B- and T-Lymphocyte Attenuator in Systemic Lupus Erythematosus Disease Pathogenesis.
Journal
Clinical pharmacology and therapeutics
ISSN: 1532-6535
Titre abrégé: Clin Pharmacol Ther
Pays: United States
ID NLM: 0372741
Informations de publication
Date de publication:
26 Apr 2024
26 Apr 2024
Historique:
received:
08
01
2024
accepted:
10
04
2024
medline:
27
4
2024
pubmed:
27
4
2024
entrez:
27
4
2024
Statut:
aheadofprint
Résumé
B- and T-lymphocyte attenuator (BTLA; CD272) is an immunoglobulin superfamily member and part of a family of checkpoint inhibitory receptors that negatively regulate immune cell activation. The natural ligand for BTLA is herpes virus entry mediator (HVEM; TNFRSF14), and binding of HVEM to BTLA leads to attenuation of lymphocyte activation. In this study, we evaluated the role of BTLA and HVEM expression in the pathogenesis of systemic lupus erythematosus (SLE), a multisystem autoimmune disease. Peripheral blood mononuclear cells from healthy volunteers (N = 7) were evaluated by mass cytometry by time-of-flight to establish baseline expression of BTLA and HVEM on human lymphocytes compared with patients with SLE during a self-reported flare (N = 5). High levels of BTLA protein were observed on B cells, CD4+, and CD8+ T cells, and plasmacytoid dendritic cells in healthy participants. HVEM protein levels were lower in patients with SLE compared with healthy participants, while BTLA levels were similar between SLE and healthy groups. Correlations of BTLA-HVEM hub genes' expression with patient and disease characteristics were also analyzed using whole blood gene expression data from patients with SLE (N = 1,760) and compared with healthy participants (N = 60). HVEM, being one of the SLE-associated genes, showed an exceptionally strong negative association with disease activity. Several other genes in the BTLA-HVEM signaling network were strongly (negative or positive) correlated, while BTLA had a low association with disease activity. Collectively, these data provide a clinical rationale for targeting BTLA with an agonist in SLE patients with low HVEM expression.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
Références
D'Cruz, D.P., Khamashta, M.A. & Hughes, G.R.V. Systemic lupus erythematosus. Lancet 369, 587–596 (2007).
Herrada, A.A. et al. Innate immune cells' contribution to systemic lupus erythematosus. Front. Immunol. 10, 772 (2019).
Cojocaru, M., Cojocaru, I.M., Silosi, I. & Vrabie, C.D. Manifestations of systemic lupus erythematosus. Maedica (Bucur) 6, 330–336 (2011).
Tsokos, G.C. Systemic lupus erythematosus. N. Engl. J. Med. 365, 2110–2121 (2011).
Moulton, V.R., Suarez‐Fueyo, A., Meidan, E., Li, H., Mizui, M. & Tsokos, G.C. Pathogenesis of human systemic lupus erythematosus: a cellular perspective. Trends Mol. Med. 23, 615–635 (2017).
Fanouriakis, A. et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann. Rheum. Dis. 78, 736–745 (2019).
Merrill, J.T., Shanahan, W.R., Scheinberg, M., Kalunian, K.C., Wofsy, D. & Martin, R.S. 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. 77, 883–889 (2018).
Merrill, J.T. et al. Efficacy and safety of atacicept in patients with systemic lupus erythematosus: results of a twenty‐four‐week, multicenter, randomized, double‐blind, placebo‐controlled, parallel‐arm, phase IIb study. Arthritis Rheumatol. 70, 266–276 (2018).
Merrill, J.T. et al. Efficacy and safety of subcutaneous tabalumab, a monoclonal antibody to B‐cell activating factor, in patients with systemic lupus erythematosus: results from ILLUMINATE‐2, a 52‐week, phase III, multicentre, randomised, double‐blind, placebo‐controlled study. Ann. Rheum. Dis. 75, 332–340 (2016).
Isenberg, D.A. et al. Efficacy and safety of subcutaneous tabalumab in patients with systemic lupus erythematosus: results from ILLUMINATE‐1, a 52‐week, phase III, multicentre, randomised, double‐blind, placebo‐controlled study. Ann. Rheum. Dis. 75, 323–331 (2016).
Reddy, V. et al. Obinutuzumab induces superior B‐cell cytotoxicity to rituximab in rheumatoid arthritis and systemic lupus erythematosus patient samples. Rheumatology (Oxford) 56, 1227–1237 (2017).
Clowse, M.E. et al. Efficacy and safety of epratuzumab in moderately to severely active systemic lupus erythematosus: results from two phase III randomized, double‐blind, placebo‐controlled trials. Arthritis Rheumatol. 69, 362–375 (2017).
Merrill, J.T. et al. The efficacy and safety of abatacept in patients with non‐life‐threatening manifestations of systemic lupus erythematosus: results of a twelve‐month, multicenter, exploratory, phase IIb, randomized, double‐blind, placebo‐controlled trial. Arthritis Rheum. 62, 3077–3087 (2010).
Furie, R. et al. Efficacy and safety of abatacept in lupus nephritis: a twelve‐month, randomized, double‐blind study. Arthritis Rheumatol. 66, 379–389 (2014).
Alexander, T. et al. The proteasome inhibitior bortezomib depletes plasma cells and ameliorates clinical manifestations of refractory systemic lupus erythematosus. Ann. Rheum. Dis. 74, 1474–1478 (2015).
Wallace, D.J. et al. Baricitinib for systemic lupus erythematosus: a double‐blind, randomised, placebo‐controlled, phase 2 trial. Lancet 392, 222–231 (2018).
Kalunian, K.C. et al. A phase II study of the efficacy and safety of rontalizumab (rhuMAb interferon‐α) in patients with systemic lupus erythematosus (ROSE). Ann. Rheum. Dis. 75, 196–202 (2016).
Furie, R. et al. Anifrolumab, an anti‐interferon‐α receptor monoclonal antibody, in moderate‐to‐severe systemic lupus erythematosus. Arthritis Rheumatol. 69, 376–386 (2017).
Morand, E.F. et al. Trial of anifrolumab in active systemic lupus erythematosus. N. Engl. J. Med. 382, 211–221 (2020).
Blanco, L.P. et al. Improved mitochondrial metabolism and reduced inflammation following attenuation of murine lupus with coenzyme Q10 analog idebenone. Arthritis Rheumatol. 72, 454–464 (2020).
Jury, E.C., Isenberg, D.A., Mauri, C. & Ehrenstein, M.R. Atorvastatin restores Lck expression and lipid raft‐associated signaling in T cells from patients with systemic lupus erythematosus. J. Immunol. 177, 7416–7422 (2006).
Kansal, R. et al. Sustained B cell depletion by CD19‐targeted CAR T cells is a highly effective treatment for murine lupus. Sci. Transl. Med. 11, eaav1648 (2019).
He, J. 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. 79, 141–149 (2020).
Cervera, R. et al. Morbidity and mortality in systemic lupus erythematosus during a 10‐year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore) 82, 299–308 (2003).
Watanabe, N. et al. BTLA is a lymphocyte inhibitory receptor with similarities to CTLA‐4 and PD‐1. Nat. Immunol. 4, 670–679 (2003).
Han, P., Goularte, O.D., Rufner, K., Wilkinson, B. & Kaye, J. An inhibitory Ig superfamily protein expressed by lymphocytes and APCs is also an early marker of thymocyte positive selection. J. Immunol. 172, 5931–5939 (2004).
Otsuki, N., Kamimura, Y., Hashiguchi, M. & Azuma, M. Expression and function of the B and T lymphocyte attenuator (BTLA/CD272) on human T cells. Biochem. Biophys. Res. Commun. 344, 1121–1127 (2006).
Sedy, J.R. et al. B and T lymphocyte attenuator regulates T cell activation through interaction with herpesvirus entry mediator. Nat. Immunol. 6, 90–98 (2005).
Krieg, C., Boyman, O., Fu, Y.X. & Kaye, J. B and T lymphocyte attenuator regulates CD8+ T cell–intrinsic homeostasis and memory cell generation. Nat. Immunol. 8, 162–171 (2007).
Deppong, C. et al. Cutting edge: B and T lymphocyte attenuator and programmed death receptor‐1 inhibitory receptors are required for termination of acute allergic airway inflammation. J. Immunol. 176, 3909–3913 (2006).
Wang, Y. et al. The role of herpesvirus entry mediator as a negative regulator of T cell‐mediated responses. J. Clin. Invest. 115, 711–717 (2005).
Davidson, A. The rationale for BAFF inhibition in systemic lupus erythematosus. Curr. Rheumatol. Rep. 14, 295–302 (2012).
Brady, M.P. et al. Serum and urine interferon gamma‐induced protein 10 (IP‐10) levels in lupus nephritis. J. Clin. Med. 11, 3199 (2022).
Hoffman, R.W. et al. Gene expression and pharmacodynamic changes in 1,760 systemic lupus erythematosus patients from two phase III trials of BAFF blockade with tabalumab. Arthritis Rheumatol. 69, 643–654 (2017).
Bolstad, B.M., Irizarry, R.A., Åstrand, M. & Speed, T.P. A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 19, 185–193 (2003).
Kuhn, A., Thu, D., Waldvogel, H.J., Faull, R.L.M. & Luthi‐Carter, R. Population‐specific expression analysis (PSEA) reveals molecular changes in diseased brain. Nat. Methods 8, 945–947 (2011).
Danaher, P. et al. Gene expression markers of tumor infiltrating leukocytes. J. Immunother. Cancer 5, 18 (2017).
R Core Team. A Language and Environment for Statistical Computing (R Foundation for Statistical Computing, Vienna). <https://www.R‐project.org> (2021).
Smyth, G.K. Limma: linear models for microarray data. In: Bioinformatics and Computational Biology Solutions Using R and Bioconductor. Statistics for Biology and Health. (eds. Gentlemen, R., Carey, V.J., Huber, W., Irizarry, R.A. & Dudoit, S.) 397–420 (Springer, New York, 2005).
Zollars, E. et al. BAFF (B cell activating factor) transcript level in peripheral blood of patients with SLE is associated with same‐day disease activity as well as global activity over the next year. Lupus Sci. Med. 2, e000063 (2015).
Banchereau, R. et al. Personalized immunomonitoring uncovers molecular networks that stratify lupus patients. Cell 165, 551–565 (2016).
Oster, C. et al. BTLA expression on Th1, Th2 and Th17 effector T‐cells of patients with systemic lupus erythematosus is associated with active disease. Int. J. Mol. Sci. 20, 4505 (2019).
Steinberg, M.W. et al. A crucial role for HVEM and BTLA in preventing intestinal inflammation. J. Exp. Med. 205, 1463–1476 (2008).
Laenen, G., Thorrez, L., Börnigen, D. & Moreau, Y. Finding the targets of a drug by integration of gene expression data with a protein interaction network. Mol. BioSyst. 9, 1676–1685 (2013).
Vilas‐Boas, A., Morais, S.A. & Isenberg, D.A. Belimumab in systemic lupus erythematosus. RMD Open 1, e000011 (2015).
Ware, C.F. Targeting lymphocyte activation through the lymphotoxin and LIGHT pathways. Immunol. Rev. 223, 186–201 (2008).
Albring, J.C. et al. Targeting of B and T lymphocyte associated (BTLA) prevents graft‐versus‐host disease without global immunosuppression. J. Exp. Med. 207, 2551–2559 (2010).