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Haploinsufficiency of immune checkpoint receptor CTLA4 induces a distinct neuroinflammatory disorder
Matthew K. Schindler, … , Daniel S. Reich, Gulbu Uzel
Matthew K. Schindler, … , Daniel S. Reich, Gulbu Uzel
Published September 21, 2020
Citation Information: J Clin Invest. 2020;130(10):5551-5561. https://doi.org/10.1172/JCI135947.
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Clinical Research and Public Health Inflammation Neuroscience Article has an altmetric score of 5

Haploinsufficiency of immune checkpoint receptor CTLA4 induces a distinct neuroinflammatory disorder

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Abstract

BACKGROUND Cytotoxic T lymphocyte antigen 4 (CTLA4) is essential for immune homeostasis. Genetic mutations causing haploinsufficiency (CTLA4h) lead to a phenotypically heterogenous, immune-mediated disease that can include neuroinflammation. The neurological manifestations of CTLA4h are poorly characterized.METHODS We performed an observational natural history study of 50 patients with CTLA4h who were followed at the NIH. We analyzed clinical, radiological, immunological, and histopathological data.RESULTS Evidence for neuroinflammation was observed in 32% (n = 16 of 50) of patients in this cohort by magnetic resonance imaging (MRI) and/or by cerebrospinal fluid analysis. Clinical symptoms were commonly absent or mild in severity, with headaches as the leading complaint (n = 13 of 16). The most striking findings were relapsing, large, contrast-enhancing focal lesions in the brain and spinal cord observed on MRI. We detected inflammation in the cerebrospinal fluid and leptomeninges before the parenchyma. Brain biopsies of inflammatory lesions from 10 patients showed perivascular and intraparenchymal mixed cellular infiltrates with little accompanying demyelination or neuronal injury.CONCLUSIONS Neuroinflammation due to CTLA4h is mediated primarily by an infiltrative process with a distinct and striking dissociation between clinical symptoms and radiological findings in the majority of patients.FUNDING NIAID, NIH, Division of Intramural Research, NINDS, NIH, Division of Intramural Research, and the National Multiple Sclerosis Society–American Brain Foundation.TRIAL REGISTRATION ClinicalTrials.gov NCT00001355.

Authors

Matthew K. Schindler, Stefania Pittaluga, Yoshimi Enose-Akahata, Helen C. Su, V. Koneti Rao, Amy Rump, Steven Jacobson, Irene Cortese, Daniel S. Reich, Gulbu Uzel

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Figure 5

CSF is inflamed in CTLA4h.

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CSF is inflamed in CTLA4h.
Flow cytometric data comparing patients with ...
Flow cytometric data comparing patients with CTLA4h with active neuroinflammatory lesions on MRI (black), a prior history of neuroinflammatory lesions (green), and no history of inflammatory lesions (orange) on MRI with a cohort of healthy controls (NDs, white circles). All graphs depict values from blood (left half of each panel) and CSF (right half). (A) Total frequency of CD4+ and CD8+ T cells within total lymphocyte counts and the ratio of CD4+ to CD8+ T cells. (B) Percentage of memory T cell subtypes (CD45RA–CD27+) in CD4+ T cells and CD8+ T cells, and memory Tfh cells (CD45RA–CXCR5+) in CD4+ T cells (right). (C) Frequency of total B cells and memory B cell subtypes, including unswitched memory (IgD+CD27+) and switched memory (IgD–CD27+) B cells. For all flow cytometric data, the Mann-Whitney U test was performed for comparisons between ND and CTLA4 cohorts, within each compartment (i.e., peripheral blood and CSF). Significance was set at P < 0.05. Each flow cytometric experiment for lymphocyte subsets from peripheral blood that was paired with a CSF sample obtained at the same time represents a single experiment, given the nature of the specimen (CSF obtained by LP) and the limited amount of specimen that could be obtained, as well as the sensitivity for the timing of the procedure according to the clinical status and the treatment course of the patient.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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