Dysfunctional B cell and interferon signaling in autoimmune polyendocrine syndrome type 1

Abstract Purpose: Autoimmune polyendocrine syndrome type I (APS-1) is a devastating autoimmune disease characterised by mutations in the AIRE gene. Because of failure of negative selection, these patients produce autoreactive B and T cells against affected tissues, which lead to a range of autoimmune manifestations. The rarity of APS-1 and inaccessibility of thymic tissue have limited immunological studies. We here hypothesized that lack of AIRE expression in thymus affect immune cells in blood. Methods: Whole blood microarray analysis (N=16 APS-I patients vs 16 controls) and qPCR of molecules in affected pathways. Single cell sequencing of naïve B cells and flow cytometry analysis of a B cell panel in PBMCs to investigate properties of B cells in APS-I patients compared to age and sex matched healthy controls. Results: We here show significant downregulation of B cell and IFN-I responses in APS-I patients compared to healthy donors in microarray and system biology deconvolution experiments. Single B cell transcriptomics support downregulation of several of the same molecules including CD74, CD40 and CD79A. Flow cytometry protein experiments revealed an imbalance of plasma (higher) vs transitional B cells (lower) in APS-I patients, followed up by a lower level of CD79b within transitional B cells in patients, but a non-consistent higher level of CD74 within this subset. Conclusion: We found disturbances in blood immune cell subsets from APS-I patients. Harmonious lower blood cell levels of the B-cell associated CD79A/B were found compared to healthy controls, but further studies are needed to verify the consistency of our findings.