Abatacept Restores Dysregulated Transcriptomic and Proteomic Profiling in LRBA Deficiency and CTLA-4 Insufficiency

This study investigates the effectiveness of abatacept via flow cytometric and multi-omics approaches in treating lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency, an immune disorder characterized by infections, autoimmunity, and lymphoproliferation. Integrative analyses revealed that long-term abatacept use boosted the naive T-cell pool through increased thymic output while simultaneously reducing memory T cells and cytokine productions of CD4+ T cells and decreasing autoreactive B cells. Abatacept also normalized the imbalanced T helper (TH) 1 and TH17 responses. By using targeted and single-cell transcriptomics together with plasma proteomic analyses, we observed a complex interaction involving upregulated CD28 and T-cell receptor signaling pathways, accompanied by increased expression of inhibitory checkpoint proteins to maintain immune homeostasis in the absence of the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). The immune dysregulation involved multiple pathway repercussions, including upregulation of inflammatory pathways, cytokine and chemokine-mediated responses, antimicrobial peptides, interferon-related genes, complement system, and toll-like receptor signaling, which normalized under abatacept. Thus, targeted treatment can re-establish the broadly disturbed immune regulation in LRBA deficiency. Overall design: Patient blood samples were collected before and after abatacept treatment and PBMCs were separated using ficoll density gradient, cryopreserved, then put through single cell RNA sequencing.