A novel estrogen receptor 1: sphingomyelin phosphodiesterase acid-like 3B pathway mediates rituximab response in myositis patients.

Autor:	Parkes JE; School of Pharmacy and Pharmaceutical Sciences, Binghamton University, Binghamton, NY, USA., Boehler JF; School of Pharmacy and Pharmaceutical Sciences, Binghamton University, Binghamton, NY, USA.; Solid Biosciences Inc, Cambridge, MA, USA., Li N; School of Pharmacy and Pharmaceutical Sciences, Binghamton University, Binghamton, NY, USA., Kendra RM; School of Pharmacy and Pharmaceutical Sciences, Binghamton University, Binghamton, NY, USA., O'Hanlon TP; Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, MD, USA., Hoffman EP; School of Pharmacy and Pharmaceutical Sciences, Binghamton University, Binghamton, NY, USA., Peterson JM; School of Pharmacy and Pharmaceutical Sciences, Binghamton University, Binghamton, NY, USA.; School of Exercise and Rehabilitative Sciences, The University of Toledo, OH, USA., Miller FW; Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, MD, USA., Rider LG; Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda, MD, USA., Nagaraju K; School of Pharmacy and Pharmaceutical Sciences, Binghamton University, Binghamton, NY, USA.
Jazyk:	angličtina
Zdroj:	Rheumatology (Oxford, England) [Rheumatology (Oxford)] 2023 Aug 01; Vol. 62 (8), pp. 2864-2871.
DOI:	10.1093/rheumatology/keac687
Abstrakt:	Objectives: The B-cell depleting biologic, rituximab, is used to treat refractory autoimmune myositis. However, the beneficial effects of rituximab appear to outweigh the known contribution of B cells in myositis. We aimed to elucidate how myositis patients respond differently to rituximab and possible alternative mechanisms of action. Methods: Here we have: (i) comprehensively investigated concurrent mRNA and microRNA expression in muscle biopsies taken at baseline and 16 weeks post treatment in 10 patients who were part of the rituximab in myositis (RIM) trial; and (ii) investigated the beneficial effect of rituximab on myositis muscle cells. Results: Our analyses identified an increased number of changes in gene expression in biopsies from patients who had a clinical response to rituximab (n = 5) compared with non-responders (n = 5). The two groups had completely different changes in microRNA and mRNA expression following rituximab therapy, with the exception of one mRNA, BHMT2. Networks of mRNA and microRNA with opposite direction of expression changes highlighted ESR1 as upregulated in responders. We confirmed ESR1 upregulation upon rituximab treatment of immortalized myotubes and primary human dermatomyositis muscle cells in vitro, demonstrating a direct effect of rituximab on muscle cells. Notably, despite showing a response to rituximab, human dermatomyositis primary muscle cells did not express the rituximab target, CD20. However, these cells expressed a possible alternative target of rituximab, sphingomyelinase-like phosphodiesterase 3 b (SMPDL3B). Conclusion: In addition to B-cell depletion, rituximab may be beneficial in myositis due to increased ESR1 signalling mediated by rituximab binding to SMPDL3B on skeletal muscle cells. (Published by Oxford University Press on behalf of the British Society for Rheumatology 2022.)
Databáze:	MEDLINE
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