Dysregulated PI3K Signaling in B Cells of CVID Patients

Harder, Ina; Münchhalfen, Matthias; Andrieux, Geoffroy; Boerries, Melanie; Grimbacher, Bodo; Eibel, Hermann; Maccari, Maria Elena; Ehl, Stephan; Wienands, Jürgen; Jellusova, Julia; Warnatz, Klaus; Keller, Baerbel

doi:10.3390/cells11030464

Open AccessArticle

Dysregulated PI3K Signaling in B Cells of CVID Patients

by

Ina Harder

^1,2,

Matthias Münchhalfen

³

,

Geoffroy Andrieux

⁴

,

Melanie Boerries

^4,5,

Bodo Grimbacher

^6,7,8,9,10,

Hermann Eibel

^1,2,

Maria Elena Maccari

^6,11

,

Stephan Ehl

⁶

,

Jürgen Wienands

³

,

Julia Jellusova

^12,13,

Klaus Warnatz

^1,2,* and

Baerbel Keller

^1,2,*

¹

Department of Rheumatology and Clinical Immunology, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

²

Center for Chronic Immunodeficiency (CCI), Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

³

Institute of Cellular and Molecular Immunology, University Medical Center Göttingen, Göttingen, Germany

⁴

Institute of Medical Bioinformatics and Systems Medicine, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

⁵

German Cancer Consortium (DKTK), Partner site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany

⁶

Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg, Germany

⁷

Clinic of Rheumatology and Clinical Immunology, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg, Germany

⁸

DZIF—German Center for Infection Research, Satellite Center Freiburg, Freiburg, Germany

⁹

CIBSS—Centre for Integrative Biological Signalling Studies, Albert-Ludwigs University, Freiburg, Germany

¹⁰

RESIST—Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Freiburg, Germany

¹¹

Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

¹²

Institute of Clinical Chemistry and Pathobiochemistry, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, 81675 Munich, Germany

¹³

TranslaTUM, Center for Translational Cancer Research, Technical University of Munich, 81675 Munich, Germany

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Cells 2022, 11(3), 464; https://doi.org/10.3390/cells11030464

Submission received: 16 December 2021 / Revised: 24 January 2022 / Accepted: 26 January 2022 / Published: 28 January 2022

(This article belongs to the Special Issue B Cell Signaling and Activation in Autoimmunity)

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Abstract

The altered wiring of signaling pathways downstream of antigen receptors of T and B cells contributes to the dysregulation of the adaptive immune system, potentially causing immunodeficiency and autoimmunity. In humans, the investigation of such complex systems benefits from nature’s experiments in patients with genetically defined primary immunodeficiencies. Disturbed B-cell receptor (BCR) signaling in a subgroup of common variable immunodeficiency (CVID) patients with immune dysregulation and expanded T-bet^highCD21^low B cells in peripheral blood has been previously reported. Here, we investigate PI3K signaling and its targets as crucial regulators of survival, proliferation and metabolism by intracellular flow cytometry, imaging flow cytometry and RNAseq. We observed increased basal but disturbed BCR-induced PI3K signaling, especially in T-bet^highCD21^low B cells from CVID patients, translating into impaired activation of crucial downstream molecules and affecting proliferation, survival and the metabolic profile. In contrast to CVID, increased basal activity of PI3K in patients with a gain-of-function mutation in PIK3CD and activated PI3K delta syndrome (APDS) did not result in impaired BCR-induced AKT-mTOR-S6 phosphorylation, highlighting that signaling defects in B cells in CVID and APDS patients are fundamentally different and that assessing responses to BCR stimulation is an appropriate confirmative diagnostic test for APDS. The active PI3K signaling in vivo may render autoreactive T-bet^highCD21^low B cells in CVID at the same time to be more sensitive to mTOR or PI3K inhibition.

Keywords: CVID; B cells; immune dysregulation; PI3K; mTOR; S6; FOXO1; BCR signaling; CD21^low B cells; APDS

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MDPI and ACS Style

Harder, I.; Münchhalfen, M.; Andrieux, G.; Boerries, M.; Grimbacher, B.; Eibel, H.; Maccari, M.E.; Ehl, S.; Wienands, J.; Jellusova, J.; et al. Dysregulated PI3K Signaling in B Cells of CVID Patients. Cells 2022, 11, 464. https://doi.org/10.3390/cells11030464

AMA Style

Harder I, Münchhalfen M, Andrieux G, Boerries M, Grimbacher B, Eibel H, Maccari ME, Ehl S, Wienands J, Jellusova J, et al. Dysregulated PI3K Signaling in B Cells of CVID Patients. Cells. 2022; 11(3):464. https://doi.org/10.3390/cells11030464

Chicago/Turabian Style

Harder, Ina, Matthias Münchhalfen, Geoffroy Andrieux, Melanie Boerries, Bodo Grimbacher, Hermann Eibel, Maria Elena Maccari, Stephan Ehl, Jürgen Wienands, Julia Jellusova, and et al. 2022. "Dysregulated PI3K Signaling in B Cells of CVID Patients" Cells 11, no. 3: 464. https://doi.org/10.3390/cells11030464

APA Style

Harder, I., Münchhalfen, M., Andrieux, G., Boerries, M., Grimbacher, B., Eibel, H., Maccari, M. E., Ehl, S., Wienands, J., Jellusova, J., Warnatz, K., & Keller, B. (2022). Dysregulated PI3K Signaling in B Cells of CVID Patients. Cells, 11(3), 464. https://doi.org/10.3390/cells11030464

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Dysregulated PI3K Signaling in B Cells of CVID Patients

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