Small molecule inhibitors of nuclear export and the amelioration of lupus by modulation of plasma cell generation and survival

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dc.contributor.affiliationUniversity of Rochester Medical Center, Rochester, New York
dc.contributor.emailjennifer_anolik@urmc.rochester.edu (Jennifer H. Anolik) ; javier_rangelmoreno@urmc.rochester.edu (Javier RangelMoreno)
dc.creatorRangel-Moreno, Javieres_ES
dc.creatorGarcia-Hernandez, Maria de la Luzes_ES
dc.creatorOwen, Teresaes_ES
dc.creatorBarnard, Jenniferes_ES
dc.creatorVillanueva, Enriquees_ES
dc.creatorKashyap, Trinayanes_ES
dc.creatorArgueta, Christianes_ES
dc.creatorDominguez, Armandoes_ES
dc.creatorTamir, Sharones_ES
dc.creatorLandesman, Yosefes_ES
dc.creatorGoldman, Bruce I.es_ES
dc.creatorRitchlin, Christopher T.es_ES
dc.creatorAnolik, Jennifer H.es_ES
dc.date2022
dc.date.accessioned2024-12-06T17:21:47Z
dc.date.accessioned2026-03-27T15:30:43Z
dc.date.available2024-12-06T17:21:47Z
dc.date.issued2022
dc.date.published2022
dc.descriptionObjective: To investigate the hypothesis that selective inhibitors of nuclear export (SINE compounds), recently approved for treatment of refractory plasma cell (PC) malignancy, may have potential in the treatment of lupus. Methods: Female NZB/NZW mice were treated with the SINE compound KPT-350 or vehicle control. Tissue specimens were harvested and analyzed by flow cytometry, using standard markers. Nephritis was monitored by determining the proteinuria score and by histologic analysis of kidney specimens. Serum anti-double-stranded DNA (anti-dsDNA) levels were measured by enzyme-linked immunosorbent assay, and total numbers of IgG-secreting and dsDNA-specific antibody-secreting cells were assessed by enzyme-linked immunospot assay. Results: KPT-350 abrogated murine lupus nephritis at both early and late stages of the disease and rapidly impaired generation of autoreactive PCs in germinal centers (GCs). SINE compounds inhibited the production of NF-κB-driven homeostatic chemokines by stromal cells, altering splenic B and T cell strategic positioning and significantly reducing follicular helper T cell, GC B cell, and autoreactive PC counts. KPT-350 also decreased levels of cytokines and chemokines involved in PC survival and recruitment in the kidney of lupus-prone mice. Exportin 1, the target of SINE compounds, was detected in GCs of human tonsils, splenic B cells of lupus patients, and multiple B cell subsets in the kidneys of patients with lupus nephritis. Conclusion: Collectively, our results provide support for the therapeutic potential of SINE compounds, via their targeting of several molecular and cellular pathways critical in lupus pathogenesis, including autoantibody production by plasma cells.es_ES
dc.formatPDFes_ES
dc.identifierJC01NC22es_ES
dc.identifier.doi10.1002/art.42128
dc.identifier.eissn2326-5205
dc.identifier.issn2326-5191
dc.identifier.organizacionInstituto Nacional de Psiquiatría Ramón de la Fuente Muñiz
dc.identifier.placeEstados Unidos
dc.identifier.urihttps://doi.org/10.1002/art.42128
dc.identifier.urihttps://pmc.ncbi.nlm.nih.gov/articles/PMC9339462/
dc.identifier.urihttps://repositorio.inprf.gob.mx/handle/123456789/8136
dc.language.isoenges_ES
dc.publisherWileyes_ES
dc.relation74(8):1363-1375
dc.relation.jnabreviadoARTHRITIS RHEUMATOL
dc.relation.journalArthritis & Rheumatology
dc.rightsAcceso Cerradoes_ES
dc.titleSmall molecule inhibitors of nuclear export and the amelioration of lupus by modulation of plasma cell generation and survivales_ES
dc.typeArtículoes_ES

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