Download This Paper
Preprints with The Lancet is a collaboration between The Lancet Group of journals and SSRN to facilitate the open sharing of preprints for early engagement, community comment, and collaboration. Preprints available here are not Lancet publications or necessarily under review with a Lancet journal. These preprints are early-stage research papers that have not been peer-reviewed. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. The findings should not be used for clinical or public health decision-making or presented without highlighting these facts. For more information, please see the FAQs.
Single-Cell Landscape of Immunological Responses in CTLA4 Haploinsufficiency Patient after Abatacept Therapy
36 Pages Posted: 4 Mar 2024
More...Abstract
Background: Heterozygous germline mutations in the cytotoxic T lymphocyte antigen-4 (CTLA4) gene have been identified as the cause of a rare immune dysregulation syndrome in humans. Abatacept (CTLA4 Ig) has been approved for treatment of CTLA4 haploinsufficiency; however, its therapeutic mechanism remains unknown.
Methods: Following a 10-month observation period, abatacept treatment effectively alleviated disease symptoms without restoring CTLA4 expression and ligand capture. To gain insight into the immune response landscape associated with abatacept therapy, mass cytometry and single-cell RNA sequencing were performed on peripheral blood mononuclear cells from a patient with CTLA4 haploinsufficiency before and after treatment with abatacept.
Findings: Abatacept treatment modulated proportions of T and B naïve and memory cells but did not significantly impact B-cell development. Additionally, both adaptive and innate immune activation were mitigated. Notably, abatacept treatment led to a reduction in expression of mitochondrial genes across various immune cells, suggesting a metabolic reprogramming effect.
Interpretation: These results offer a theoretical foundation for utilization of abatacept in CTLA4 haploinsufficiency and have significant implications for understanding the mechanism of immune checkpoints.
Funding: This study was supported by grants from the National High Level Hospital Clinical Research Funding (grant number 2022-PUMCH-D-002, 2022-PUMCH-B-013), the National Natural Science Foundation of China (82171799), and Chinese Academy of Medical Science Innovation Fund for Medical Sciences (2021-I2M-1-016).
Declaration of Interest: The authors declare no conflicts of interest.
Ethical Approval: The study was approved by the Ethics Committee of PUMC Hospital Review Board.
Keywords: CTLA4, Abatacept, CyTOF, Single-Cell RNA Sequencing
Suggested Citation: Suggested Citation