High-content cytometry and transcriptomic biomarker profiling of human B-cell activation - 25/12/13
, Claudia Ilginus a, Kaan Boztug, MD b, c, d, Julia Skokowa, PhD e, Laszlo Marodi, MD f, Anna Szaflarska, MD g, Mareike Sass b, Claudio Pignata, MD h, Sara Sebnem Kilic, MD i, Isabel Caragol, MD j, Ulrich Baumann, MD a, Christoph Klein, MD b, k, Karl Welte, MD e, Gesine Hansen, MD a, ∗Abstract |
Background |
Primary antibody deficiencies represent the most prevalent, although very heterogeneous, group of inborn immunodeficiencies, with a puzzling complexity of cellular and molecular processes involved in disease pathogenesis.
Objective |
We aimed to study in detail the kinetics of CD40 ligand/IL-21–induced B-cell differentiation to define new biomarker sets for further research into primary antibody deficiencies.
Methods |
We applied high-content screening methods to monitor B-cell activation on the cellular (chip cytometry) and transcriptomic (RNA microarray) levels.
Results |
The complete activation process, including stepwise changes in protein and RNA expression patterns, entry into the cell cycle, proliferation and expression of activation-induced cytidine deaminase (AID), DNA repair enzymes, and post–class-switch expression of IgA and IgG, was successfully monitored during in vitro differentiation. We identified a number of unknown pathways engaged during B-cell activation, such as CXCL9/CXCL10 secretion by B cells. Finally, we evaluated a deduced set of biomarkers on a group of 18 patients with putative or proved intrinsic B-cell defects recruited from the European Society for Immunodeficiencies database and successfully predicted 2 AID defects and 1 DNA repair defect. Complete absence of class-switched B cells was a sensitive predictor of AID deficiency and should be further evaluated as a diagnostic biomarker.
Conclusion |
The biomarkers found in this study could be used to further study the complex process of B-cell activation and to understand conditions that lead to the development of primary antibody deficiencies.
Le texte complet de cet article est disponible en PDF.Key words : Primary immunodeficiency, primary antibody deficiency, B-cell immunology, chip cytometry
Abbreviations used : AID, CD40L, CSR, CVID, MACS, PID
Plan
| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 133 - N° 1
P. 172 - janvier 2014 Retour au numéro
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