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. 2025 Sep 16:S0091-6749(25)00946-7.
doi: 10.1016/j.jaci.2025.08.027. Online ahead of print.

Abatacept restores dysregulated transcriptomic and proteomic profile in disorders of CTLA-4 insufficiency

Mehmet Cihangir Catak  1 , Naz Surucu  2 , Feyza Bayram Catak  1 , Altan Kara  3 , Selin Cildir  4 , Royala Babayeva  1 , Basak Kayaoglu  2 , Alper Bulutoglu  1 , Baran Erman  5 , Ibrahim Serhat Karakus  1 , Ahmad Al-Shaibi  6 , Satanay Hubrack  6 , Esra Karabiber  7 , Figen Celebi Celik  8 , Gamze Akgun  1 , Dilek Baser  1 , Sevgi Bilgic Eltan  1 , Asena Pinar Sefer  1 , Selcen Bozkurt  1 , Necmiye Ozturk  1 , Ayca Kiykim  9 , Cigdem Aydogmus  10 , Ferah Genel  8 , Nesrin Gulez  8 , Esra Yucel  9 , Alisan Yildiran  11 , Ayse Metin  12 , Elif Karakoc-Aydiner  1 , Ahmet Ozen  1 , Mayda Gursel  13 , Gökhan Cildir  14 , Bernice Lo  15 , Safa Baris  16
Affiliations

Abatacept restores dysregulated transcriptomic and proteomic profile in disorders of CTLA-4 insufficiency

Mehmet Cihangir Catak et al. J Allergy Clin Immunol. .

Abstract

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.

Keywords: CTLA-4 insufficiency; LRBA deficiency; abatacept; immune checkpoint dysregulation; multiomics profiling.

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Conflict of interest statement

Disclosure statement Supported by a grant from the Marmara University Scientific Research Project Coordination Unit (ADT-2022-10661) and the Jeffrey Modell Foundation to S.B. and by Sidra Medicine (IRF 2022) to B.L. Data and materials availability: The data generated during the study are included in the published main text and Supplemental file. Targeted RNA-sequencing (NanoString) and proteomics data are available on Figshare (doi.org/10.6084/m9.figshare.28873160). Single-cell RNA sequence data supporting this study’s findings have been deposited in the Gene Expression Omnibus database (GSE296828). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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