Cellular and molecular regulation of the programmed death-1/programmed death ligand system and its role in multiple sclerosis and other autoimmune diseases

Journal of Autoimmunity - Tập 123 - Trang 102702 - 2021
Jorge Ibañez-Vega1, Constanza Vilchez2, Karin Jimenez2, Carlos Guevara3, Paula I. Burgos4, Rodrigo Naves1
1Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile
2Faculty of Natural Sciences, Mathematics and Environment, Universidad Tecnológica Metropolitana, Santiago, Chile
3Department of Neurology and Neurosurgery, Hospital Clínico Universidad de Chile, Santiago, Chile
4Department of Clinical Immunology and Rheumatology, School of Medicine, Pontificia Universidad Católica de Chile, Chile

Tài liệu tham khảo

Obregon, 2017, Update on dendritic cell-induced immunological and clinical tolerance, Front. Immunol., 8, 1514, 10.3389/fimmu.2017.01514 Nagai, 2019, The CD28–B7 family of co-signaling molecules, Adv. Exp. Med. Biol., 1189, 25, 10.1007/978-981-32-9717-3_2 Jiang, 2020, Progress and challenges in precise treatment of tumors with PD-1/PD-L1 blockade, Front. Immunol., 11, 339, 10.3389/fimmu.2020.00339 Sun, 2020, Targeting glycosylated PD-1 induces potent anti-tumor immunity, Canc. Res., 2298, 10.1158/0008-5472.CAN-19-3133 Topalian, 2012, Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity, Curr. Opin. Immunol., 24, 207, 10.1016/j.coi.2011.12.009 Chen, 2019, Mechanisms regulating PD-L1 expression on tumor and immune cells, J. Immunother. Cancer, 7, 305, 10.1186/s40425-019-0770-2 Zamani, 2016, PD-1/PD-L and autoimmunity: a growing relationship, Cell. Immunol., 310, 27, 10.1016/j.cellimm.2016.09.009 Fife, 2011, The role of the PD-1 pathway in autoimmunity and peripheral tolerance, Ann. N. Y. Acad. Sci., 1217, 45, 10.1111/j.1749-6632.2010.05919.x Pedoeem, 2014, Programmed death-1 pathway in cancer and autoimmunity, Clin. Immunol., 153, 145, 10.1016/j.clim.2014.04.010 Kivisäkk, 2019, Co-signaling molecules in neurological diseases, Adv. Exp. Med. Biol., 1189, 233, 10.1007/978-981-32-9717-3_9 Gonsette, 2012, Self-tolerance in multiple sclerosis, Acta Neurol. Belg., 112, 133, 10.1007/s13760-012-0061-x Joller, 2012, Immune checkpoints in central nervous system autoimmunity, Immunol. Rev., 248, 122, 10.1111/j.1600-065X.2012.01136.x Kroner, 2005, A PD-1 polymorphism is associated with disease progression in multiple sclerosis, Ann. Neurol., 58, 50, 10.1002/ana.20514 Pawlak-Adamska, 2017, PD-1 gene polymorphic variation is linked with first symptom of disease and severity of relapsing-remitting form of MS, J. Neuroimmunol., 305, 115, 10.1016/j.jneuroim.2017.02.006 Salmaninejad, 2018, PD-1 and cancer: molecular mechanisms and polymorphisms, Immunogenetics, 70, 73, 10.1007/s00251-017-1015-5 Keir, 2008, PD-1 and its ligands in tolerance and immunity, Annu. Rev. Immunol., 26, 677, 10.1146/annurev.immunol.26.021607.090331 Lin, 2020, Progress in PD-1/PD-L1 pathway inhibitors: from biomacromolecules to small molecules, Eur. J. Med. Chem., 186, 111876, 10.1016/j.ejmech.2019.111876 Zhu, 2017, Soluble PD-1 and PD-L1: predictive and prognostic significance in cancer, Oncotarget, 8, 97671, 10.18632/oncotarget.18311 Liu, 2015, Soluble PD-1 aggravates progression of collagen-induced arthritis through Th1 and Th17 pathways, Arthritis Res. Ther., 17, 340, 10.1186/s13075-015-0859-z Wu, 2009, Soluble PD-1 is associated with aberrant regulation of T cells activation in aplastic anemia, Immunol, Invest, 38, 408 Bommarito, 2017, Inflammatory cytokines compromise programmed cell death-1 (PD-1)-mediated T cell suppression in inflammatory arthritis through up-regulation of soluble PD-1, Clin. Exp. Immunol., 188, 455, 10.1111/cei.12949 Philips, 2020, The structural features that distinguish PD-L2 from PD-L1 emerged in placental mammals, J. Biol. Chem., 295, 4372, 10.1074/jbc.AC119.011747 Man, 2017, Transcription factor IRF4 promotes CD8+ T cell exhaustion and limits the development of memory-like T cells during chronic infection, Immunity, 47, 1129, 10.1016/j.immuni.2017.11.021 Azuma, 2019, Co-signal molecules in T-Cell Activation: historical overview and perspective, Adv. Exp. Med. Biol., 1189, 3, 10.1007/978-981-32-9717-3_1 Taylor, 2016, Glycogen synthase kinase 3 inactivation drives T-bet-mediated downregulation of Co-receptor PD-to enhance CD8+ cytolytic T cell responses, Immunity, 44, 274, 10.1016/j.immuni.2016.01.018 Terawaki, 2011, IFN-α directly promotes programmed cell death-1 transcription and limits the duration of T cell-mediated immunity, J. Immunol., 186, 2772, 10.4049/jimmunol.1003208 Maeda, 2019, Glucocorticoids potentiate the inhibitory capacity of programmed cell death 1 by up-regulating its expression on T cells, J. Biol. Chem., 294, 10.1074/jbc.RA119.010379 Wang, 2017, The roles of microRNAs in regulating the expression of PD-1/PD-L1 immune checkpoint, Int. J. Mol. Sci., 18, 2540, 10.3390/ijms18122540 Redd, 2018, H3K4me3 mediates the NF-κB p50 homodimer binding to the pdcd1 promoter to activate PD-1 transcription in T cells, OncoImmunology, 7, 10.1080/2162402X.2018.1483302 Bally, 2020, PD-1 expression during acute infection is repressed through an LSD1–blimp-1 Axis, J. Immunol., 204, 449, 10.4049/jimmunol.1900601 Röver, 2018, PD-1 (PDCD1) promoter methylation is a prognostic factor in patients with diffuse lower-grade gliomas harboring isocitrate dehydrogenase (IDH) mutations, EBioMedicine, 28, 97, 10.1016/j.ebiom.2018.01.016 Ørskov, 2015, Hypomethylation and up-regulation of PD-1 in T cells by azacytidine in MDS/AML patients: a rationale for combined targeting of PD-1 and DNA methylation, Oncotarget, 6, 9612, 10.18632/oncotarget.3324 Garcia-Diaz, 2017, Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression, Cell Rep., 19, 1189, 10.1016/j.celrep.2017.04.031 Qin, 2020, NPM1 upregulates the transcription of PD-L1 and suppresses T cell activity in triple-negative breast cancer, Nat. Commun., 11, 1669, 10.1038/s41467-020-15364-z Yan, 2020, Interferon regulatory factor 1 (IRF-1) and IRF-2 regulate PD-L1 expression in hepatocellular carcinoma (HCC ) cells, Cancer Immunol, Immunotherapy, 1, 1891 Yoyen-Ermis, 2019, Myeloid maturation potentiates STAT3-mediated atypical IFN-γ signaling and upregulation of PD-1 ligands in AML and MDS, Sci. Rep., 9, 11697, 10.1038/s41598-019-48256-4 Peng, 2019, BCL6-Mediated silencing of PD-1 ligands in germinal center B cells maintains follicular T cell population, J. Immunol., 202, 704, 10.4049/jimmunol.1800876 Woods, 2015, HDAC inhibition upregulates PD-1 ligands in melanoma and augments immunotherapy with PD-1 blockade, Cancer Immunol. Res., 3, 1375, 10.1158/2326-6066.CIR-15-0077-T Lv, 2020, PD-L1 gene promoter methylation represents a potential diagnostic marker in advanced gastric cancer, Oncol. Lett., 19, 1223 Zhu, 2020, Epigenetically silenced PD-L1 confers drug resistance to anti-PD1 therapy in gastric cardia adenocarcinoma, Int. Immunopharm., 82, 106245, 10.1016/j.intimp.2020.106245 Schonfeld, 2020, The polymorphism rs975484 in the protein arginine methyltransferase 1 gene modulates expression of immune checkpoint genes in hepatocellular carcinoma, J. Biol. Chem., 295, 7126, 10.1074/jbc.RA120.013401 Xu, 2020, Long noncoding RNAs control the modulation of immune checkpoint molecules in cancer, Cancer Immunol. Res., 8, 937, 10.1158/2326-6066.CIR-19-0696 Franchini, 2019, Microtubule-driven stress granule dynamics regulate inhibitory immune checkpoint expression in T cells, Cell Rep., 26, 94, 10.1016/j.celrep.2018.12.014 Rafiq, 2019, A mechano-signalling network linking microtubules, myosin IIA filaments and integrin-based adhesions, Nat. Mater., 18, 638, 10.1038/s41563-019-0371-y Okada, 2017, Blockage of core fucosylation reduces cell-surface expression of PD-1 and promotes anti-tumor immune responses of T cells, cell rep, 20, 1017, 10.1016/j.celrep.2017.07.027 Pentcheva-Hoang, 2007, Programmed death-1 concentration at the immunological synapse is determined by ligand affinity and availability, Proc. Natl. Acad. Sci. U.S.A., 104, 17765, 10.1073/pnas.0708767104 Meng, 2018, FBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity of T cells, Nature, 564, 130, 10.1038/s41586-018-0756-0 Lyle, 2019, c-Cbl targets PD-1 in immune cells for proteasomal degradation and modulates colorectal tumor growth, Sci. Rep., 9, 20257, 10.1038/s41598-019-56208-1 Hsu, 2018, Posttranslational modifications of PD-L1 and their applications in cancer therapy, Canc. Res., 78, 6349, 10.1158/0008-5472.CAN-18-1892 Wang, 2019, Autophagy inhibition enhances PD-L1 expression in gastric cancer, J. Exp. Clin. Canc. Res., 38, 140, 10.1186/s13046-019-1148-5 Yao, 2019, Inhibiting PD-L1 palmitoylation enhances T-cell immune responses against tumours, Nat. Biomed. Eng., 3, 306, 10.1038/s41551-019-0375-6 Su, 2020, EGFR-ERK pathway regulates CSN6 to contribute to PD-L1 expression in glioblastoma, Mol. Carcinog., 59, 520, 10.1002/mc.23176 Wang, 2019, HIP1R targets PD-L1 to lysosomal degradation to alter T cell–mediated cytotoxicity, Nat. Chem. Biol., 15, 42, 10.1038/s41589-018-0161-x Frigola, 2011, Identification of a soluble form of B7-H1 that retains immunosuppressive activity and is associated with aggressive renal cell carcinoma, Clin. Canc. Res., 17, 1915, 10.1158/1078-0432.CCR-10-0250 Xavier Frigola, 2012, Soluble B7-H1: differences in production between dendritic cells and T cells, Immunol, Letture, 23, 78 Jang, 2015, Imaging of cell–cell communication in a vertical orientation reveals high-resolution structure of immunological synapse and novel PD-1 dynamics, J. Immunol., 195, 1320, 10.4049/jimmunol.1403143 Saito, 2019, Molecular dynamics of co-signal molecules in T-cell activation, Adv. Exp. Med. Biol., 1189, 135, 10.1007/978-981-32-9717-3_5 Fife, 2009, Interactions between programmed death-1 and programmed death ligand-1 promote tolerance by blocking the T cell receptor-induced stop signal, Nat. Immunol., 10, 1185, 10.1038/ni.1790 Hui, 2017, T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition, Science, 355, 1428, 10.1126/science.aaf1292 Sugiura, 2019, Restriction of PD-1 function by cis-PD-L1/CD80 interactions is required for optimal T cell responses, Science, 364, 558, 10.1126/science.aav7062 Saeidi, 2018, T-cell exhaustion in chronic infections: reversing the state of exhaustion and reinvigorating optimal protective immune responses, Front. Immunol., 9, 2569, 10.3389/fimmu.2018.02569 Liu, 2020, PD-1-Mediated PI3K/Akt/mTOR, caspase 9/caspase 3 and ERK pathways are involved in regulating the apoptosis and proliferation of CD4+ and CD8+ T cells during BVDV infection in vitro, Front. Immunol., 11, 467, 10.3389/fimmu.2020.00467 Patsoukis, 2015, PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation, Nat. Commun., 6, 6692, 10.1038/ncomms7692 Latchman, 2004, PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells, Proc. Natl. Acad. Sci. U.S.A., 101, 10691, 10.1073/pnas.0307252101 Probst, 2005, Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4, Nat. Immunol., 6, 280, 10.1038/ni1165 Wang, 2008, Programmed death 1 ligand signaling regulates the generation of adaptative Foxp3+CD4+ regulatory T Cells, Proc. Natl. Acad. Sci. U.S.A., 105, 9331, 10.1073/pnas.0710441105 Francisco, 2009, PD-L1 regulates the development, maintenance, and function of induced regulatory T cells, J. Exp. Med., 206, 3015, 10.1084/jem.20090847 Sambucci, 2018, FoxP3 isoforms and PD-1 expression by T regulatory cells in multiple sclerosis, Sci. Rep., 8, 363674, 10.1038/s41598-018-21861-5 Amarnath, 2011, The PDL1-PD1 Axis converts human Th1 cells into regulatory T cells, Immunology, 3, 111 Stathopoulou, 2018, PD-1 inhibitory receptor downregulates asparaginyl endopeptidase and maintains Foxp3 transcription factor stability in induced regulatory T cells, Immunity, 49, 247, 10.1016/j.immuni.2018.05.006 Ransohoff, 2015, Multiple sclerosis - a quiet revolution, Nature, 11, 134 Walton, 2020, Rising prevalence of multiple sclerosis worldwide: insights from the Atlas of MS, third edition, Mult. Scler. J., 26, 1816, 10.1177/1352458520970841 Confavreux, 2014, The clinical course of multiple sclerosis, Handb. Clin. Neurol., 122, 343, 10.1016/B978-0-444-52001-2.00014-5 Mahad, 2015, Pathological mechanisms in progressive multiple sclerosis, Lancet Neurol., 14, 183, 10.1016/S1474-4422(14)70256-X Grigoriadis, 2015, A basic overview of multiple sclerosis immunopathology, Eur. J. Neurol., 22, 3, 10.1111/ene.12798 Javan, 2016, Downregulation of immunosuppressive molecules, PD-1 and PD-L1 but not PD-L2, in the patients with multiple sclerosis, Iran J Allergy Asthma Immunol., 15, 296 Trabattoni, 2009, Costimulatory pathways in multiple sclerosis: distinctive expression of PD-1 and PD-L1 in patients with different patterns of disease, J. Immunol., 183, 4984, 10.4049/jimmunol.0901038 George, 2012, Pharmacology and therapeutic potential of interferons, Pharmacol. Ther., 135, 44, 10.1016/j.pharmthera.2012.03.006 Feng, 2019, Interferon-β corrects massive gene dysregulation in multiple sclerosis: short-term and long-term effects on immune regulation and neuroprotection, EBioMedicine, 49, 269, 10.1016/j.ebiom.2019.09.059 Schreiner, 2004, Interferon-β enhances monocyte and dendritic cell expression of B7-H1 (PD-L1), a strong inhibitor of autologous T-cell activation: relevance for the immune modulatory effect in multiple sclerosis, J. Neuroimmunol., 155, 172, 10.1016/j.jneuroim.2004.06.013 Wiesemann, 2008, Effects of interferon-β on co-signaling molecules: upregulation of CD40, CD86 and PD-L2 on monocytes in relation to clinical response to interferon-β treatment in patients with multiple sclerosis, Mult. Scler., 14, 166, 10.1177/1352458507081342 Pittet, 2011, The majority of infiltrating CD8 T lymphocytes in multiple sclerosis lesions is insensitive to enhanced PD-L1 levels on CNS cells, Glia, 59, 841, 10.1002/glia.21158 Ortler, 2008, B7-H1 restricts neuroantigen-specific T cell responses and confines inflammatory CNS damage: implications for the lesion pathogenesis of multiple sclerosis, Eur. J. Immunol., 38, 1734, 10.1002/eji.200738071 Pittet, 2011, Human brain endothelial cells endeavor to immunoregulate CD8 T cells via PD-1 ligand expression in multiple sclerosis, J. Neuroinflammation, 8, 155, 10.1186/1742-2094-8-155 Lovett-Racke, 2017, Contribution of EAE to understanding and treating multiple sclerosis, J. Neuroimmunol., 304, 40, 10.1016/j.jneuroim.2016.08.013 Robinson, 2014, The experimental autoimmune encephalomyelitis (EAE) model of MS. utility for understanding disease pathophysiology and treatment, Handb. Clin. Neurol., 122, 173, 10.1016/B978-0-444-52001-2.00008-X Kroner, 2009, Accelerated course of experimental autoimmune encephalomyelitis in PD-1-deficient central nervous system myelin mutants, Am. J. Pathol., 174, 2290, 10.2353/ajpath.2009.081012 Zhu, 2006, Differential role of programmed death-ligand 1 and programmed death-ligand 2 in regulating the susceptibility and chronic progression of experimental autoimmune encephalomyelitis, J. Immunol., 176, 3480, 10.4049/jimmunol.176.6.3480 Magnus, 2005, Microglial expression of the B7 family member B7 homolog 1 confers strong immune inhibition: implications for immune responses and autoimmunity in the CNS, J. Neurosci., 25, 2537, 10.1523/JNEUROSCI.4794-04.2005 Salama, 2003, Critical role of the programmed death-1 (PD-1) pathway in regulation of experimental autoimmune encephalomyelitis, J. Exp. Med., 198, 71, 10.1084/jem.20022119 Schreiner, 2008, PD-1 ligands expressed on myeloid-derived APC in the CNS regulate T-cell responses in EAE, Eur. J. Immunol., 38, 2706, 10.1002/eji.200838137 Carter, 2007, PD-1/PD-L1, but not PD-1/PD-L2, interactions regulate the severity of experimental autoimmune encephalomyelitis, J. Neuroimmunol., 182, 124, 10.1016/j.jneuroim.2006.10.006 Hu, 2016, Programmed death ligand-1 on microglia regulates Th1 differentiation via nitric oxide in experimental autoimmune encephalomyelitis, Neurosci. Bull., 32, 70, 10.1007/s12264-015-0010-9 Chunhe Wang, 2010, Down-modulation of programmed death 1 alters regulatory T cells and promotes experimental autoimmune encephalomyelitis, J. Neurosci., 88, 7 Yogev, 2012, Dendritic cells ameliorate autoimmunity in the CNS by controlling the homeostasis of PD-1 receptor+ regulatory T cells, Immunity, 37, 264, 10.1016/j.immuni.2012.05.025 Hirata, 2005, Prevention of experimental autoimmune encephalomyelitis by transfer of embryonic stem cell-derived dendritic cells expressing myelin oligodendrocyte glycoprotein peptide along with TRAIL or programmed death-1 ligand, J. Immunol., 174, 1888, 10.4049/jimmunol.174.4.1888 Gold, 2009, Estrogen treatment in multiple sclerosis, J. Neurol. Sci., 286, 99, 10.1016/j.jns.2009.05.028 Wang, 2009, Oestrogen modulates experimental autoimmune encephalomyelitis and interleukin-17 production via programmed death 1, Immunology, 126, 329, 10.1111/j.1365-2567.2008.03051.x Bodhankar, 2013, PD-1 interaction with PD-L1 but not PD-L2 on B-cells mediates protective effects of estrogen against EAE, J. Clin. Cell. Immunol., 143 Seifert, 2019, Estrogen-induced compensatory mechanisms protect IL-10-deficient mice from developing EAE, J. Neuroinflammation, 16, 195, 10.1186/s12974-019-1588-z Cao, 2020, The change of PD1, PDL1 in experimental autoimmune encephalomyelitis treated by 1,25(OH)2D3, J. Neuroimmunol., 338, 577079, 10.1016/j.jneuroim.2019.577079 Bin Chang, 2020, Dendritic cell upregulation of programmed death ligand-1 via DNA demethylation inhibits experimental autoimmune encephalomyelitis, J. Autoimmun., 107, 102362, 10.1016/j.jaut.2019.102362 Ottum, 2015, Opposing roles of interferon-gamma on cells of the central nervous system in autoimmune neuroinflammation, Front. Immunol., 6, 539, 10.3389/fimmu.2015.00539 Arellano, 2015, Stage-specific role of interferon-gamma in experimental autoimmune encephalomyelitis and multiple sclerosis, Front. Immunol., 6, 492, 10.3389/fimmu.2015.00492 Cheng, 2007, vol. 185, 75 White, 2018, Innate IFN-γ ameliorates experimental autoimmune encephalomyelitis and promotes myeloid expansion and PDL-1 expression, Sci. Rep., 8, 259, 10.1038/s41598-017-18543-z Sun, 2019, The PD-1/PD-Ls pathway is up-regulated during the suppression of experimental autoimmune encephalomyelitis treated by Astragalus polysaccharides, J. Neuroimmunol., 332, 78, 10.1016/j.jneuroim.2019.03.019 Li, 2020, Characterization and anti-tumor bioactivity of astragalus polysaccharides by immunomodulation, Int. J. Biol. Macromol., 145, 985, 10.1016/j.ijbiomac.2019.09.189 Tangye, 2013, The good, the bad and the ugly - TFH cells in human health and disease, Nat. Rev. Immunol., 13, 412, 10.1038/nri3447 Good-Jacobson, 2010, PD-1 regulates germinal center B cell survival and the formation and affinity of long-lived plasma cells, Nat. Immunol., 11, 535, 10.1038/ni.1877 He, 2013, Circulating precursor CCR7(lo)PD-1(hi) CXCR5+ CD4+ T cells indicate Tfh cell activity and promote antibody responses upon antigen reexposure, Immunity, 39, 770, 10.1016/j.immuni.2013.09.007 Magliozzi, 2007, Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology, Brain, 130, 1089, 10.1093/brain/awm038 Guo, 2018, T follicular helper-like cells are involved in the pathogenesis of experimental autoimmune encephalomyelitis, Front. Immunol., 9, 944, 10.3389/fimmu.2018.00944 Quinn, 2018, Role of TFH cells in promoting T Helper 17-induced neuroinflammation, Front. Immunol., 9, 382, 10.3389/fimmu.2018.00382 Fan, 2015, Follicular helper CD4+ T cells in human neuroautoimmune diseases and their animal models, Mediat. Inflamm., 638968 Bertsias, 2009, Genetic, immunologic, and immunohistochemical analysis of the programmed death 1/programmed death ligand 1 pathway in human systemic lupus erythematosus, Arthritis Rheum., 60, 207, 10.1002/art.24227 Gao, 2017, Meta-analysis of programmed cell death 1 polymorphisms with systemic lupus erythematosus risk, Oncotarget, 8, 36885, 10.18632/oncotarget.16378 Nielsen, 2003, Association of a putative regulatory polymorphism in the PD-1 gene with susceptibility to type 1 diabetes, Tissue Antigens, 62, 492, 10.1046/j.1399-0039.2003.00136.x Liu, 2014, A promoter region polymorphism in PDCD-1 gene is associated with risk of rheumatoid arthritis in the Han Chinese population of southeastern China, Int. J. Genomics. 2014, 247637 Kong, 2005, A new haplotype of PDCD1 is associated with rheumatoid arthritis in Hong Kong Chinese, Arthritis Rheum., 52, 1058, 10.1002/art.20966 Lee, 2006, Association of the programmed cell death 1 (PDCD1) gene polymorphism with ankylosing spondylitis in the Korean population, Arthritis Res. Ther., 8, R136, 10.1186/ar2071 Yang, 2011, Association of polymorphisms in the programmed cell death 1 (PD-1) and PD-1 ligand genes with ankylosing spondylitis in a Chinese population, Clin. Exp. Rheumatol., 29, 13 Yang, 2015, The programmed cell death 1 gene polymorphisms (PD 1.3 G/A, PD 1.5 C/T and PD 1.9 C/T) and susceptibility to ankylosing spondylitis: a meta-analysis, J. Orthop. Sci., 20, 55, 10.1007/s00776-014-0648-6 Qian, 2018, Association of PD-1 and PD-L1 genetic polymorphyisms with type 1 diabetes susceptibility, J. Diabetes Res., 1614683 Hayashi, 2008, Association of an A/C single nucleotide polymorphism in programmed cell death-ligand 1 gene with Graves' disease in Japanese patients, Eur. J. Endocrinol., 158, 817, 10.1530/EJE-07-0649 Mitchell, 2009, Programmed death ligand 1 (PD-L1) gene variants contribute to autoimmune Addison’s disease and Graves’ disease susceptibility, J. Clin. Endocrinol. Metab., 94, 5139, 10.1210/jc.2009-1404 Wang, 2007, Polymorphisms of genes for programmed cell death 1 ligands in patients with rheumatoid arthritis, J. Clin. Immunol., 27, 563, 10.1007/s10875-007-9113-z Wang, 2007, Ligands for programmed cell death 1 gene in patients with systemic lupus erythematosus, J. Rheumatol., 34, 721 Liu, 2009, Variable increased expression of program death-1 and program death-1 ligands on peripheral mononuclear cells is not impaired in patients with systemic lupus erythematosus, J. Biomed. Biotechnol., 406136 Luo, 2018, Elevated expression of PD-1 on T cells correlates with disease activity in rheumatoid arthritis, Mol. Med. Rep., 17, 3297 Kanai, 2003, Blockade of B7-H1 suppresses the development of chronic intestinal inflammation, J. Immunol., 171, 4156, 10.4049/jimmunol.171.8.4156 Legány, 2017, The role of B7 family costimulatory molecules and indoleamine 2,3-dioxygenase in primary Sjögren’s syndrome and systemic sclerosis, Immunol. Res., 65, 622, 10.1007/s12026-016-8880-0 Tsutsumi, 2006, Phenotypic and genetic analyses of T-cell-mediated immunoregulation in patients with Type 1 diabetes, Diabet. Med., 23, 1145, 10.1111/j.1464-5491.2006.01951.x Li, 2020, PD-1 and PD-L1 expression in peripheral CD4/CD8+ T cells is restored in the partial remission phase in type 1 diabetes, J Clin Endocrinol Metab, 105, dgaa130, 10.1210/clinem/dgaa130 Granados, 2017, Programmed cell death-1, PD-1, is dysregulated in T cells from children with new onset type 1 diabetes, PloS One, 12, 10.1371/journal.pone.0183887 Luo, 2016, PD-L1-expressing neutrophils as a novel indicator to assess disease activity and severity of systemic lupus erythematosus, Arthritis Res. Ther., 18, 47, 10.1186/s13075-016-0942-0 Zhao, 2020, Low expressions of PD-L1 and CTLA-4 by induced CD4+CD25+ Foxp3+ Tregs in patients with SLE and their correlation with the disease activity, Cytokine, 133, 155119, 10.1016/j.cyto.2020.155119 Mozaffarian, 2008, Active systemic lupus erythematosus is associated with failure of antigen-presenting cells to express programmed death ligand-1, Rheumatology, 47, 1335, 10.1093/rheumatology/ken256 Wan, 2006, Aberrant regulation of synovial T cell activation by soluble costimulatory molecules in rheumatoid arthritis, J. Immunol., 177, 8844, 10.4049/jimmunol.177.12.8844 Floudas, 2020, Pathogenic, glycolytic PD-1+ B cells accumulate in the hypoxic RA joint, JCI Insight, 5, 10.1172/jci.insight.139032 Moret, 2014, Synovial T cell hyporesponsiveness to myeloid dendritic cells is reversed by preventing PD-1/PD-L1 interactions, Arthritis Res. Ther., 16, 497, 10.1186/s13075-014-0497-x Kobayashi, 2005, Enhanced expression of programmed death-1 (PD-1)/PD-L1 in salivary glands of patients with Sjögren’s syndrome, J. Rheumatol., 32, 2156 Mataki, 2007, Expression of PD-1, PD-L1, and PD-L2 in the liver in autoimmune liver diseases, Am. J. Gastroenterol., 102, 302, 10.1111/j.1572-0241.2006.00948.x Oikawa, 2007, Intrahepatic expression of the co-stimulatory molecules programmed death-1, and its ligands in autoimmune liver disease, Pathol. Int., 57, 485, 10.1111/j.1440-1827.2007.02129.x Agina, 2019, Hepatic expression of programmed death-1 (PD-1) and its ligand, PD-L1, in children with autoimmune hepatitis: relation to treatment response, Clin. Exp. Hepatol., 5, 256, 10.5114/ceh.2019.87642 Nishimura, 1998, Immunological studies on PD-1-deficient mice: implication of PD-1 as a negative regulator for B cell responses, Int. Immunol., 10, 1563, 10.1093/intimm/10.10.1563 Nishimura, 1999, Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor, Immunity, 11, 141, 10.1016/S1074-7613(00)80089-8 Tanaka, 2001, Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice, Science, 291, 319, 10.1126/science.291.5502.319 Keir, 2006, Tissue expression of PD-L1 mediates peripheral T cell tolerance, J. Exp. Med., 203, 883, 10.1084/jem.20051776 Raptopoulou, 2010, The programmed death 1/programmed death ligand 1 inhibitory pathway is up-regulated in rheumatoid synovium and regulates peripheral T cell responses in human and murine arthritis, Arthritis Rheum., 62, 1870, 10.1002/art.27500 Dong, 2004, B7-H1 determines accumulation and deletion of intrahepatic CD8+ T lymphocytes, Immunity, 20, 327, 10.1016/S1074-7613(04)00050-0 Lucas, 2008, Programmed death ligand 1 regulates a critical checkpoint for autoimmune myocarditis and pneumonitis in MRL mice, J. Immunol., 181, 2513, 10.4049/jimmunol.181.4.2513 Wang, 2010, PD-1 deficiency results in the development of fatal myocarditis in MRL mice, Int. Immunol., 22, 443, 10.1093/intimm/dxq026 Li, 2021, Programmed death-ligand 2 deficiency exacerbates experimental autoimmune myocarditis in mice, Int. J. Mol. Sci., 22, 1426, 10.3390/ijms22031426 Ansari, 2003, The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice, J. Exp. Med., 198, 63, 10.1084/jem.20022125 Kasagi, 2010, Anti-Programmed cell death 1 antibody reduces CD4+ PD-1+ T cells and relieves the lupus-like nephritis of NZB/W F1 mice, J. Immunol., 184, 2337, 10.4049/jimmunol.0901652 Wong, 2013, Blockade of programmed death-1 in young (New Zealand black × New Zealand white)F1 mice promotes the suppressive capacity of CD4+ regulatory T cells protecting from lupus-like disease, J. Immunol., 190, 5402, 10.4049/jimmunol.1202382 Ding, 2006, Delivering PD-1 inhibitory signal concomitant with blocking ICOS co-stimulation suppresses lupus-like syndrome in autoimmune BXSB mice, Clin. Immunol., 118, 258, 10.1016/j.clim.2005.10.017 Song, 2015, Protective effects of Fc-fused PD-L1 on two different animal models of colitis, Gut, 64, 260, 10.1136/gutjnl-2014-307311 El Khatib, 2015, β-cell-targeted blockage of PD1 and CTLA4 pathways prevents development of autoimmune diabetes and acute allogeneic islets rejection, Gene Ther., 22, 430, 10.1038/gt.2015.18 Ben Nasr, 2017, PD-L1 genetic overexpression or pharmacological restoration in hematopoietic stem and progenitor cells reverses autoimmune diabetes, Sci. Transl. Med., 9, 10.1126/scitranslmed.aam7543 Zhang, 2020, Engineered PD-L1-expressing platelets reverse new-onset type 1 diabetes, Adv. Mater., 32 Simpson, 2010, Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus, Arthritis Rheum., 62, 234, 10.1002/art.25032 Wang, 2013, High frequencies of activated B cells and T follicular helper cells are correlated with disease activity in patients with new-onset rheumatoid arthritis, Clin. Exp. Immunol., 174, 212, 10.1111/cei.12162 Szabo, 2013, Follicular helper T cells may play an important role in the severity of primary Sjögren’s syndrome, Clin. Immunol., 147, 95, 10.1016/j.clim.2013.02.024 yi Li, 2012, Role of the frequency of blood CD4+ CXCR5+ CCR6+ T cells in autoimmunity in patients with Sjögren’s syndrome, Biochem. Biophys. Res. Commun., 422, 238, 10.1016/j.bbrc.2012.04.133 Viisanen, 2017, Circulating CXCR5+PD-1+ICOS+ Follicular T helper cells are increased close to the diagnosis of type 1 diabetes in children with multiple autoantibodies, Diabetes, 66, 437, 10.2337/db16-0714 Liu, 2018, Constitutive changes in circulating follicular helper T cells and their subsets in patients with graves disease, J. Immunol. Res., 7 Zhao, 2018, Increased circulating Tfh17 and PD-1+ Tfh cells are associated with autoantibodies in Hashimoto’s thyroiditis, Autoimmunity, 51, 352, 10.1080/08916934.2018.1516761 Luo, 2013, Expansion of circulating counterparts of follicular helper T cells in patients with myasthenia gravis, J. Neuroimmunol., 256, 55, 10.1016/j.jneuroim.2012.12.001 Li, 2015, Association of circulating follicular helper T cells with disease course of NMO spectrum disorders, J. Neuroimmunol., 278, 239, 10.1016/j.jneuroim.2014.11.011 Szabo, 2014, The histopathology of labial salivary glands in primary sjögren’s syndrome: focusing on follicular helper T cells in the inflammatory infiltrates, Mediat. Inflamm., 631787 Szabó, 2016, A comprehensive investigation on the distribution of circulating follicular T helper cells and B cell subsets in primary Sjögren’s syndrome and systemic lupus erythematosus, Clin. Exp. Immunol., 183, 76, 10.1111/cei.12703 Brokstad, 2018, T follicular-like helper cells in the peripheral blood of patients with primary Sjögren’s syndrome, Scand. J. Immunol., 88, 10.1111/sji.12679 Rao, 2017, Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis, Nature, 542, 110, 10.1038/nature20810 Ekman, 2019, Circulating CXCR5−PD-1hi peripheral T helper cells are associated with progression to type 1 diabetes, Diabetologia, 62, 1681, 10.1007/s00125-019-4936-8 Bocharnikov, 2019, PD-1hiCXCR5- T peripheral helper cells promote B cell responses in lupus via MAF and IL-21, JCI Insight, 4, 10.1172/jci.insight.130062 Huang, 2019, Membrane-associated epithelial cell adhesion molecule is slowly cleaved by -secretase prior to efficient proteasomal degradation of its intracellular domain, J. Biol. Chem., 294, 3051, 10.1074/jbc.RA118.005874 Sherman, 2020, Proteasome inhibitors: harnessing proteostasis to combat disease, Molecules, 25, 671, 10.3390/molecules25030671 Macleod, 2015, The role and therapeutic targeting of α-, β-and γ-secretase in Alzheimer's disease, Futur. Sci. OA., 1, FSO11, 10.4155/fso.15.9