Background/Purpose: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. BAFF/APRIL-targeted therapy exert therapeutic effects through the inhibition of B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), with the expectation of achieving more rapid treatment outcomes. However, achieving clinical efficacy, particularly in terms of early response, has not always been successful. Recently, it has been observed that the expression of type I interferon-stimulated genes (ISGs) on CD8⁺ T cells may be associated with distinct treatment responses and prognoses in SLE patients. The heterogeneity in clinical response to BAFF/APRIL antagonism raises the possibility that ISGs may potentially contribute to the resistance exhibited by some patients towards BAFF/APRIL-targeted therapy. This study aims to detect the critical ISGs involved in the early response to BAFF/APRIL-targeted therapy for SLE by gene expression analysis of peripheral CD8⁺ T cells.

Methods: Six SLE patients and three healthy controls (HC) were investigated. All SLE patients received BAFF/APRIL-targeted treatment at least 12 weeks, including three patients with active disease and three patients in the lupus low disease activity state (LLDAS). CD8⁺ T cells were isolated from peripheral blood mononuclear cells, followed by RNA transcriptome sequencing analysis. The SLE-related ISGs were screened from two datasets of the Gene Expression Omnibus database. Differential expression analysis was conducted to investigate the similarities and disparities in gene expression across various samples. And then, enrichment analysis of differentially expressed ISGs (DEISGs) was performed.

Results: Significant variations in gene expression profiles of CD8⁺ T cells were observed among the three sample groups. A total of 756 DEGs were identified between active SLE and HC, while 602 DEGs were identified between active SLE and SLE in LLDAS. Interestingly, analysis of SLE-related ISGs clearly discriminated between active SLE and SLE in LLDAS. ISGs were found to be significantly up-regulated in active SLE patients following BAFF/APRIL-targeted treatment. By GO enrichment analysis, the terms, such as related to ” type I interferon signaling pathway, response to type I interferon, regulation of virus life cycle and cystein-type endopeptidase activity involved in cell apoptosis ” were found in these DEISGs. KEGG enrichment analysis revealed that DEISGs mainly participated in virus-related diseases. The protein-protein interaction network revealed robust interactions among these DEISGs. Then, USP18, SPATS2L, IFI6 and OAS3 were selected as hub ISGs.

Conclusion: The pathogenesis of SLE is multifaceted, with one contributing factor being the excessive production of IFNs and subsequent upregulation of downstream ISGs. The present study revealed an up-regulation of ISGs expression on CD8⁺ T cells in SLE patients exhibiting an inadequate early response to BAFF/APRIL-targeted therapy, suggesting that these altered ISGs characteristics may promote the progression of lupus via BAFF/APRIL-independent pathways. This may help explain the limited and variable clinical success with BAFF/APRIL antagonists in SLE patients.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/interferon-stimulated-genes-on-peripheral-cd8-t-cells-of-sle-patients-were-the-keys-for-early-response-to-baff-april-targeted-therapy/