Search

The formation of mammalian dendritic cells (DCs) is controlled by multiple hematopoietic transcription factors, including IRF8. Loss of IRF8 exerts a differential effect on DC subsets, including plasmacytoid DCs (pDCs) and the classical DC lineages cDC1 and cDC2. In humans, cDC2-related subsets have been described including AXL + SIGLEC6 + pre-DC, DC2 and DC3. The origin of this heterogeneity is unknown. Using high-dimensional analysis, in vitro differentiation, and an allelic series of human IRF8 deficiency, we demonstrated that cDC2 (CD1c + DC) heterogeneity originates from two distinct pathways of development. The lymphoid-primed IRF8 hi pathway, marked by CD123 and BTLA, carried pDC, cDC1, and DC2 trajectories, while the common myeloid IRF8 lo pathway, expressing SIRPA, formed DC3s and monocytes. We traced distinct trajectories through the granulocyte-macrophage progenitor (GMP) compartment showing that AXL + SIGLEC6 + pre-DCs mapped exclusively to the DC2 pathway. In keeping with their lower requirement for IRF8, DC3s expand to replace DC2s in human partial IRF8 deficiency., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Erdheim‐Chester disease (ECD) is rare histiocytosis with a wide range of clinical manifestations. Somatic mutations are key to the pathogenesis of the disease; however, the relationship between germline genetic variants and ECD has not been examined so far. The present study aims to explore the inherited genetic component of ECD by performing the first genome‐wide association study. Methods: After quality controls, a cohort of 255 patients with ECD and 7,471 healthy donors was included in this study. Afterward, a logistic regression followed by in silico functional annotation was performed. Results: A signal at the 18q12.3 genomic region was identified as a new susceptibility locus for ECD (P = 2.75 × 10−11; Odds Ratio = 2.09). This association was annotated to the SETBP1 gene, which is involved in clonal haematopoiesis. Functional annotation of this region and of the identified suggestive signals revealed additional genes that could be potentially involved in the pathogenesis of the disease. Conclusion: Overall, this work demonstrates that germline genetic variants can impact on the development of ECD and suggests new pathways with a potential pathogenic role. [ABSTRACT FROM AUTHOR]