TY - JOUR
T1 - Abatacept restores dysregulated transcriptomic and proteomic profile in disorders of CTLA-4 insufficiency
AU - Catak, Mehmet Cihangir
AU - Surucu, Naz
AU - Bayram Catak, Feyza
AU - Kara, Altan
AU - Cildir, Selin
AU - Babayeva, Royala
AU - Kayaoglu, Basak
AU - Bulutoglu, Alper
AU - Erman, Baran
AU - Karakus, Ibrahim Serhat
AU - Al-Shaibi, Ahmad
AU - Hubrack, Satanay
AU - Karabiber, Esra
AU - Celik, Figen Celebi
AU - Akgun, Gamze
AU - Baser, Dilek
AU - Bilgic Eltan, Sevgi
AU - Sefer, Asena Pinar
AU - Bozkurt, Selcen
AU - Ozturk, Necmiye
AU - Kiykim, Ayca
AU - Aydogmus, Cigdem
AU - Genel, Ferah
AU - Gulez, Nesrin
AU - Yucel, Esra
AU - Yildiran, Alisan
AU - Metin, Ayse
AU - Karakoc-Aydiner, Elif
AU - Ozen, Ahmet
AU - Gursel, Mayda
AU - Cildir, Gökhan
AU - Lo, Bernice
AU - Baris, Safa
N1 - Publisher Copyright:
© 2025 American Academy of Allergy, Asthma & Immunology
PY - 2025/12
Y1 - 2025/12
N2 - 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. (J Allergy Clin Immunol 2025;156:1725-42.)
AB - 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. (J Allergy Clin Immunol 2025;156:1725-42.)
KW - Abatacept
KW - CTLA-4 insufficiency
KW - Im-mune checkpoint dysregulation
KW - LRBA deficiency
KW - Multiomics profiling
UR - https://www.scopus.com/pages/publications/105019761849
U2 - 10.1016/j.jaci.2025.08.027
DO - 10.1016/j.jaci.2025.08.027
M3 - Article
C2 - 40967277
AN - SCOPUS:105019761849
SN - 0091-6749
VL - 156
SP - 1725
EP - 1742
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 6
ER -