Dysregulated B cell function in Ataxia-telangiectasia patients with IgA deficiency

Background Patients with Ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. Deficiencies in both, cellular and humoral immunity, including IgA deficiency caused by a disturbed B- and T cell homeostasis have been described. Overall survival of patients with IgA deficiency is significantly diminished. The aim of this study was to elucidate the epigenetic dysregulation in B cell function in A-T patients with IgA deficiency and the background of abnormal B-cell function in patients with IgA deficiency by mimicking the germline center environment.

Methods In well-characterized A-T patients, B cell differentiation and isotype switching as well as B cell receptor signaling was analyzed by flow cytometry and ELISA techniques in the CD40 cell culture system. miRNA expression in the peripheral blood of patients was examined by NGS and differential gene expression in B cells was examined by RT² Profiler PCR Array. The evaluation of the biological targets of the miRNAs was performed by pathway enrichment analysis and protein-protein interaction network analysis.

Results A-T patients with IgA deficiency (IgA-D) exhibited significantly decreased naïve B cell numbers, increased non-switched memory B cells and switched memory B cells compared to patients with normal IgA (nIgA). No isotype switching to IgA+B cells or IgA release could be detected. In IgA-D patients B cell genes such as IL11, CCR2, IL11, TNFSF14, CD40, CD8B, NOS2 and IL-13 were differently expressed on the transcriptional level. NGS and KEGG pathway analysis identified significantly dysregulated miR-181b-5p which is involved in the p53 pathway and targeting ATM. Further, NGS revealed eight miRNAs which were differently expressed between IgA-D and nIgA patients and involved in the B cell receptor pathway. SYK, RAS and AKT are predicted targets of these miRNAs and are strongly associated within a protein-protein interaction network in BCR signaling.

Conclusion This study demonstrates an intrinsic defect in B cells from A-T patients with IgA deficiency. NGS analysis further showed an aberrant miRNA expression profile impacting the B cell receptor signaling in A-T patients with IgA deficiency. The identified targets might be a promising approach to further elucidate the B cell intrinsic defect that underlie this special phenotype. However, further experiments are needed to validate these miRNAs and their predicted targets.

V-01f | Seltene Erkrankungen

8:30 – 10:00

SH 0.101

Publication History

Article published online:
09 March 2023