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Войти в исследования The Journal of allergy and clinical immunology · 2025
Abatacept restores dysregulated transcriptomic and proteomic profile in disorders of CTLA-4 insufficiency.
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Catak Mehmet Cihangir, Surucu Naz, Bayram Catak Feyza, Kara Altan, Cildir Selin, Babayeva Royala, Kayaoglu Basak, Bulutoglu Alper, Erman Baran, Karakus Ibrahim Serhat, Al-Shaibi Ahmad, Hubrack Satanay, Karabiber Esra, Celik Figen Celebi, Akgun Gamze, Baser Dilek, Bilgic Eltan Sevgi, Sefer Asena Pinar, Bozkurt Selcen, Ozturk Necmiye, Kiykim Ayca, Aydogmus Cigdem, Genel Ferah, Gulez Nesrin, Yucel Esra, Yildiran Alisan, Metin Ayse, Karakoc-Aydiner Elif, Ozen Ahmet, Gursel Mayda, Cildir Gökhan, Lo Bernice, Baris Safa
Аннотация
BACKGROUND: Lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) insufficiency are rare primary immune dysregulation disorders. Both conditions result from impaired maintenance of CTLA-4, a critical inhibitory checkpoint molecule. Despite the known benefits of abatacept (a CTLA-4-Ig fusion protein) treatment, its precise immunologic effects remain unclear.
OBJECTIVE: We comprehensively investigated the effect of abatacept therapy on patients with LRBA deficiency and CTLA-4 insufficiency using an integrative multiomics approach.
METHODS: The study combined longitudinal flow cytometry, targeted and single-cell transcriptomics, and plasma proteomics in patients receiving abatacept treatment.
RESULTS: Abatacept treatment increased thymic output and expansion of naive T and B cells while reducing memory T-cell subsets, CD4+ T-cell cytokine production, and CD21low B cells. Multimodal transcriptomic and proteomic analyses revealed previously unrecognized immunopathogenic mechanisms, including increased CD28 and T-cell receptor signaling as well as compensatory upregulation of inhibitory checkpoint proteins (LAG3, TIGIT, ADORA2A, VSIR, HAVCR2) in response to CTLA-4 insufficiency. Proteomic profiling confirmed the upregulation of inflammatory mediators, including CHI3L1, CXCL13, and CSF1. Most of these transcriptomic and proteomic abnormalities were reversed after abatacept therapy; notably, gene signatures derived from lymphocytes exhibited greater normalization than those associated with myeloid cells. Furthermore, identified shared and disease-specific molecular signatures distinguished LRBA-deficient patients from those with CTLA-4 insufficiency, revealing more severe immune dysregulation in LRBA deficiency. Single-cell RNA sequencing validated the reversal of checkpoint dysregulation and the expression of inflammation-related genes across lymphoid and myeloid lineages.
CONCLUSION: Abatacept effectively corrects key immune circuits in both diseases. This integrative systems-level approach offers new mechanisms and therapeutic targets, supporting personalized intervention strategies.
OBJECTIVE: We comprehensively investigated the effect of abatacept therapy on patients with LRBA deficiency and CTLA-4 insufficiency using an integrative multiomics approach.
METHODS: The study combined longitudinal flow cytometry, targeted and single-cell transcriptomics, and plasma proteomics in patients receiving abatacept treatment.
RESULTS: Abatacept treatment increased thymic output and expansion of naive T and B cells while reducing memory T-cell subsets, CD4+ T-cell cytokine production, and CD21low B cells. Multimodal transcriptomic and proteomic analyses revealed previously unrecognized immunopathogenic mechanisms, including increased CD28 and T-cell receptor signaling as well as compensatory upregulation of inhibitory checkpoint proteins (LAG3, TIGIT, ADORA2A, VSIR, HAVCR2) in response to CTLA-4 insufficiency. Proteomic profiling confirmed the upregulation of inflammatory mediators, including CHI3L1, CXCL13, and CSF1. Most of these transcriptomic and proteomic abnormalities were reversed after abatacept therapy; notably, gene signatures derived from lymphocytes exhibited greater normalization than those associated with myeloid cells. Furthermore, identified shared and disease-specific molecular signatures distinguished LRBA-deficient patients from those with CTLA-4 insufficiency, revealing more severe immune dysregulation in LRBA deficiency. Single-cell RNA sequencing validated the reversal of checkpoint dysregulation and the expression of inflammation-related genes across lymphoid and myeloid lineages.
CONCLUSION: Abatacept effectively corrects key immune circuits in both diseases. This integrative systems-level approach offers new mechanisms and therapeutic targets, supporting personalized intervention strategies.