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22q11.2 Deletion-Associated Blood-Brain Barrier Permeability Potentiates Systemic Capillary Leak Syndrome Neurologic Features

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Abstract

We present a case study of a young male with a history of 22q11.2 deletion syndrome (22qDS), diagnosed with systemic capillary leak syndrome (SCLS) who presented with acute onset of diffuse anasarca and sub-comatose obtundation. We hypothesized that his co-presentation of neurological sequelae might be due to blood-brain barrier (BBB) susceptibility conferred by the 22q11.2 deletion, a phenotype that we have previously identified in 22qDS. Using pre- and post-intravenous immunoglobulins (IVIG) patient serum, we studied circulating biomarkers of inflammation and assessed the potential susceptibility of the 22qDS BBB. We employed in vitro cultures of differentiated BBB-like endothelial cells derived from a 22qDS patient and a healthy control. We found evidence of peripheral inflammation and increased serum lipopolysaccharide (LPS) alongside endothelial cells in circulation. We report that the patient’s serum significantly impairs barrier function of the 22qDS BBB compared to control. Only two other cases of pediatric SCLS with neurologic symptoms have been reported, and genetic risk factors have been suggested in both instances. As the third case to be reported, our findings are consistent with the hypothesis that genetic susceptibility of the BBB conferred by genes such as claudin-5 deleted in the 22q11.2 region promoted neurologic involvement during SCLS in this patient.

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Data Availability

The raw data supporting the conclusions of this study will be made available by the authors, without undue reservation, to any qualified researcher.

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Acknowledgements

We thank Dr. Amit Bar-Or’s lab for sharing access to their LSR Fortessa, as well as the University of Pennsylvania Cytomics and Cell Sorting Resource Laboratory for their maintenance of the machines. We appreciate the generosity of Dr. Mark Khan’s lab for sharing their ECIS measurement device. We thank the support of the Immune Dysregulation Program at CHOP and appreciate the doctors, nurses, and staff at CHOP who aided in caring for the patient described here and taking samples for study. Lastly, we want to thank the patient and his family, as well as the control donor.

Funding

The has supported this work by the following grants: Uytengsu-Hamilton 22q11 Neuropsychiatry Research Program of the Maternal and Child Health Research Institute (MCHRI) at Stanford University, grant UH22QEXTFY22-03 (JIA), NIH MH134797-01 (JIA), NIH MH110185-03 and MH066912 (SA), and Jeffrey Modell Foundation (NR). AMC held a scholarship from the Blavatnik Family Foundation. HK held a fellowship from the Multiple Sclerosis Society of Canada (MSSC).

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Authors and Affiliations

  1. Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, 380 South University Avenue, 412 Hill, Philadelphia, PA, 19104-4539, USA

    Alexis M. Crockett, Hania Kebir & Jorge I. Alvarez

  2. Department of Child and Adolescent Psychiatry, Children’s Hospital of Philadelphia, Philadelphia, USA

    Stewart A. Anderson

  3. Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA

    Stewart A. Anderson

  4. Division of Immunology and Allergy, Children’s Hospital of Philadelphia, Philadelphia, USA

    Soma Jyonouchi & Neil Romberg

  5. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA

    Soma Jyonouchi & Neil Romberg

  6. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA

    Neil Romberg & Jorge I. Alvarez

Authors
  1. Alexis M. Crockett
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  2. Hania Kebir
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  3. Stewart A. Anderson
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  4. Soma Jyonouchi
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  5. Neil Romberg
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  6. Jorge I. Alvarez
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Contributions

AMC and HK: Carried out the experiments. AMC and JIA: Drafted the initial manuscript. NR and SJ: Provided clinical care. SA: Provided reagents and supervision to iPSC assays. JIA: supervised the study. All authors: Revised the manuscript critically for important intellectual content.

Corresponding author

Correspondence to Jorge I. Alvarez.

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Ethics Approval and Consent to Participate

Consent from the next of kin was obtained for the case presented here under a human subject’s protocol approved by the Children’s Hospital of Philadelphia (CHOP).

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The subject and his family were provided the opportunity to review the case report prior to submission and provided assent/consent for this work to be published.

Conflicts of Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Crockett, A.M., Kebir, H., Anderson, S.A. et al. 22q11.2 Deletion-Associated Blood-Brain Barrier Permeability Potentiates Systemic Capillary Leak Syndrome Neurologic Features. J Clin Immunol 44, 87 (2024). https://doi.org/10.1007/s10875-024-01686-w

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