407
Views
1
CrossRef citations to date
0
Altmetric
Reviews

Dysregulated translational factors and epigenetic regulations orchestrate in B cells contributing to autoimmune diseases

ORCID Icon, ORCID Icon, , , & ORCID Icon
Pages 1-25 | Received 19 Apr 2021, Accepted 10 Jul 2021, Published online: 27 Aug 2021

References

  • Busslinger M. Transcriptional control of early B cell development. Annu Rev Immunol. 2004;22:55–79. doi:10.1146/annurev.immunol.22.012703.104807.
  • Dias S, Silva HJr., Cumano A, Vieira P. Interleukin-7 is necessary to maintain the B cell potential in common lymphoid progenitors. J Exp Med. 2005;201(6):971–979. doi:10.1084/jem.20042393.
  • LeBien TW, Tedder TF. B lymphocytes: how they develop and function. Blood. 2008;112(5):1570–1580. doi:10.1182/blood-2008-02-078071.
  • Ise W, Kurosaki T. Plasma cell differentiation during the germinal center reaction. Immunol Rev. 2019;288(1):64–74. doi:10.1111/imr.12751.
  • Parker DC. T cell-dependent B cell activation. Annu Rev Immunol. 1993;11:331–360. doi:10.1146/annurev.iy.11.040193.001555.
  • Johanson TM, Lun ATL, Coughlan HD, et al. Transcription-factor-mediated supervision of global genome architecture maintains B cell identity. Nat Immunol. 2018;19(11):1257–1264. doi:10.1038/s41590-018-0234-8.
  • Lu R. Interferon regulatory factor 4 and 8 in B-cell development. Trends Immunol. 2008;29(10):487–492. doi:10.1016/j.it.2008.07.006.
  • Meffre E, O’Connor KC. Impaired B-cell tolerance checkpoints promote the development of autoimmune diseases and pathogenic autoantibodies. Immunol Rev. 2019;292(1):90–101. doi:10.1111/imr.12821.
  • Shapiro-Shelef M, Calame K. Regulation of plasma-cell development. Nat Rev Immunol. 2005;5(3):230–242. doi:10.1038/nri1572.
  • Shaffer AL, Lin KI, Kuo TC, et al. Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. Immunity. 2002;17(1):51–62. doi:10.1016/S1074-7613(02)00335-7.
  • Reimold AM, Iwakoshi NN, Manis J, et al. Plasma cell differentiation requires the transcription factor XBP-1. Nature. 2001;412(6844):300–307. doi:10.1038/35085509.
  • Mandal M, Okoreeh MK, Kennedy DE, et al. CXCR4 signaling directs Igk recombination and the molecular mechanisms of late B lymphopoiesis. Nat Immunol. 2019;20(10):1393–1403. doi:10.1038/s41590-019-0468-0.
  • Herzog S, Reth M, Jumaa H. Regulation of B-cell proliferation and differentiation by pre-B-cell receptor signalling. Nat Rev Immunol. 2009;9(3):195–205. doi:10.1038/nri2491.
  • Sheng Y, Zhang J, Li K, et al. Bach2 overexpression represses Th9 cell differentiation by suppressing IRF4 expression in systemic lupus erythematosus. FEBS Open Bio. 2021;11(2):395–403. doi:10.1002/2211-5463.
  • Rubtsova K, Rubtsov AV, Thurman JM, et al. B cells expressing the transcription factor T-bet drive lupus-like autoimmunity. J Clin Invest. 2017;127(4):1392–1404. doi:10.1172/jci91250.
  • Murphy G, Isenberg DA. New therapies for systemic lupus erythematosus - past imperfect, future tense. Nat Rev Rheumatol. 2019;15(7):403–412. doi:10.1038/s41584-019-0235-5.
  • Rizzi M, Lorenzetti R, Fischer K, et al. Impact of tofacitinib treatment on human B-cells in vitro and in vivo. J Autoimmun. 2017;77:55–66. doi:10.1016/j.jaut.2016.10.005.
  • Béguelin W, Teater M, Gearhart MD, et al. EZH2 and BCL6 cooperate to assemble CBX8-BCOR complex to repress bivalent promoters, mediate germinal center formation and lymphomagenesis. Cancer Cell. 2016;30(2):197–213. doi:10.1016/j.ccell.2016.07.006.
  • Cang S, Iragavarapu C, Savooji J, et al. ABT-199 (venetoclax) and BCL-2 inhibitors in clinical development. J Hematol Oncol. 2015;8:129. doi:10.1186/s13045-015-0224-3.
  • Levels MJ, Fehres CM, van Baarsen LGM, et al. BOB.1 controls memory B-cell fate in the germinal center reaction. J Autoimmun. 2019;101:131–144. doi:10.1016/j.jaut.2019.04.011.
  • Zhan T, Wang B, Fu J, et al. Artesunate inhibits Sjögren’s syndrome-like autoimmune responses and BAFF-induced B cell hyperactivation via TRAF6-mediated NF-κB signaling. Phytomedicine. 2021;80:153381. doi:10.1016/j.phymed.2020.153381.
  • Wang X, Chen X, Huang W, et al. Losartan suppresses the inflammatory response in collagen-induced arthritis by inhibiting the MAPK and NF-κB pathways in B and T cells. Inflammopharmacology. 2019;27(3):487–502. doi:10.1007/s10787-018-0545-2.
  • Nakayama Y, Kosek J, Capone L, et al. Aiolos overexpression in systemic lupus erythematosus B cell subtypes and BAFF-induced memory B cell differentiation are reduced by CC-220 modulation of cereblon activity. J Immunol. 2017;199(7):2388–2407. doi:10.4049/jimmunol.1601725.
  • Dörner T, Lipsky PE. Beyond pan-B-cell-directed therapy - new avenues and insights into the pathogenesis of SLE. Nat Rev Rheumatol. 2016;12(11):645–657. doi:10.1038/nrrheum.2016.158.
  • Merrill JT, Shanahan WR, Scheinberg M, et al. Phase III trial results with blisibimod, a selective inhibitor of B-cell activating factor, in subjects with systemic lupus erythematosus (SLE): results from a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2018;77(6):883–889. doi:10.1136/annrheumdis-2018-213032.
  • Navarra SV, Guzmán RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet (London, England). 2011;377(9767):721–731. doi:10.1016/S0140-6736(10)61354-2.
  • Vincent FB, Saulep-Easton D, Figgett WA, et al. The BAFF/APRIL system: emerging functions beyond B cell biology and autoimmunity. Cytokine Growth Factor Rev. 2013;24(3):203–215. doi:10.1016/j.cytogfr.2013.04.003.
  • Emery P, Rondon J, Parrino J, et al. Safety and tolerability of subcutaneous sarilumab and intravenous tocilizumab in patients with rheumatoid arthritis. Rheumatology (Oxford, England). 2019;58(5):849–858. doi:10.1093/rheumatology/key361.
  • Takeuchi T, Thorne C, Karpouzas G, et al. Sirukumab for rheumatoid arthritis: the phase III SIRROUND-D study. Ann Rheum Dis. 2017;76(12):2001–2008. doi:10.1136/annrheumdis-2017-211328.
  • Long D, Chen Y, Wu H, et al. Clinical significance and immunobiology of IL-21 in autoimmunity. J Autoimmun. 2019;99:1–14. doi:10.1016/j.jaut.2019.01.013.
  • Onuora S. Abatacept no better than placebo for pSS. Nat Rev Rheumatol. 2020;16(4):186. doi:10.1038/s41584-020-0390-8.
  • van Nimwegen JF, Mossel E, van Zuiden GS, et al. Abatacept treatment for patients with early active primary Sjogren’s syndrome: a single-centre, randomised, double-blind, placebo-controlled, phase 3 trial (ASAP-III study). Lancet Rheumatol. 2020;2:e153–e163. doi:10.1016/S2665-9913(19)30160-2.
  • Baer AN, Gottenberg J-E, St Clair EW, et al. Efficacy and safety of abatacept in active primary Sjögren’s syndrome: results of a phase III, randomised, placebo-controlled trial. Ann Rheum Dis. 2020;80:339–348. doi:10.1136/annrheumdis-2020-218599.
  • Klavdianou K, Lazarini A, Fanouriakis A. Targeted biologic therapy for systemic lupus erythematosus: emerging pathways and drug pipeline. BioDrugs. 2020;34(2):133–147. doi:10.1007/s40259-020-00405-2.
  • Paradowska-Gorycka A, Roszak M, Stypinska B, et al. IL-6 and TGF-β gene polymorphisms, their serum levels, as well as HLA profile, in patients with systemic lupus erythematosus. Clin Exp Rheumatol. 2019;37:963–975.
  • Ulff-Møller CJ, Asmar F, Liu Y, et al. Twin DNA methylation profiling reveals flare-dependent interferon signature and B cell promoter hypermethylation in systemic lupus erythematosus. Arthritis Rheumatol. 2018;70(6):878–890. doi:10.1002/art.40422.
  • Chen S, Pu W, Guo S, et al. Genome-wide DNA methylation profiles reveal common epigenetic patterns of interferon-related genes in multiple autoimmune diseases. Front Genet. 2019;10:223. doi:10.3389/fgene.2019.00223.
  • Absher DM, Li X, Waite LL, et al. Genome-wide DNA methylation analysis of systemic lupus erythematosus reveals persistent hypomethylation of interferon genes and compositional changes to CD4+ T-cell populations. PLoS Genet. 2013;9(8):e1003678. doi:10.1371/journal.pgen.1003678.
  • Julià A, Absher D, López-Lasanta M, et al. Epigenome-wide association study of rheumatoid arthritis identifies differentially methylated loci in B cells. Hum Mol Genet. 2017;26(14):2803–2811. doi:10.1093/hmg/ddx177.
  • Ocskó T, Tóth DM, Hoffmann G, et al. Transcription factor Zbtb38 downregulates the expression of anti-inflammatory IL1r2 in mouse model of rheumatoid arthritis. Biochim Biophys Acta Gene Regul Mech. 2018;1861(11):1040–1047. doi:10.1016/j.bbagrm.2018.09.007.
  • Miceli-Richard C, Wang-Renault S-F, Boudaoud S, et al. Overlap between differentially methylated DNA regions in blood B lymphocytes and genetic at-risk loci in primary Sjögren’s syndrome. Ann Rheum Dis. 2016;75(5):933–940. doi:10.1136/annrheumdis-2014-206998.
  • Maltby VE, Lea RA, Graves MC, et al. Genome-wide DNA methylation changes in CD19+ B cells from relapsing-remitting multiple sclerosis patients . Sci Rep. 2018;8(1):17418. doi:10.1038/s41598-018-35603-0.
  • Paul DS, Teschendorff AE, Dang MAN, et al. Increased DNA methylation variability in type 1 diabetes across three immune effector cell types. Nat Commun. 2016;7:13555. doi:10.1038/ncomms13555.
  • Zhao M, Huang W, Zhang Q, et al. Aberrant epigenetic modifications in peripheral blood mononuclear cells from patients with pemphigus vulgaris. Br J Dermatol. 2012;167(3):523–531. doi:10.1111/j.1365-2133.2012.11007.x.
  • 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. doi:10.1002/art.41208.
  • Hung K-H, Woo YH, Lin I-Y, et al. The KDM4A/KDM4C/NF-κB and WDR5 epigenetic cascade regulates the activation of B cells. Nucleic Acids Res. 2018;46(11):5547–5560. doi:10.1093/nar/gky281.
  • Spadoni MB, Bumiller-Bini V, Petzl-Erler ML, et al. First glimpse of epigenetic effects on pemphigus foliaceus. J Invest Dermatol. 2020;140(2):488–491.e1. doi:10.1016/j.jid.2019.07.691.
  • Garchow BG, Bartulos Encinas O, Leung YT, et al. Silencing of microRNA-21 in vivo ameliorates autoimmune splenomegaly in lupus mice. EMBO Mol Med. 2011;3(10):605–615. doi:10.1002/emmm.201100171.
  • Yuan Y, Kasar S, Underbayev C, et al. Role of microRNA-15a in autoantibody production in interferon-augmented murine model of lupus. Mol Immunol. 2012;52(2):61–70. doi:10.1016/j.molimm.2012.04.007.
  • Liu Y, Dong J, Mu R, et al. MicroRNA-30a promotes B cell hyperactivity in patients with systemic lupus erythematosus by direct interaction with Lyn. Arthritis Rheum. 2013;65(6):1603–1611. doi:10.1002/art.37912.
  • Luo S, Liu Y, Liang G, et al. The role of microRNA-1246 in the regulation of B cell activation and the pathogenesis of systemic lupus erythematosus. Clin Epigenet. 2015;7:24. doi:10.1186/s13148-015-0063-7.
  • Wang M, Chen H, Qiu J, et al. Antagonizing miR-7 suppresses B cell hyperresponsiveness and inhibits lupus development. J Autoimmun. 2020;109:102440. doi:10.1016/j.jaut.2020.102440.
  • van Nieuwenhuijze A, Dooley J, Humblet-Baron S, et al. Defective germinal center B-cell response and reduced arthritic pathology in microRNA-29a-deficient mice. Cell Mol Life Sci. 2017;74(11):2095–2106. doi:10.1007/s00018-017-2456-6.
  • Shi X, Ye L, Xu S, et al. Downregulated miR‑29a promotes B cell overactivation by upregulating Crk‑like protein in systemic lupus erythematosus. Mol Med Rep. 2020;22(2):841–849. doi:10.3892/mmr.2020.11166.
  • Alivernini S, Kurowska-Stolarska M, Tolusso B, et al. MicroRNA-155 influences B-cell function through PU.1 in rheumatoid arthritis. Nat Commun. 2016;7:12970. doi:10.1038/ncomms12970.
  • Wang-Renault S-F, Boudaoud S, Nocturne G, et al. Deregulation of microRNA expression in purified T and B lymphocytes from patients with primary Sjögren’s syndrome. Ann Rheum Dis. 2018;77(1):133–140. doi:10.1136/annrheumdis-2017-211417.
  • Annibali V, Umeton R, Palermo A, et al. Analysis of coding and non-coding transcriptome of peripheral B cells reveals an altered interferon response factor (IRF)-1 pathway in multiple sclerosis patients. J Neuroimmunol. 2018;324:165–171. doi:10.1016/j.jneuroim.2018.09.005.
  • Miller JP, Izon D, DeMuth W, et al. The earliest step in B lineage differentiation from common lymphoid progenitors is critically dependent upon interleukin 7. J Exp Med. 2002;196(5):705–711. doi:10.1084/jem.20020784.
  • Seet CS, Brumbaugh RL, Kee BL. Early B cell factor promotes B lymphopoiesis with reduced interleukin 7 responsiveness in the absence of E2A. J Exp Med. 2004;199(12):1689–1700. doi:10.1084/jem.20032202.
  • Zandi S, Mansson R, Tsapogas P, et al. EBF1 is essential for B-lineage priming and establishment of a transcription factor network in common lymphoid progenitors. J Immunol. 2008;181(5):3364–3372. doi:10.4049/jimmunol.181.5.3364.
  • Cobaleda C, Schebesta A, Delogu A, Busslinger M. Pax5: the guardian of B cell identity and function. Nat Immunol. 2007;8(5):463–470. doi:10.1038/ni1454.
  • Akazawa S, Kobayashi M, Kuriya G, et al. Haploinsufficiency of interferon regulatory factor 4 strongly protects against autoimmune diabetes in NOD mice. Diabetologia. 2015;58(11):2606–2614. doi:10.1007/s00125-015-3724-3.
  • Clark MR, Mandal M, Ochiai K, Singh H. Orchestrating B cell lymphopoiesis through interplay of IL-7 receptor and pre-B cell receptor signalling. Nat Rev Immunol. 2014;14(2):69–80. doi:10.1038/nri3570.
  • O’Shea JJ, Plenge R. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity. 2012;36(4):542–550. doi:10.1016/j.immuni.2012.03.014. (2012).
  • Nemazee D. Receptor editing in lymphocyte development and central tolerance. Nat Rev Immunol. 2006;6(10):728–740. doi:10.1038/nri1939.
  • Cadera EJ, Wan F, Amin RH, et al. NF-kappaB activity marks cells engaged in receptor editing. J Exp Med. 2009;206(8):1803–1816. doi:10.1084/jem.20082815.
  • Basso K, Dalla-Favera R. Germinal centres and B cell lymphomagenesis. Nat Rev Immunol. 2015;15(3):172–184. doi:10.1038/nri3814.
  • Stavnezer J, Schrader CE. IgH chain class switch recombination: mechanism and regulation. J Immunol. 2014;193(11):5370–5378. doi:10.4049/jimmunol.1401849.
  • Zhu Z, Yang C, Wen L, et al. Bach2 regulates aberrant activation of B cell in systemic lupus erythematosus and can be negatively regulated by BCR-ABL/PI3K. Exp Cell Res. 2018;365(1):138–144. doi:10.1016/j.yexcr.2018.02.034.
  • Shinnakasu R, Inoue T, Kometani K, et al. Regulated selection of germinal-center cells into the memory B cell compartment. Nat Immunol. 2016;17(7):861–869. doi:10.1038/ni.3460.
  • Kallies A, Hawkins ED, Belz GT, et al. Transcriptional repressor Blimp-1 is essential for T cell homeostasis and self-tolerance. Nat Immunol. 2006;7(5):466–474. doi:10.1038/ni1321.
  • Calame K. Transcription factors that regulate memory in humoral responses. Immunol Rev. 2006;211:269–279. doi:10.1111/j.0105-2896.2006.00377.x.
  • Lin KI, Angelin-Duclos C, Kuo TC, Calame K. Blimp-1-dependent repression of Pax-5 is required for differentiation of B cells to immunoglobulin M-secreting plasma cells. Mol Cell Biol. 2002;22(13):4771–4780. doi:10.1128/mcb.22.13.4771-4780.2002.
  • Shaffer AL, Yu X, He Y, et al. BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity. 2000;13(2):199–212. doi:10.1016/S1074-7613(00)00020-0.
  • John SA, Clements JL, Russell LM, Garrett-Sinha LA. Ets-1 regulates plasma cell differentiation by interfering with the activity of the transcription factor Blimp-1. J Biol Chem. 2008;283(2):951–962. doi:10.1074/jbc.M705262200.
  • Lee S-R, Rutan JA, Monteith AJ, et al. Receptor cross-talk spatially restricts p-ERK during TLR4 stimulation of autoreactive B cells. J Immunol. 2012;189(8):3859–3868. doi:10.4049/jimmunol.1200940.
  • Jacob A, Cooney D, Pradhan M, Coggeshall KM. Convergence of signaling pathways on the activation of ERK in B cells. J Biol Chem. 2002;277(26):23420–23426. doi:10.1074/jbc.M202485200.
  • Ozaki K, Spolski R, Ettinger R, et al. Regulation of B cell differentiation and plasma cell generation by IL-21, a novel inducer of Blimp-1 and Bcl-6. J Immunol. 2004;173(9):5361–5371. doi:10.4049/jimmunol.173.9.5361.
  • Sjöstrand M, Johansson A, Aqrawi L, et al. The expression of BAFF is controlled by IRF transcription factors. J Immunol. 2016;196(1):91–96. doi:10.4049/jimmunol.1501061.
  • Lee S-T, Xiao Y, Muench MO, et al. A global DNA methylation and gene expression analysis of early human B-cell development reveals a demethylation signature and transcription factor network. Nucleic Acids Res. 2012;40(22):11339–11351. doi:10.1093/nar/gks957.
  • Li R, Cauchy P, Ramamoorthy S, et al. Dynamic EBF1 occupancy directs sequential epigenetic and transcriptional events in B-cell programming. Genes Dev. 2018;32(2):96–111. doi:10.1101/gad.309583.117.
  • Jiang X-X, Nguyen Q, Chou Y, et al. Control of B cell development by the histone H2A deubiquitinase MYSM1. Immunity. 2011;35(6):883–896. doi:10.1016/j.immuni.2011.11.010.
  • Ji Z, Sheng Y, Miao J, et al. The histone methyltransferase Setd2 is indispensable for V(D)J recombination. Nat Commun. 2019;10(1):3353 doi:10.1038/s41467-019-11282-x.
  • Su I-H, Basavaraj A, Krutchinsky AN, et al. Ezh2 controls B cell development through histone H3 methylation and Igh rearrangement. Nat Immunol. 2003;4(2):124–131. doi:10.1038/ni876.
  • Lio C-W, Zhang J, González-Avalos E, et al. Tet2 and Tet3 cooperate with B-lineage transcription factors to regulate DNA modification and chromatin accessibility. Elife. 2016;5:e18290. doi:10.7554/eLife.18290.
  • Yen W-F, Sharma R, Cols M, et al. Distinct requirements of CHD4 during B cell development and antibody response. Cell Rep. 2019;27(5):1472–1486.e5. doi:10.1016/j.celrep.2019.04.011.
  • Kleiman E, Loguercio S, Feeney AJ. Epigenetic enhancer marks and transcription factor binding influence Vκ gene rearrangement in pre-B cells and pro-B cells. Front Immunol. 2018;9:2074. doi:10.3389/fimmu.2018.02074.
  • Lu X, Chu C-S, Fang T, et al. MTA2/NuRD regulates B cell development and cooperates with OCA-B in controlling the pre-B to immature B cell transition. Cell Rep. 2019;28(2):472–485.e5. doi:10.1016/j.celrep.2019.06.029.
  • Maier H, Ostraat R, Gao H, et al. Early B cell factor cooperates with Runx1 and mediates epigenetic changes associated with mb-1 transcription. Nat Immunol. 2004;5(10):1069–1077. doi:10.1038/ni1119.
  • Li G, So AY-L, Sookram R, et al. Epigenetic silencing of miR-125b is required for normal B-cell development. Blood. 2018;131(17):1920–1930. doi:10.1182/blood-2018-01-824540.
  • Oakes CC, Seifert M, Assenov Y, et al. DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia. Nat Genet. 2016;48(3):253–264. doi:10.1038/ng.3488.
  • Shaknovich R, Cerchietti L, Tsikitas L, et al. DNA methyltransferase 1 and DNA methylation patterning contribute to germinal center B-cell differentiation. Blood. 2011;118(13):3559–3569. doi:10.1182/blood-2011-06-357996.
  • Chen C, Zhai S, Zhang L, et al. Uhrf1 regulates germinal center B cell expansion and affinity maturation to control viral infection. J Exp Med. 2018;215(5):1437–1448. doi:10.1084/jem.20171815.
  • Good-Jacobson KL, Chen Y, Voss AK, et al. Regulation of germinal center responses and B-cell memory by the chromatin modifier MOZ. Proc Natl Acad Sci USA. 2014;111(26):9585–9590. doi:10.1073/pnas.1402485111.
  • Dorsett Y, McBride KM, Jankovic M, et al. MicroRNA-155 suppresses activation-induced cytidine deaminase-mediated Myc-Igh translocation. Immunity. 2008;28(5):630–638. doi:10.1016/j.immuni.2008.04.002.
  • de Yébenes VG, Belver L, Pisano DG, et al. miR-181b negatively regulates activation-induced cytidine deaminase in B cells. J Exp Med. 2008;205(10):2199–2206. doi:10.1084/jem.20080579.
  • Gan H, Shen T, Chupp DP, et al. B cell Sirt1 deacetylates histone and non-histone proteins for epigenetic modulation of AID expression and the antibody response. Sci Adv. 2020;6(14):eaay2793. doi:10.1126/sciadv.aay2793.
  • Jiang Y, Ortega-Molina A, Geng H, et al. CREBBP inactivation promotes the development of HDAC3-dependent lymphomas. Cancer Discov. 2017;7(1):38–53. doi:10.1158/2159-8290.Cd-16-0975.
  • Zhang J, Vlasevska S, Wells VA, et al. The CREBBP acetyltransferase is a haploinsufficient tumor suppressor in B-cell lymphoma. Cancer Discov. 2017;7(3):322–337. doi:10.1158/2159-8290.Cd-16-1417.
  • Guo M, Price MJ, Patterson DG, et al. EZH2 represses the B cell transcriptional program and regulates antibody-secreting cell metabolism and antibody production. J Immunol. 2018;200(3):1039–1052. doi:10.4049/jimmunol.1701470.
  • Haines RR, Barwick BG, Scharer CD, et al. The histone demethylase LSD1 regulates B cell proliferation and plasmablast differentiation. J Immunol. 2018;201(9):2799–2811. doi:10.4049/jimmunol.1800952.
  • Ortega-Molina A, Boss IW, Canela A, et al. The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development. Nat Med. 2015;21(10):1199–1208. doi:10.1038/nm.3943.
  • Santoni de Sio FR, Massacand J, Barde I, et al. KAP1 regulates gene networks controlling mouse B-lymphoid cell differentiation and function. Blood. 2012;119(20):4675–4685. doi:10.1182/blood-2011-12-401117.
  • Xiao C, Srinivasan L, Calado DP, et al. Lymphoproliferative disease and autoimmunity in mice with increased miR-17-92 expression in lymphocytes. Nat Immunol. 2008;9(4):405–414. doi:10.1038/ni1575.
  • White CA, Pone EJ, Lam T, et al. Histone deacetylase inhibitors upregulate B cell microRNAs that silence AID and Blimp-1 expression for epigenetic modulation of antibody and autoantibody responses. J Immunol. 2014;193(12):5933–5950. doi:10.4049/jimmunol.1401702.
  • White CA, Seth Hawkins J, Pone EJ, et al. AID dysregulation in lupus-prone MRL/Fas(lpr/lpr) mice increases class switch DNA recombination and promotes interchromosomal c-Myc/IgH loci translocations: modulation by HoxC4. Autoimmunity. 2011;44(8):585–598. doi:10.3109/08916934.2011.577128.
  • Hao F, Tian M, Feng Y, et al. Abrogation of lupus nephritis in somatic hypermutation-deficient MRL/lpr mice. J Immunol. 2018;200(12):3905–3912. doi:10.4049/jimmunol.1800115.
  • Qian Y, Wang H, Clarke SH. Impaired clearance of apoptotic cells induces the activation of autoreactive anti-Sm marginal zone and B-1 B cells. J Immunol. 2004;172(1):625–635. doi:10.4049/jimmunol.172.1.625.
  • Tsokos GC, Lo MS, Costa Reis P, Sullivan KE. New insights into the immunopathogenesis of systemic lupus erythematosus. Nat Rev Rheumatol. 2016;12(12):716–730. doi:10.1038/nrrheum.2016.186.
  • Jackson SW, Jacobs HM, Arkatkar T, et al. B cell IFN-γ receptor signaling promotes autoimmune germinal centers via cell-intrinsic induction of BCL-6. J Exp Med. 2016;213(5):733–750. doi:10.1084/jem.20151724.
  • Scharer CD, Blalock EL, Mi T, et al. Epigenetic programming underpins B cell dysfunction in human SLE. Nat Immunol. 2019;20(8):1071–1082. doi:10.1038/s41590-019-0419-9.
  • Zheng Y, Lu Y, Huang X, et al. BACH2 regulates the function of human CD4+ CD45RA- Foxp3l ° cytokine-secreting T cells and promotes B-cell response in systemic lupus erythematosus. Eur J Immunol. 2020;50(3):426–438. doi:10.1002/eji.201948320.
  • Zhao L-D, Liang D, Wu X-N, et al. Contribution and underlying mechanisms of CXCR4 overexpression in patients with systemic lupus erythematosus. Cell Mol Immunol. 2017;14(10):842–849. doi:10.1038/cmi.2016.47.
  • Jang E, Kim UK, Jang K, et al. Bach2 deficiency leads autoreactive B cells to produce IgG autoantibodies and induce lupus through a T cell-dependent extrafollicular pathway. Exp Mol Med. 2019;51(12):1–13. doi:10.1038/s12276-019-0352-x.
  • Gateva V, Sandling JK, Hom G, et al. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat Genet. 2009;41(11):1228–1233. doi:10.1038/ng.468.
  • Luo J, Niu X, Liu H, et al. Up-regulation of transcription factor Blimp1 in systemic lupus erythematosus. Mol Immunol. 2013;56(4):574–582. doi:10.1016/j.molimm.2013.05.241.
  • Luo J, Niu X, Zhang M, et al. Inhibition of B lymphocyte-induced maturation protein-1 reduces the production of autoantibody and alleviates symptoms of systemic lupus erythematosus. Autoimmunity. 2015;48(2):80–86. doi:10.3109/08916934.2014.976627.
  • Zhou Z, Li A, Wang Z, et al. Blimp-1 siRNA inhibits B cell differentiation and prevents the development of lupus in mice. Hum Immunol. 2013;74(3):297–301. doi:10.1016/j.humimm.2012.11.019.
  • Lu Q, Wang JY, Wang L, et al. Self DNA from lymphocytes that have undergone activation-induced cell death enhances murine B cell proliferation and antibody production. PLoS One. 2014;9(10):e109095. doi:10.1371/journal.pone.0109095.
  • Bönelt P, Wöhner M, Minnich M, et al. Precocious expression of Blimp1 in B cells causes autoimmune disease with increased self-reactive plasma cells. EMBO J. 2019;38(2):e100010. doi:10.15252/embj.2018100010.
  • Giltiay NV, Shu GL, Shock A, Clark EA. Targeting CD22 with the monoclonal antibody epratuzumab modulates human B-cell maturation and cytokine production in response to Toll-like receptor 7 (TLR7) and B-cell receptor (BCR) signaling. Arthritis Res Ther. 2017;19(1):91. doi:10.1186/s13075-017-1284-2.
  • Manni M, Gupta S, Nixon BG, et al. IRF4-Dependent and IRF4-Independent Pathways Contribute to DC Dysfunction in Lupus. PLoS One. 2015;10(11):e0141927. doi:10.1371/journal.pone.0141927.
  • Min H-K, Kim S-M, Park J-S, et al. Fn14-Fc suppresses germinal center formation and pathogenic B cells in a lupus mouse model via inhibition of the TWEAK/Fn14 Pathway. J Transl Med. 2016;14:98. doi:10.1186/s12967-016-0846-4.
  • Biswas PS, Gupta S, Chang E, et al. Phosphorylation of IRF4 by ROCK2 regulates IL-17 and IL-21 production and the development of autoimmunity in mice. J Clin Invest. 2010;120(9):3280–3295. doi:10.1172/jci42856.
  • Stirzaker RA, Biswas PS, Gupta S, et al. Administration of fasudil, a ROCK inhibitor, attenuates disease in lupus-prone NZB/W F1 female mice. Lupus. 2012;21(6):656–661. doi:10.1177/0961203312436862.
  • Weiss JM, Chen W, Nyuydzefe MS, et al. ROCK2 signaling is required to induce a subset of T follicular helper cells through opposing effects on STATs in autoimmune settings. Sci Signal. 2016;9(437):ra73. doi:10.1126/scisignal.aad8953.
  • Graham RR, Kozyrev SV, Baechler EC, et al. A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nat Genet. 2006;38(5):550–555. doi:10.1038/ng1782.
  • Savitsky DA, Yanai H, Tamura T, et al. Contribution of IRF5 in B cells to the development of murine SLE-like disease through its transcriptional control of the IgG2a locus. Proc Natl Acad Sci USA. 2010;107(22):10154–10159. doi:10.1073/pnas.1005599107.
  • De S, Zhang B, Shih T, et al. B cell-intrinsic role for IRF5 in TLR9/BCR-induced human B cell activation, proliferation, and plasmablast differentiation. Front Immunol. 2017;8:1938. doi:10.3389/fimmu.2017.01938.
  • Jenks SA, Cashman KS, Zumaquero E, et al. Distinct effector B cells induced by unregulated toll-like receptor 7 contribute to pathogenic responses in systemic lupus erythematosus. Immunity. 2018;49(4):725–739.e6. doi:10.1016/j.immuni.2018.08.015.
  • Hritzo Ahye MK, Golding A. Cytoplasmic FOXO1 identifies a novel disease-activity associated B cell phenotype in SLE. Lupus Sci Med. 2018;5(1):e000296. doi:10.1136/lupus-2018-000296.
  • De Groof A, Ducreux J, Aleva F, et al. STAT3 phosphorylation mediates the stimulatory effects of interferon alpha on B cell differentiation and activation in SLE. Rheumatology (Oxford). 2020;59(3):668–677. doi:10.1093/rheumatology/kez354.
  • Klarquist J, Cantrell R, Lehn MA, et al. Type I IFN drives experimental systemic lupus erythematosus by distinct mechanisms in CD4 T cells and B cells. ImmunoHorizons. 2020;4(3):140–152. doi:10.4049/immunohorizons.2000005.
  • Aue A, Szelinski F, Weißenberg SY, et al. Elevated STAT1 expression but not phosphorylation in lupus B cells correlates with disease activity and increased plasmablast susceptibility. Rheumatology (Oxford). 2020;59(11):3435–3442. doi:10.1093/rheumatology/keaa187.
  • Chodisetti SB, Fike AJ, Domeier PP, et al. Type II but not type I IFN signaling is indispensable for TLR7-promoted development of autoreactive B cells and systemic autoimmunity. J Immunol. 2020;204(4):796–809. doi:10.4049/jimmunol.1901175.
  • Rosser EC, Mauri C. Regulatory B cells: origin, phenotype, and function. Immunity. 2015;42(4):607–612. doi:10.1016/j.immuni.2015.04.005.
  • Wang X, Wei Y, Xiao H, et al. Pre-existing CD19-independent GL7(-) Breg cells are expanded during inflammation and in mice with lupus-like disease. Mol Immunol. 2016;71:54–63. doi:10.1016/j.molimm.2016.01.011.
  • Menon M, Blair PA, Isenberg DA, Mauri C. A regulatory feedback between plasmacytoid dendritic cells and regulatory B cells is aberrant in systemic lupus erythematosus. Immunity. 2016;44(3):683–697. doi:10.1016/j.immuni.2016.02.012.
  • Blair PA, Noreña LY, Flores-Borja F, et al. CD19(+)CD24(hi)CD38(hi) B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients. Immunity. 2010;32(1):129–140. doi:10.1016/j.immuni.2009.11.009.
  • Facciotti F, Larghi P, Bosotti R, et al. Evidence for a pathogenic role of extrafollicular, IL-10-producing CCR6 + B helper T cells in systemic lupus erythematosus. Proc Natl Acad Sci USA. 2020;117(13):7305–7316. doi:10.1073/pnas.1917834117.
  • Meng X, Grötsch B, Luo Y, et al. Hypoxia-inducible factor-1α is a critical transcription factor for IL-10-producing B cells in autoimmune disease. Nat Commun. 2018;9(1):251. doi:10.1038/s41467-017-02683-x.
  • Lieberman LA, Tsokos GC. The IL-2 defect in systemic lupus erythematosus disease has an expansive effect on host immunity. J Biomed Biotechnol. 2010; 2010:740619. doi:10.1155/2010/740619. (2010).
  • He J, Zhang R, Shao M, et al. Efficacy and safety of low-dose IL-2 in the treatment of systemic lupus erythematosus: a randomised, double-blind, placebo-controlled trial. Ann Rheum Dis. 2020;79(1):141–149. doi:10.1136/annrheumdis-2019-215396.
  • Wang S, Wang J, Kumar V, et al. IL-21 drives expansion and plasma cell differentiation of autoreactive CD11chiT-bet + B cells in SLE. Nat Commun. 2018;9(1):1758. doi:10.1038/s41467-018-03750-7.
  • Huang X, Wu H, Qiu H, et al. The expression of Bcl-6 in circulating follicular helper-like T cells positively correlates with the disease activity in systemic lupus erythematosus. Clin Immunol. 2016;173:161–170. doi:10.1016/j.clim.2016.10.017.
  • Terrier B, Costedoat-Chalumeau N, Garrido M, et al. Interleukin 21 correlates with T cell and B cell subset alterations in systemic lupus erythematosus. J Rheumatol. 2012;39(9):1819–1828. doi:10.3899/jrheum.120468.
  • McHugh J. Systemic lupus erythematosus: B cell-derived IL-6 promotes disease. Nat Rev Rheumatol. 2017;13(11):633. doi:10.1038/nrrheum.2017.163.
  • Arkatkar T, Du SW, Jacobs HM, et al. B cell-derived IL-6 initiates spontaneous germinal center formation during systemic autoimmunity. J Exp Med. 2017;214(11):3207–3217. doi:10.1084/jem.20170580.
  • Steri M, Orrù V, Idda ML, et al. Overexpression of the cytokine BAFF and autoimmunity risk. N Engl J Med. 2017;376(17):1615–1626. doi:10.1056/NEJMoa1610528.
  • Sellam J, Miceli-Richard C, Gottenberg J-E, et al. Decreased B cell activating factor receptor expression on peripheral lymphocytes associated with increased disease activity in primary Sjögren’s syndrome and systemic lupus erythematosus. Ann Rheum Dis. 2007;66(6):790–797. doi:10.1136/ard.2006.065656.
  • Breitbach ME, Ramaker RC, Roberts K, et al. Population-specific patterns of epigenetic defects in the B cell lineage in patients with systemic lupus erythematosus. Arthritis Rheumatol. 2020;72(2):282–291. doi:10.1002/art.41083.
  • Scharer CD, Blalock EL, Barwick BG, et al. ATAC-seq on biobanked specimens defines a unique chromatin accessibility structure in naïve SLE B cells. Sci Rep. 2016;6:27030. doi:10.1038/srep27030.
  • Rohraff DM, He Y, Farkash EA, et al. Inhibition of EZH2 ameliorates lupus-like disease in MRL/lpr mice. Arthritis Rheumatol. 2019;71(10):1681–1690. doi:10.1002/art.40931.
  • Zumaquero E, Stone SL, Scharer CD, et al. IFNγ induces epigenetic programming of human T-bet(hi) B cells and promotes TLR7/8 and IL-21 induced differentiation. Elife. 2019;8:e41641. doi:10.7554/eLife.41641.
  • Hagman J, Ramírez J, Lukin K. B lymphocyte lineage specification, commitment and epigenetic control of transcription by early B cell factor 1. Curr Top Microbiol Immunol. 2012;356:17–38. doi:10.1007/82_2011_139.
  • Pitzalis C, Kelly S, Humby F. New learnings on the pathophysiology of RA from synovial biopsies. Curr Opin Rheumatol. 2013;25(3):334–344. doi:10.1097/BOR.0b013e32835fd8eb.
  • Klimiuk PA, Goronzy JJ, Björ Nsson J, et al. Tissue cytokine patterns distinguish variants of rheumatoid synovitis. Am J Pathol. 1997;151(5):1311–1319.
  • Seyler TM, Park YW, Takemura S, et al. BLyS and APRIL in rheumatoid arthritis. J Clin Invest. 2005;115(11):3083–3092. doi:10.1172/jci25265.
  • Dörner T, Radbruch A, Burmester GR. B-cell-directed therapies for autoimmune disease. Nat Rev Rheumatol. 2009;5(8):433–441. doi:10.1038/nrrheum.2009.141.
  • Lu DR, McDavid AN, Kongpachith S, et al. T cell-dependent affinity maturation and innate immune pathways differentially drive autoreactive B cell responses in rheumatoid arthritis. Arthritis Rheumatol. 2018;70(11):1732–1744. doi:10.1002/art.40578.
  • Harre U, Georgess D, Bang H, et al. Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J Clin Invest. 2012;122(5):1791–1802. doi:10.1172/jci60975.
  • Sun M, Rethi B, Krishnamurthy A, et al. Anticitrullinated protein antibodies facilitate migration of synovial tissue-derived fibroblasts. Ann Rheum Dis. 2019;78(12):1621–1631. doi:10.1136/annrheumdis-2018-214967.
  • Olalekan SA, Cao Y, Hamel KM, Finnegan A. B cells expressing IFN-γ suppress Treg-cell differentiation and promote autoimmune experimental arthritis. Eur J Immunol. 2015;45(4):988–998. doi:10.1002/eji.201445036.
  • Rivellese F, Humby F, Bugatti S, et al. B cell synovitis and clinical phenotypes in rheumatoid arthritis: relationship to disease stages and drug exposure. Arthritis Rheumatol. 2020;72(5):714–725. doi:10.1002/art.41184.
  • Cole S, Walsh A, Yin X, et al. Integrative analysis reveals CD38 as a therapeutic target for plasma cell-rich pre-disease and established rheumatoid arthritis and systemic lupus erythematosus. Arthritis Res Ther. 2018;20(1):85. doi:10.1186/s13075-018-1578-z.
  • Cao J, Wang S, Wei C, et al. Agrimophol suppresses RANKL-mediated osteoclastogenesis through Blimp1-Bcl6 axis and prevents inflammatory bone loss in mice. Int Immunopharmacol. 2021;90:107137. doi:10.1016/j.intimp.2020.107137. [InsertedFromOnline
  • Ota Y, Niiro H, Ota S-I, et al. Generation mechanism of RANKL(+) effector memory B cells: relevance to the pathogenesis of rheumatoid arthritis. Arthritis Res Ther. 2016;18:67. doi:10.1186/s13075-016-0957-6.
  • Ihn HJ, Lee T, Lee D, et al. Inhibitory effect of KP-A038 on osteoclastogenesis and inflammatory bone loss is associated with downregulation of Blimp1. Front Pharmacol. 2019;10:367. doi:10.3389/fphar.2019.00367.
  • Ruiz-Larrañaga O, Uribarri M, Alcaro MC, et al. Genetic variants associated with rheumatoid arthritis patients and serotypes in European populations. Clin Exp Rheumatol. 2016;34(2):236–241.
  • McAllister K, Yarwood A, Bowes J, et al. Identification of BACH2 and RAD51B as rheumatoid arthritis susceptibility loci in a meta-analysis of genome-wide data. Arthritis Rheum. 2013;65(12):3058–3062. doi:10.1002/art.38183.
  • Mo XB, Zhang YH, Lei SF. Integrative analysis identifies potential causal methylation-mRNA regulation chains for rheumatoid arthritis. Mol Immunol. 2021;131:89–96. doi:10.1016/j.molimm.2020.12.021.
  • Honne K, Hallgrímsdóttir I, Wu C, et al. A longitudinal genome-wide association study of anti-tumor necrosis factor response among Japanese patients with rheumatoid arthritis. Arthritis Res Ther. 2016;18:12. doi:10.1186/s13075-016-0920-6.
  • Tarlinton D, Light A, Metcalf D, et al. Architectural defects in the spleens of Nkx2-3-deficient mice are intrinsic and associated with defects in both B cell maturation and T cell-dependent immune responses. J Immunol. 2003;170(8):4002–4010. doi:10.4049/jimmunol.170.8.4002.
  • Khanfar E, Olasz K, Gábris F, et al. Ameliorated autoimmune arthritis and impaired B cell receptor-mediated Ca(2+) influx in Nkx2-3 knock-out mice. Int J Mol Sci. 2020;21(17):6162. doi:10.3390/ijms21176162.
  • Li Y, Takahashi Y, Fujii S-I, et al. EAF2 mediates germinal centre B-cell apoptosis to suppress excessive immune responses and prevent autoimmunity. Nat Commun. 2016;7:10836. doi:10.1038/ncomms10836.
  • Levels MJ, Van Tok MN, Cantaert T, et al. The transcriptional coactivator Bob1 is associated with pathologic B cell responses in autoimmune tissue inflammation. Arthritis Rheumatol. 2017;69(4):750–762. doi:10.1002/art.39993.
  • Chiu Y-K, Lin I-Y, Su S-T, et al. Transcription factor ABF-1 suppresses plasma cell differentiation but facilitates memory B cell formation. J Immunol. 2014;193(5):2207–2217. doi:10.4049/jimmunol.1400411.
  • Korneev KV, Sviriaeva EN, Mitkin NA, et al. Minor C allele of the SNP rs7873784 associated with rheumatoid arthritis and type-2 diabetes mellitus binds PU.1 and enhances TLR4 expression. Biochim Biophys Acta Mol Basis Dis. 2020;1866(3):165626. doi:10.1016/j.bbadis.2019.165626.
  • Rodríguez-Carrio J, Alperi-López M, López P, et al. Profiling of B-cell factors and their decoy receptors in rheumatoid arthritis: association with clinical features and treatment outcomes. Front Immunol. 2018;9:2351. doi:10.3389/fimmu.2018.02351.
  • Woo YJ, Yoon BY, Jhun JY, et al. Regulation of B cell activating factor (BAFF) receptor expression by NF-ΚB signaling in rheumatoid arthritis B cells. Exp Mol Med. 2011;43(6):350–357. doi:10.3858/emm.2011.43.6.038.
  • Bankó Z, Pozsgay J, Szili D, et al. Induction and differentiation of IL-10-producing regulatory B cells from healthy blood donors and rheumatoid arthritis patients. J Immunol. 2017;198(4):1512–1520. doi:10.4049/jimmunol.1600218.
  • Huber K, Sármay G, Kövesdi D. MZ B cells migrate in a T-bet dependent manner and might contribute to the remission of collagen-induced arthritis by the secretion of IL-10. Eur J Immunol. 2016;46(9):2239–2246. doi:10.1002/eji.201546248.
  • Kam N-W, Liu D, Cai Z, et al. Synoviocytes-derived interleukin 35 potentiates B cell response in patients with osteoarthritis and rheumatoid arthritis. J Rheumatol. 2018;45(4):563–573. doi:10.3899/jrheum.161363.
  • Robak T, Gladalska A, Stepień H, Robak E. Serum levels of interleukin-6 type cytokines and soluble interleukin-6 receptor in patients with rheumatoid arthritis. Mediators Inflamm. 1998;7(5):347–353. doi:10.1080/09629359890875.
  • Boyapati A, Schwartzman S, Msihid J, et al. Association of high serum interleukin-6 levels with severe progression of rheumatoid arthritis and increased treatment response differentiating sarilumab from adalimumab or methotrexate in a post hoc analysis. Arthritis Rheumatol. 2020;72(9):1456–1466. doi:10.1002/art.41299.
  • Moura RA, Quaresma C, Vieira AR, et al. B-cell phenotype and IgD-CD27- memory B cells are affected by TNF-inhibitors and tocilizumab treatment in rheumatoid arthritis. PLoS One. 2017;12(9):e0182927. doi:10.1371/journal.pone.0182927.
  • Dam EM, Maier AC, Hocking AM, et al. Increased binding of specificity protein 1 to the IL21R promoter in B cells results in enhanced B cell responses in rheumatoid arthritis. Front Immunol. 2018;9:1978. doi:10.3389/fimmu.2018.01978.
  • Rao DA, Gurish MF, Marshall JL, et al. Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature. 2017;542(7639):110–114. doi:10.1038/nature20810.
  • Glossop JR, Emes RD, Nixon NB, et al. Genome-wide DNA methylation profiling in rheumatoid arthritis identifies disease-associated methylation changes that are distinct to individual T- and B-lymphocyte populations. Epigenetics. 2014;9(9):1228–1237. doi:10.4161/epi.29718.
  • Glossop JR, Emes RD, Nixon NB, et al. Genome-wide profiling in treatment-naive early rheumatoid arthritis reveals DNA methylome changes in T and B lymphocytes. Epigenomics. 2016;8(2):209–224. doi:10.2217/epi.15.103.
  • Dozmorov MG, Wren JD, Alarcón-Riquelme ME. Epigenomic elements enriched in the promoters of autoimmunity susceptibility genes. Epigenetics. 2014;9(2):276–285. doi:10.4161/epi.27021.
  • Tóth DM, Ocskó T, Balog A, et al. Amelioration of autoimmune arthritis in mice treated with the DNA methyltransferase inhibitor 5’-azacytidine. Arthritis Rheumatol. 2019;71(8):1265–1275. doi:10.1002/art.40877.
  • de Andres MC, Perez-Pampin E, Calaza M, et al. Assessment of global DNA methylation in peripheral blood cell subpopulations of early rheumatoid arthritis before and after methotrexate. Arthritis Res Ther. 2015;17:233. doi:10.1186/s13075-015-0748-5.
  • Thai T-H, Calado DP, Casola S, et al. Regulation of the germinal center response by microRNA-155. Science. 2007;316(5824):604–608. doi:10.1126/science.1141229.
  • Teng G, Hakimpour P, Landgraf P, et al. MicroRNA-155 is a negative regulator of activation-induced cytidine deaminase. Immunity. 2008;28(5):621–629. doi:10.1016/j.immuni.2008.03.015.
  • Killedar SJ, Killedar SY, Eckenrode SE, et al. Early pathogenic events associated with Sjögren’s syndrome (SjS)-like disease of the NOD mouse using microarray analysis. Lab Invest. 2006;86(12):1243–1260. doi:10.1038/labinvest.3700487.
  • Haacke EA, Bootsma H, Spijkervet FKL, et al. FcRL4+ B-cells in salivary glands of primary Sjögren’s syndrome patients. J Autoimmun. 2017;81:90–98. doi:10.1016/j.jaut.2017.03.012.
  • Hayakawa I, Tedder TF, Zhuang Y. B-lymphocyte depletion ameliorates Sjögren’s syndrome in Id3 knockout mice. Immunology. 2007;122(1):73–79. doi:10.1111/j.1365-2567.2007.02614.x.
  • Le Pottier L, Devauchelle V, Fautrel A, et al. Ectopic germinal centers are rare in Sjogren’s syndrome salivary glands and do not exclude autoreactive B cells. J Immunol. 2009;182(6):3540–3547. doi:10.4049/jimmunol.0803588.
  • Pangalis GA, Angelopoulou MK, Vassilakopoulos TP, et al. B-chronic lymphocytic leukemia, small lymphocytic lymphoma, and lymphoplasmacytic lymphoma, including Waldenström’s macroglobulinemia: a clinical, morphologic, and biologic spectrum of similar disorders. Semin Hematol. 1999;36:104–114.
  • Guerrier T, Le Pottier L, Devauchelle V, et al. Role of toll-like receptors in primary Sjögren’s syndrome with a special emphasis on B-cell maturation within exocrine tissues. J Autoimmun. 2012;39(1–2):69–76. doi:10.1016/j.jaut.2012.01.016.
  • Sun J-L, Zhang H-Z, Liu S-Y, et al. Elevated EPSTI1 promote B cell hyperactivation through NF-κB signalling in patients with primary Sjögren’s syndrome. Ann Rheum Dis. 2020;79(4):518–524. doi:10.1136/annrheumdis-2019-216428.
  • Nordmark G, Kristjansdottir G, Theander E, et al. Association of EBF1, FAM167A(C8orf13)-BLK and TNFSF4 gene variants with primary Sjögren’s syndrome. Genes Immun. 2011;12(2):100–109. doi:10.1038/gene.2010.44.
  • Nguyen CQ, Gao J-H, Kim H, et al. IL-4-STAT6 signal transduction-dependent induction of the clinical phase of Sjögren’s syndrome-like disease of the nonobese diabetic mouse. J Immunol. 2007;179(1):382–390. doi:10.4049/jimmunol.179.1.382.
  • Pertovaara M, Silvennoinen O, Isomäki P. STAT-5 is activated constitutively in T cells, B cells and monocytes from patients with primary Sjögren’s syndrome. Clin Exp Immunol. 2015;181(1):29–38. doi:10.1111/cei.12614.
  • Davies R, Hammenfors D, Bergum B, et al. Aberrant cell signalling in PBMCs upon IFN-α stimulation in primary Sjögren’s syndrome patients associates with type I interferon signature. Eur J Immunol. 2018;48(7):1217–1227. doi:10.1002/eji.201747213.
  • Zhang C-J, Wang C, Jiang M, et al. Act1 is a negative regulator in T and B cells via direct inhibition of STAT3. Nat Commun. 2018;9(1):2745. doi:10.1038/s41467-018-04974-3.
  • Jonsson MV, Szodoray P, Jellestad S, et al. Association between circulating levels of the novel TNF family members APRIL and BAFF and lymphoid organization in primary Sjögren’s syndrome. J Clin Immunol. 2005;25(3):189–201. doi:10.1007/s10875-005-4091-5.
  • Blokland SLM, van Vliet-Moret FM, Hillen MR, et al. Epigenetically quantified immune cells in salivary glands of Sjögren’s syndrome patients: a novel tool that detects robust correlations of T follicular helper cells with immunopathology. Rheumatology (Oxford). 2020;59(2):335–343. doi:10.1093/rheumatology/kez268.
  • Veroni C, Serafini B, Rosicarelli B, et al. Transcriptional profile and Epstein-Barr virus infection status of laser-cut immune infiltrates from the brain of patients with progressive multiple sclerosis. J Neuroinflammation. 2018;15(1):18. doi:10.1186/s12974-017-1049-5.
  • Rizzo F, Giacomini E, Mechelli R, et al. Interferon-β therapy specifically reduces pathogenic memory B cells in multiple sclerosis patients by inducing a FAS-mediated apoptosis. Immunol Cell Biol. 2016;94(9):886–894. doi:10.1038/icb.2016.55.
  • Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017;376(3):221–234. doi:10.1056/NEJMoa1601277.
  • Simon M, Ipek R, Homola GA, et al. Anti-CD52 antibody treatment depletes B cell aggregates in the central nervous system in a mouse model of multiple sclerosis. J Neuroinflammation. 2018;15(1):225. doi:10.1186/s12974-018-1263-9.
  • Willis MD, Robertson NP. Alemtuzumab for multiple sclerosis. Curr Neurol Neurosci Rep. 2016;16(9):84. doi:10.1007/s11910-016-0685-y.
  • Ramesh A, Schubert RD, Greenfield AL, et al. A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis. Proc Natl Acad Sci USA. 2020;117(37):22932–22943. doi:10.1073/pnas.2008523117.
  • Karaky M, Fedetz M, Potenciano V, et al. SP140 regulates the expression of immune-related genes associated with multiple sclerosis and other autoimmune diseases by NF-κB inhibition. Hum Mol Genet. 2018;27(23):4012–4023. doi:10.1093/hmg/ddy284.
  • Rijvers L, Melief M-J, van Langelaar J, et al. The role of autoimmunity-related gene CLEC16A in the B cell receptor-mediated HLA class II pathway. J Immunol. 2020;205(4):945–956. doi:10.4049/jimmunol.1901409.
  • Li R, Rezk A, Miyazaki Y, et al. Proinflammatory GM-CSF-producing B cells in multiple sclerosis and B cell depletion therapy. Sci Transl Med. 2015;7(310):310ra166. doi:10.1126/scitranslmed.aab4176.
  • Radomir L, Kramer MP, Perpinial M, et al. The survival and function of IL-10-producing regulatory B cells are negatively controlled by SLAMF5. Nat Commun. 2021;12(1):1893. doi:10.1038/s41467-021-22230-z.
  • Giacomini E, Rizzo F, Etna MP, et al. Thymosin-α1 expands deficient IL-10-producing regulatory B cell subsets in relapsing-remitting multiple sclerosis patients. Mult Scler. 2018;24(2):127–139. doi:10.1177/1352458517695892.
  • International Multiple Sclerosis Genetics Consortium (IMSGC), Beecham AH, Patsopoulos NA, et al. Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis. Nat Genet. 2013;45:1353–1360. doi:10.1038/ng.2770.
  • Severa M, Rizzo F, Srinivasan S, et al. A cell type-specific transcriptomic approach to map B cell and monocyte type I interferon-linked pathogenic signatures in Multiple Sclerosis. J Autoimmun. 2019;101:1–16. doi:10.1016/j.jaut.2019.04.006.
  • Chen D, Ireland SJ, Remington G, et al. CD40-mediated NF-κB activation in B cells is increased in multiple sclerosis and modulated by therapeutics. J Immunol. 2016;197(11):4257–4265. doi:10.4049/jimmunol.1600782.
  • Kular L, Liu Y, Ruhrmann S, et al. DNA methylation as a mediator of HLA-DRB1*15:01 and a protective variant in multiple sclerosis. Nat Commun. 2018;9(1):2397. doi:10.1038/s41467-018-04732-5.
  • Ewing E, Kular L, Fernandes SJ, et al. Combining evidence from four immune cell types identifies DNA methylation patterns that implicate functionally distinct pathways during Multiple Sclerosis progression. EBioMedicine. 2019;43:411–423. doi:10.1016/j.ebiom.2019.04.042.
  • Smith MJ, Simmons KM, Cambier JC. B cells in type 1 diabetes mellitus and diabetic kidney disease. Nat Rev Nephrol. 2017;13(11):712–720. doi:10.1038/nrneph.2017.138.
  • Egia-Mendikute L, Arpa B, Rosell-Mases E, et al. B-lymphocyte phenotype determines T-lymphocyte subset differentiation in autoimmune diabetes. Front Immunol. 2019;10:1732. doi:10.3389/fimmu.2019.01732.
  • Deng C, Xiang Y, Tan T, et al. Altered peripheral B-lymphocyte subsets in type 1 diabetes and latent autoimmune diabetes in adults. Diabetes Care. 2016;39(3):434–440. doi:10.2337/dc15-1765.
  • Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H, et al. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N Engl J Med. 2009;361(22):2143–2152. doi:10.1056/NEJMoa0904452.
  • Da Rosa LC, Boldison J, De Leenheer E, et al. B cell depletion reduces T cell activation in pancreatic islets in a murine autoimmune diabetes model. Diabetologia. 2018;61(6):1397–1410. doi:10.1007/s00125-018-4597-z.
  • Wilson CS, Spaeth JM, Karp J, et al. B lymphocytes protect islet β cells in diabetes prone NOD mice treated with imatinib. JCI Insight. 2019;5(9):e125317. doi:10.1172/jci.insight.125317.
  • Smith MJ, Rihanek M, Wasserfall C, et al. Loss of B-cell anergy in type 1 diabetes is associated with high-risk HLA and non-HLA disease susceptibility alleles. Diabetes. 2018;67(4):697–703. doi:10.2337/db17-0937.
  • von Wnuck Lipinski K, Sattler K, Peters S, et al. Hepatocyte nuclear factor 1a is a cell-intrinsic transcription factor required for B cell differentiation and development in mice. J Immunol. 2016;196(4):1655–1665. doi:10.4049/jimmunol.1500897.
  • Hu H, Peng L, Jiang H, et al. Silenced CHOP protects pancreatic B-cell function by targeting peroxisome proliferator-activated receptor-γ coactivator-1α through nuclear factor-κB signaling pathway in diabetes mellitus. J Cell Biochem. 2019;120(8):12595–12603. doi:10.1002/jcb.28526.
  • Kumar P, Natarajan K, Shanmugam N. High glucose driven expression of pro-inflammatory cytokine and chemokine genes in lymphocytes: molecular mechanisms of IL-17 family gene expression. Cell Signal. 2014;26(3):528–539. doi:10.1016/j.cellsig.2013.11.031.
  • Berry GJ, Budgeon LR, Cooper TK, et al. The type 1 diabetes resistance locus B10 Idd9.3 mediates impaired B-cell lymphopoiesis and implicates microRNA-34a in diabetes protection. Eur J Immunol. 2014;44(6):1716–1727. doi:10.1002/eji.201344116.
  • Wada N, Nishifuji K, Yamada T, et al. Aire-dependent thymic expression of desmoglein 3, the autoantigen in pemphigus vulgaris, and its role in T-cell tolerance. J Invest Dermatol. 2011;131(2):410–417. doi:10.1038/jid.2010.330.
  • Zhou S, Liu Z, Yuan H, et al. Autoreactive B cell differentiation in diffuse ectopic lymphoid-like structures of inflamed pemphigus lesions. J Invest Dermatol. 2020;140(2):309–318.e8. doi:10.1016/j.jid.2019.07.717.
  • Hébert V, Petit M, Maho-Vaillant M, et al. Modifications of the transcriptomic profile of autoreactive B cells from pemphigus patients after treatment with rituximab or a standard corticosteroid regimen. Front Immunol. 2019;10:1794. doi:10.3389/fimmu.2019.01794.
  • Berkani N, Joly P, Golinski M-L, et al. B-cell depletion induces a shift in self antigen specific B-cell repertoire and cytokine pattern in patients with bullous pemphigoid. Sci Rep. 2019;9(1):3525. doi:10.1038/s41598-019-40203-7.
  • Al-Salama ZT, Scott LJ. Baricitinib: a review in rheumatoid arthritis. Drugs. 2018;78(7):761–772. doi:10.1007/s40265-018-0908-4.
  • Zhang M, Lee F, Knize A, et al. Development of an ICOSL and BAFF bispecific inhibitor AMG 570 for systemic lupus erythematosus treatment. Clin Exp Rheumatol. 2019;37(6):906–914.
  • Chamberlain C, Colman PJ, Ranger AM, et al. Repeated administration of dapirolizumab pegol in a randomised phase I study is well tolerated and accompanied by improvements in several composite measures of systemic lupus erythematosus disease activity and changes in whole blood transcriptomic profiles. Ann Rheum Dis. 2017;76(11):1837–1844. doi:10.1136/annrheumdis-2017-211388.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.