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

Pilar Ortiz-Aljaro, Marco Antonio Montes-Cano, José-Raúl García-Lozano, Virginia Aquino, Rosario Carmona, Javier Perez-Florido, Francisco José García-Hernández, Joaquín Dopazo, María Francisca González-Escribano, Pilar Ortiz-Aljaro, Marco Antonio Montes-Cano, José-Raúl García-Lozano, Virginia Aquino, Rosario Carmona, Javier Perez-Florido, Francisco José García-Hernández, Joaquín Dopazo, María Francisca González-Escribano

Abstract

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 (rs = 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.

Trial registration: ClinicalTrials.gov NCT03919643.

Conflict of interest statement

The authors declare no competing interests.

© 2022. The Author(s).

Figures

Figure 1
Figure 1
Median levels of sBAFF and sAPRIL in patients and controls.
Figure 2
Figure 2
Median of the relative expression of non-functional isoforms of BAFF and APRIL. (a) Median of the relative expression εAPRIL/α+γ− in patients and controls. (b) Median of the relative expression βAPRIL/α+γ in patients with and without nephritis. (c) Median of the relative expression ΔBAFF/functional isoforms in patients with and without dsDNA antibodies.

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