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Protein and functional isoform levels and genetic variants of the BAFF and APRIL pathway components in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is the prototype of an autoimmune disease. Belimumab, a monoclonal antibody targets BAFF, is the only biologic approved for SLE and active lupus nephritis. BAFF is a cytokine with a key-regulatory role in the B cell homeostasis, which acts by binding to three recep...

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Autores principales: Ortiz-Aljaro, Pilar, Montes-Cano, Marco Antonio, García-Lozano, José-Raúl, Aquino, Virginia, Carmona, Rosario, Perez-Florido, Javier, García-Hernández, Francisco José, Dopazo, Joaquín, González-Escribano, María Francisca
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9250527/
https://www.ncbi.nlm.nih.gov/pubmed/35780200
http://dx.doi.org/10.1038/s41598-022-15549-0
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author Ortiz-Aljaro, Pilar
Montes-Cano, Marco Antonio
García-Lozano, José-Raúl
Aquino, Virginia
Carmona, Rosario
Perez-Florido, Javier
García-Hernández, Francisco José
Dopazo, Joaquín
González-Escribano, María Francisca
author_facet Ortiz-Aljaro, Pilar
Montes-Cano, Marco Antonio
García-Lozano, José-Raúl
Aquino, Virginia
Carmona, Rosario
Perez-Florido, Javier
García-Hernández, Francisco José
Dopazo, Joaquín
González-Escribano, María Francisca
author_sort Ortiz-Aljaro, Pilar
collection PubMed
description Systemic lupus erythematosus (SLE) is the prototype of an autoimmune disease. Belimumab, a monoclonal antibody targets BAFF, is the only biologic approved for SLE and active lupus nephritis. BAFF is a cytokine with a key-regulatory role in the B cell homeostasis, which acts by binding to three receptors: BAFF-R, TACI and BCMA. TACI and BCMA also bind APRIL. Many studies reported elevated soluble BAFF and APRIL levels in the sera of SLE patients, but other questions about the role of this system in the disease remain open. The study aimed to investigate the utility of the cytokine levels in serum and urine as biomarkers, the role of non-functional isoforms, and the association of gene variants with the disease. This case–control study includes a cohort (women, 18–60 years old) of 100 patients (48% with nephritis) and 100 healthy controls. We used ELISA assays to measure the cytokine concentrations in serum (sBAFF and sAPRIL) and urine (uBAFF and uAPRIL); TaqMan Gene Expression Assays to quantify the relative mRNA expression of ΔBAFF, βAPRIL, and εAPRIL, and next-generation sequencing to genotype the cytokine (TNFSF13 and TNFSF13B) and receptor (TNFRSF13B, TNFRSF17 and TNFRSF13C) genes. The statistical tests used were: Kruskal–Wallis (qualitative variables), the Spearman Rho coefficient (correlations), the Chi-square and SKAT (association of common and rare genetic variants, respectively). As expected, sBAFF and sAPRIL levels were higher in patients than in controls (p ≤ 0.001) but found differences between patient subgroups. sBAFF and sAPRIL significantly correlated only in patients with nephritis (r(s) = 0.67, p ≤ 0.001) and βAPRIL levels were lower in patients with nephritis (p = 0.04), and ΔBAFF levels were lower in patients with dsDNA antibodies (p = 0.04). Rare variants of TNFSF13 and TNFRSF13B and TNFSF13 p.Gly67Arg and TNFRSF13B p.Val220Ala were associated with SLE. Our study supports differences among SLE patient subgroups with diverse clinical features in the BAFF/APRIL pathway. In addition, it suggests the involvement of genetic variants in the susceptibility to the disease.
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spelling pubmed-92505272022-07-04 Protein and functional isoform levels and genetic variants of the BAFF and APRIL pathway components in systemic lupus erythematosus Ortiz-Aljaro, Pilar Montes-Cano, Marco Antonio García-Lozano, José-Raúl Aquino, Virginia Carmona, Rosario Perez-Florido, Javier García-Hernández, Francisco José Dopazo, Joaquín González-Escribano, María Francisca Sci Rep Article Systemic lupus erythematosus (SLE) is the prototype of an autoimmune disease. Belimumab, a monoclonal antibody targets BAFF, is the only biologic approved for SLE and active lupus nephritis. BAFF is a cytokine with a key-regulatory role in the B cell homeostasis, which acts by binding to three receptors: BAFF-R, TACI and BCMA. TACI and BCMA also bind APRIL. Many studies reported elevated soluble BAFF and APRIL levels in the sera of SLE patients, but other questions about the role of this system in the disease remain open. The study aimed to investigate the utility of the cytokine levels in serum and urine as biomarkers, the role of non-functional isoforms, and the association of gene variants with the disease. This case–control study includes a cohort (women, 18–60 years old) of 100 patients (48% with nephritis) and 100 healthy controls. We used ELISA assays to measure the cytokine concentrations in serum (sBAFF and sAPRIL) and urine (uBAFF and uAPRIL); TaqMan Gene Expression Assays to quantify the relative mRNA expression of ΔBAFF, βAPRIL, and εAPRIL, and next-generation sequencing to genotype the cytokine (TNFSF13 and TNFSF13B) and receptor (TNFRSF13B, TNFRSF17 and TNFRSF13C) genes. The statistical tests used were: Kruskal–Wallis (qualitative variables), the Spearman Rho coefficient (correlations), the Chi-square and SKAT (association of common and rare genetic variants, respectively). As expected, sBAFF and sAPRIL levels were higher in patients than in controls (p ≤ 0.001) but found differences between patient subgroups. sBAFF and sAPRIL significantly correlated only in patients with nephritis (r(s) = 0.67, p ≤ 0.001) and βAPRIL levels were lower in patients with nephritis (p = 0.04), and ΔBAFF levels were lower in patients with dsDNA antibodies (p = 0.04). Rare variants of TNFSF13 and TNFRSF13B and TNFSF13 p.Gly67Arg and TNFRSF13B p.Val220Ala were associated with SLE. Our study supports differences among SLE patient subgroups with diverse clinical features in the BAFF/APRIL pathway. In addition, it suggests the involvement of genetic variants in the susceptibility to the disease. Nature Publishing Group UK 2022-07-02 /pmc/articles/PMC9250527/ /pubmed/35780200 http://dx.doi.org/10.1038/s41598-022-15549-0 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Ortiz-Aljaro, Pilar
Montes-Cano, Marco Antonio
García-Lozano, José-Raúl
Aquino, Virginia
Carmona, Rosario
Perez-Florido, Javier
García-Hernández, Francisco José
Dopazo, Joaquín
González-Escribano, María Francisca
Protein and functional isoform levels and genetic variants of the BAFF and APRIL pathway components in systemic lupus erythematosus
title Protein and functional isoform levels and genetic variants of the BAFF and APRIL pathway components in systemic lupus erythematosus
title_full Protein and functional isoform levels and genetic variants of the BAFF and APRIL pathway components in systemic lupus erythematosus
title_fullStr Protein and functional isoform levels and genetic variants of the BAFF and APRIL pathway components in systemic lupus erythematosus
title_full_unstemmed Protein and functional isoform levels and genetic variants of the BAFF and APRIL pathway components in systemic lupus erythematosus
title_short Protein and functional isoform levels and genetic variants of the BAFF and APRIL pathway components in systemic lupus erythematosus
title_sort protein and functional isoform levels and genetic variants of the baff and april pathway components in systemic lupus erythematosus
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9250527/
https://www.ncbi.nlm.nih.gov/pubmed/35780200
http://dx.doi.org/10.1038/s41598-022-15549-0
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