Interferon Enhances B Cell Activation Associated With FOXM1 Induction: Potential Novel Therapeutic Strategy for Targeting the Plasmablasts of Systemic Lupus Erythematosus

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2021 Feb 26

PMID 33633721

Citations 16

Authors

Kanae Akita

Ken Yasaka

Tsuyoshi Shirai

Tomonori Ishii

Hideo Harigae

Hiroshi Fujii

Affiliations

Soon will be listed here.

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease. It is characterized by the production of various pathogenic autoantibodies and is suggested to be triggered by increased type I interferon (IFN) signature. Previous studies have identified increased plasmablasts in the peripheral blood of SLE patients. The biological characteristics of SLE plasmablasts remain unknown, and few treatments that target SLE plasmablasts have been applied despite the unique cellular properties of plasmablasts compared with other B cell subsets and plasma cells. We conducted microarray analysis of naïve and memory B cells and plasmablasts (CD38CD43 B cells) that were freshly isolated from healthy controls and active SLE (n = 4, each) to clarify the unique biological properties of SLE plasmablasts. The results revealed that all B cell subsets of SLE expressed more type I IFN-stimulated genes. In addition, SLE plasmablasts upregulated the expression of cell cycle-related genes associated with higher FOXM1 and FOXM1-regulated gene expression levels than that in healthy controls. This suggests that a causative relationship exists between type I IFN priming and enhanced proliferative capacity through FOXM1. The effects of pretreatment of IFN on B cell activation and FOXM1 inhibitor FDI-6 on B cell proliferation and survival were investigated. Pretreatment with IFN promoted B cell activation after stimulation with anti-IgG/IgM antibody. Flow cytometry revealed that pretreatment with IFN preferentially enhanced the Atk and p38 pathways after triggering B cell receptors. FDI-6 inhibited cell division and induced apoptosis in activated B cells. These effects were pronounced in activated B cells pretreated with interferon . This study can provide better understanding of the pathogenic mechanism of interferon-stimulated genes on SLE B cells and an insight into the development of novel therapeutic strategies.

Citing Articles

High-throughput identification of functional regulatory SNPs in systemic lupus erythematosus.

Wang Q, Kim T, Martinez-Bonet M, Aguiar V, Sim S, Cui J Nat Commun. 2024; 15(1):6804.

PMID: 39122710 PMC: 11315931. DOI: 10.1038/s41467-024-50710-5.

Association of autoantibodies with the IFN signature and NETosis in patients with systemic lupus erythematosus.

Kaan E, Brunekreef T, Drylewicz J, van den Hoogen L, van der Linden M, Leavis H J Transl Autoimmun. 2024; 9:100246.

PMID: 39027720 PMC: 11254743. DOI: 10.1016/j.jtauto.2024.100246.

Impact of subcutaneous belimumab on disease activity, patient satisfaction, and metabolic profile in long-lasting systemic lupus erythematosus.

Yamato M, Shirai T, Ishii Y, Sato H, Ishii T, Fujii H Clin Rheumatol. 2024; 43(3):1023-1035.

PMID: 38334937 DOI: 10.1007/s10067-024-06904-9.

Comprehensive analysis of immune cell landscapes revealed that immune cell ratio eosinophil/B.cell.memory is predictive of survival in sepsis.

Wang L, Zhang G, Sun W, Zhang Y, Tian Y, Yang X Eur J Med Res. 2023; 28(1):565.

PMID: 38053180 PMC: 10696691. DOI: 10.1186/s40001-023-01506-8.

Role of IFN-α in Rheumatoid Arthritis.

Lin C, Isaacs J, Cooles F Curr Rheumatol Rep. 2023; 26(2):37-52.

PMID: 38051494 PMC: 10787895. DOI: 10.1007/s11926-023-01125-6.

References

Jenks S, Cashman K, Woodruff M, Lee F, Sanz I . Extrafollicular responses in humans and SLE. Immunol Rev. 2019; 288(1):136-148. PMC: 6422038. DOI: 10.1111/imr.12741. View

Dorner T, Furie R . Novel paradigms in systemic lupus erythematosus. Lancet. 2019; 393(10188):2344-2358. DOI: 10.1016/S0140-6736(19)30546-X. View

Liossis S, Kovacs B, Dennis G, Kammer G, Tsokos G . B cells from patients with systemic lupus erythematosus display abnormal antigen receptor-mediated early signal transduction events. J Clin Invest. 1996; 98(11):2549-57. PMC: 507712. DOI: 10.1172/JCI119073. View

Furie R, Morand E, Bruce I, Manzi S, Kalunian K, Vital E . Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomised, controlled, phase 3 trial. Lancet Rheumatol. 2024; 1(4):e208-e219. DOI: 10.1016/S2665-9913(19)30076-1. View

Nutt S, Hodgkin P, Tarlinton D, Corcoran L . The generation of antibody-secreting plasma cells. Nat Rev Immunol. 2015; 15(3):160-71. DOI: 10.1038/nri3795. View

Morikawa K, Kubagawa H, Suzuki T, Cooper M . Recombinant interferon-alpha, -beta, and -gamma enhance the proliferative response of human B cells. J Immunol. 1987; 139(3):761-6. View

Lee D, Lee W, Kwon M, Lee H . Dual inhibition of FOXM1 and its compensatory signaling pathway decreased the survival of ovarian cancer cells. Oncol Rep. 2020; 45(1):390-400. DOI: 10.3892/or.2020.7845. View

Covens K, Verbinnen B, Geukens N, Meyts I, Schuit F, Van Lommel L . Characterization of proposed human B-1 cells reveals pre-plasmablast phenotype. Blood. 2013; 121(26):5176-83. DOI: 10.1182/blood-2012-12-471953. View

Elgueta R, Benson M, de Vries V, Wasiuk A, Guo Y, Noelle R . Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol Rev. 2009; 229(1):152-72. PMC: 3826168. DOI: 10.1111/j.1600-065X.2009.00782.x. View

10.

Hiepe F, Dorner T, Hauser A, Hoyer B, Mei H, Radbruch A . Long-lived autoreactive plasma cells drive persistent autoimmune inflammation. Nat Rev Rheumatol. 2011; 7(3):170-8. DOI: 10.1038/nrrheum.2011.1. View

11.

Yao S, Fan L, Lam E . The FOXO3-FOXM1 axis: A key cancer drug target and a modulator of cancer drug resistance. Semin Cancer Biol. 2017; 50:77-89. PMC: 6565931. DOI: 10.1016/j.semcancer.2017.11.018. View

12.

Ruuth K, Carlsson L, Hallberg B, Lundgren E . Interferon-alpha promotes survival of human primary B-lymphocytes via phosphatidylinositol 3-kinase. Biochem Biophys Res Commun. 2001; 284(3):583-6. DOI: 10.1006/bbrc.2001.5025. View

13.

Becker A, Dao K, Han B, Kornu R, Lakhanpal S, Mobley A . SLE peripheral blood B cell, T cell and myeloid cell transcriptomes display unique profiles and each subset contributes to the interferon signature. PLoS One. 2013; 8(6):e67003. PMC: 3691135. DOI: 10.1371/journal.pone.0067003. View

14.

Ronnblom L, Alm G . An etiopathogenic role for the type I IFN system in SLE. Trends Immunol. 2001; 22(8):427-31. DOI: 10.1016/s1471-4906(01)01955-x. View

15.

Munroe M, Lu R, Zhao Y, Fife D, Robertson J, Guthridge J . Altered type II interferon precedes autoantibody accrual and elevated type I interferon activity prior to systemic lupus erythematosus classification. Ann Rheum Dis. 2016; 75(11):2014-2021. PMC: 4959992. DOI: 10.1136/annrheumdis-2015-208140. View

16.

Tsokos G . Systemic lupus erythematosus. N Engl J Med. 2011; 365(22):2110-21. DOI: 10.1056/NEJMra1100359. View

17.

Alexander T, Sarfert R, Klotsche J, Kuhl A, Rubbert-Roth A, Lorenz H . The proteasome inhibitior bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus. Ann Rheum Dis. 2015; 74(7):1474-8. PMC: 4484251. DOI: 10.1136/annrheumdis-2014-206016. View

18.

Wierstra I . The transcription factor FOXM1 (Forkhead box M1): proliferation-specific expression, transcription factor function, target genes, mouse models, and normal biological roles. Adv Cancer Res. 2013; 118:97-398. DOI: 10.1016/B978-0-12-407173-5.00004-2. View

19.

Fecher P, Caspell R, Naeem V, Karulin A, Kuerten S, Lehmann P . B Cells and B Cell Blasts Withstand Cryopreservation While Retaining Their Functionality for Producing Antibody. Cells. 2018; 7(6). PMC: 6028916. DOI: 10.3390/cells7060050. View

20.

Baechler E, Batliwalla F, Karypis G, Gaffney P, Ortmann W, Espe K . Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A. 2003; 100(5):2610-5. PMC: 151388. DOI: 10.1073/pnas.0337679100. View