy and death","volume":"20","author":"Tsokos","year":"1999","journal-title":"Immunol. Today."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/s00281-015-0535-z","article-title":"Transient Receptor Potential (TRP) channels in T cells","volume":"38","author":"Bertin","year":"2016","journal-title":"Semin. Immunopathol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"26431","DOI":"10.1016\/S0021-9258(18)47212-2","article-title":"Molecular analysis of the interaction of calcineurin with drug- immunophilin complexes","volume":"269","author":"Clipstone","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/srep38920","article-title":"Investigating the human Calcineurin Interaction Network using the i LxVP SLiM","volume":"6","author":"Sheftic","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1038\/nri1632","article-title":"NFAT proteins: Key regulators of T-cell development and function","volume":"5","author":"Macian","year":"2005","journal-title":"Nat. Rev. Immunol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fimmu.2020.00195","article-title":"The Role of Calcium\u2013Calcineurin\u2013NFAT Signaling Pathway in Health and Autoimmune Diseases","volume":"11","author":"Park","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"52762","DOI":"10.1074\/jbc.M405764200","article-title":"Crucial role for nuclear factor of activated T cells in T cell receptor-mediated regulation of human interleukin-17","volume":"279","author":"Liu","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/S1016-8478(23)13236-5","article-title":"Signaling through the murine T cell receptor induces IL-17 production in the absence of costimulation, IL-23 or dendritic cells","volume":"20","author":"Liu","year":"2005","journal-title":"Mol. Cells"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2058","DOI":"10.1002\/art.30353","article-title":"Calcium signaling in systemic lupus erythematosus T cells: A treatment target","volume":"63","author":"Kyttaris","year":"2011","journal-title":"Arthritis Rheum."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1152\/physrev.00020.2002","article-title":"Cell biology of the glomerular podocyte","volume":"83","author":"Kriz","year":"2003","journal-title":"Physiol. Rev."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Sakhi, H., Moktefi, A., Bouachi, K., Audard, V., H\u00e9nique, C., Remy, P., Ollero, M., and El Karoui, K. (2019). Podocyte Injury in Lupus Nephritis. J. Clin. Med., 8.","DOI":"10.3390\/jcm8091340"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Hall, G., Wang, L., and Spurney, R.F. (2019). TRPC Channels in Proteinuric Kidney Diseases. Cells, 9.","DOI":"10.3390\/cells9010044"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.2215\/CJN.13761119","article-title":"The evolving role of calcineurin inhibitors in treating lupus nephritis","volume":"15","author":"Peleg","year":"2020","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1038\/sj.embor.7401062","article-title":"Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death","volume":"8","author":"Cribbs","year":"2007","journal-title":"EMBO Rep."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1016\/j.transproceed.2012.07.160","article-title":"Role of bad in podocyte apoptosis induced by puromycin aminonucleoside","volume":"45","author":"Yu","year":"2013","journal-title":"Transplant. Proc."},{"key":"ref_79","first-page":"4600","article-title":"Podocyte-associated mRNA profiles in kidney tissue and in urine of patients with active lupus nephritis","volume":"8","author":"Bringhenti","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.krcp.2012.06.007","article-title":"Pharmacokinetics of tacrolimus according to body composition in recipients of kidney transplants","volume":"31","author":"Han","year":"2012","journal-title":"Kidney Res. Clin. Pract."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1136\/annrheumdis-2020-eular.5010","article-title":"OP0277\u2005AURORA Phase 3 study demonstrates voclosporin statistical superiority over standard of care in lupus nephritis (LN)","volume":"79","author":"Arriens","year":"2020","journal-title":"Ann. Rheum. Dis."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"472","DOI":"10.2165\/00003088-199324060-00004","article-title":"Cyclosporin Clinical Pharmacokinetics","volume":"24","author":"Fahr","year":"1993","journal-title":"Clin. Pharmacokinet."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1097\/FPC.0b013e328364db84","article-title":"PharmGKB summary: Cyclosporine and tacrolimus pathways","volume":"23","author":"Barbarino","year":"2013","journal-title":"Pharm. Genom."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"5944","DOI":"10.1002\/j.1460-2075.1994.tb06940.x","article-title":"Immunophilins interact with calcineurin in the absence of exogenous immunosuppressive ligands","volume":"13","author":"Cardenas","year":"1994","journal-title":"EMBO J."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1111\/j.1749-6632.1993.tb17137.x","article-title":"The Mechanism of Action of FK-506 and Cyclosporin A","volume":"696","author":"Wiederrecht","year":"1993","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Ponticelli, C., and Podest\u00e0, M.A. (2020). Calcineurin inhibitors in lupus nephritis. J. Nephrol., 2\u20135.","DOI":"10.1007\/s40620-020-00757-6"},{"key":"ref_87","first-page":"767","article-title":"The novel calcineurin inhibitor ISA247: A more potent immunosuppressant than cyclosporine in vitro","volume":"17","author":"Dambrin","year":"2005","journal-title":"Transpl. Int."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2675","DOI":"10.1111\/j.1600-6143.2011.03763.x","article-title":"The PROMISE study: A phase 2b multicenter study of voclosporin (ISA247) versus tacrolimus in de Novo kidney transplantation","volume":"11","author":"Busque","year":"2011","journal-title":"Am. J. Transplant."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1053\/j.ajkd.2018.07.008","article-title":"Immunosuppressive Treatment for Proliferative Lupus Nephritis: Summary of a Cochrane Review","volume":"72","author":"Tunnicliffe","year":"2018","journal-title":"Am. J. Kidney Dis."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1107\/S0907444910051905","article-title":"Structural basis for the cyclophilin A binding affinity and immunosuppressive potency of E-ISA247 (voclosporin)","volume":"67","author":"Kuglstatter","year":"2011","journal-title":"Acta Crystallogr. Sect. D Biol. Crystallogr."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Liao, R., Liu, Q., Zheng, Z., Fan, J., Peng, W., Kong, Q., He, H., Yang, S., Chen, W., and Tang, X. (2015). Tacrolimus protects podocytes from injury in lupus nephritis partly by stabilizing the cytoskeleton and inhibiting podocyte apoptosis. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0132724"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1093\/rheumatology\/kev404","article-title":"BSR and BHPR guideline on prescribing drugs in pregnancy and breastfeeding-Part I: Standard and biologic disease modifying anti-rheumatic drugs and corticosteroids","volume":"55","author":"Flint","year":"2016","journal-title":"Rheumatology"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1136\/annrheumdis-2016-209770","article-title":"EULAR recommendations for women\u2019s health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and\/or antiphospholipid syndrome","volume":"76","author":"Andreoli","year":"2017","journal-title":"Ann. Rheum. Dis."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1136\/annrheumdis-2015-208840","article-title":"The EULAR points to consider for use of antirheumatic drugs before pregnancy, and during pregnancy and lactation","volume":"75","author":"Skorpen","year":"2016","journal-title":"Ann. Rheum. Dis."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"481","DOI":"10.2215\/CJN.04800908","article-title":"Calcineurin inhibitor nephrotoxicity","volume":"4","author":"Naesens","year":"2009","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1159\/000351648","article-title":"Calcineurin inhibitor nephrotoxicity: A review and perspective of the evidence","volume":"37","author":"Issa","year":"2013","journal-title":"Am. J. Nephrol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1016\/j.transproceed.2010.02.029","article-title":"Posttransplantation calcineurin inhibitor-induced hemolytic uremic syndrome: Single-center experience","volume":"42","author":"Said","year":"2010","journal-title":"Transplant. Proc."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1136\/annrheumdis-2019-215089","article-title":"2019 Update of the EULAR recommendations for the management of systemic lupus erythematosus","volume":"78","author":"Fanouriakis","year":"2019","journal-title":"Ann. Rheum. Dis."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"S713","DOI":"10.1136\/annrheumdis-2020-216924","article-title":"2019 Update of the Joint European League against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR\/ERA-EDTA) recommendations for the management of lupus nephritis","volume":"79","author":"Fanouriakis","year":"2020","journal-title":"Ann. Rheum. Dis."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1177\/0961203310371155","article-title":"Cyclosporine A or intravenous cyclophosphamide for lupus nephritis: The Cyclofa-Lune study","volume":"19","author":"Havrda","year":"2010","journal-title":"Lupus"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"925","DOI":"10.2215\/CJN.02271205","article-title":"A randomized pilot trial comparing cyclosporine and azathioprine for maintenance therapy in diffuse lupus nephritis over four years","volume":"1","author":"Moroni","year":"2006","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Argolini, L.M., Frontini, G., Elefante, E., Saccon, F., Binda, V., Tani, C., Scotti, I., Carli, L., Gatto, M., and Esposito, C. (2020). Multicentric study comparing cyclosporine, mycophenolate mofetil and azathioprine in the maintenance therapy of lupus nephritis: 8 years follow up. J. Nephrol.","DOI":"10.1007\/s40620-020-00753-w"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1177\/0961203312448105","article-title":"Tacrolimus versus cyclophosphamide as treatment for diffuse proliferative or membranous lupus nephritis: A non-randomized prospective cohort study","volume":"21","author":"Wang","year":"2012","journal-title":"Lupus"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1093\/ndt\/gfr484","article-title":"Mycophenolate mofetil or tacrolimus compared with intravenous cyclophosphamide in the induction treatment for active lupus nephritis","volume":"27","author":"Li","year":"2012","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1136\/annrheumdis-2014-206456","article-title":"Tacrolimus versus mycophenolate mofetil for induction therapy of lupus nephritis: A randomised controlled trial and long-term follow-up","volume":"75","author":"Mok","year":"2016","journal-title":"Ann. Rheum. Dis."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2001","DOI":"10.1681\/ASN.2007121272","article-title":"Successful treatment of class V+IV lupus nephritis with multitarget therapy","volume":"19","author":"Bao","year":"2008","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"18","DOI":"10.7326\/M14-1030","article-title":"Multitarget therapy for induction treatment of lupus nephritis: A randomized trial","volume":"162","author":"Liu","year":"2015","journal-title":"Ann. Intern. Med."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"3671","DOI":"10.1681\/ASN.2017030263","article-title":"Multitarget therapy for maintenance treatment of lupus nephritis","volume":"28","author":"Zhang","year":"2017","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.autrev.2015.09.006","article-title":"Tacrolimus use in lupus nephritis: A systematic review and meta-analysis","volume":"15","author":"Hannah","year":"2016","journal-title":"Autoimmun. Rev."},{"key":"ref_110","first-page":"1","article-title":"TAC-TIC use of tacrolimus-based regimens in lupus nephritis","volume":"3","author":"Kraai","year":"2016","journal-title":"Lupus Sci. Med."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1053\/j.ajkd.2016.12.008","article-title":"Induction and Maintenance Immunosuppression Treatment of Proliferative Lupus Nephritis: A Network Meta-analysis of Randomized Trials","volume":"70","author":"Palmer","year":"2017","journal-title":"Am. J. Kidney Dis."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1002\/art.30293","article-title":"Trends in the incidence, demographics, and outcomes of end-stage renal disease due to lupus nephritis in the US from 1995 to 2006","volume":"63","author":"Costenbader","year":"2011","journal-title":"Arthritis Rheum."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1053\/j.ajkd.2019.10.017","article-title":"Update on Lupus Nephritis: Core Curriculum 2020","volume":"76","author":"Parikh","year":"2020","journal-title":"Am. J. Kidney Dis."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1093\/ndt\/gfh739","article-title":"Group for the ET vs CMRTS. Efficacy and safety of tacrolimus compared with cyclosporin A microemulsion in renal transplantation: 2 year follow-up results","volume":"20","author":"Montagnino","year":"2005","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/j.kint.2018.08.025","article-title":"A randomized, controlled double-blind study comparing the efficacy and safety of dose-ranging voclosporin with placebo in achieving remission in patients with active lupus nephritis","volume":"95","author":"Rovin","year":"2019","journal-title":"Kidney Int."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"2328","DOI":"10.1016\/S0140-6736(17)31472-1","article-title":"Pathogenetic insights from the treatment of rheumatoid arthritis","volume":"389","author":"McInnes","year":"2017","journal-title":"Lancet"},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Kunkl, M., Frascolla, S., Amormino, C., Volpe, E., and Tuosto, L. (2020). T Helper Cells: The Modulators of Inflammation in Multiple Sclerosis. Cells, 9.","DOI":"10.3390\/cells9020482"},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Chiricozzi, A., Romanelli, P., Volpe, E., Borsellino, G., and Romanelli, M. (2018). Scanning the Immunopathogenesis of Psoriasis. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19010179"},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"2273","DOI":"10.1016\/S0140-6736(18)30830-4","article-title":"The pathogenesis of psoriatic arthritis","volume":"391","author":"Veale","year":"2018","journal-title":"Lancet"},{"key":"ref_120","doi-asserted-by":"crossref","unstructured":"Nanke, Y., Yago, T., and Kotake, S. (2017). The Role of Th17 Cells in the Pathogenesis of Behcet\u2019s Disease. J. Clin. Med., 6.","DOI":"10.3390\/jcm6070074"},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Sugaya, M. (2020). The role of th17-related cytokines in atopic dermatitis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21041314"},{"key":"ref_122","unstructured":"(2020, December 01). Available online: https:\/\/clinicaltrials.gov\/."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1097\/BOR.0b013e328099af80","article-title":"Cyclosporine and tacrolimus for the treatment of rheumatoid arthritis","volume":"19","author":"Kitahara","year":"2007","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"5785","DOI":"10.4049\/jimmunol.1390055","article-title":"Calcineurin Inhibitors: 40 Years Later, Can\u2019t Live without \u2026","volume":"191","author":"Azzi","year":"2013","journal-title":"J. Immunol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/3\/1263\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:16:20Z","timestamp":1760159780000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/3\/1263"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,27]]},"references-count":124,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["ijms22031263"],"URL":"https:\/\/doi.org\/10.3390\/ijms22031263","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,27]]}}}