Work

Defining the role of mutant dendritic cells in pulmonary langerhans cell histiocytosis 2962

Year: 2025

Type: article

Abstract: Description PLCH occurs almost exclusively in cigarette smokers with a median duration of survival of 12.5 years. PLCH is characterized by bronchiolocentric histiocyte accumulation, inflammatory lesions, nodule formation, and cystic remodeling. A causative link between acquired BRAF kinase mutations in the myeloid/monocyte lineage and the development of neoplasms has been reported, and a common mutation in BRAF (V600E) was found in lung lesions of > 50% of PLCH patients. Although this causal link represents an important breakthrough, the mechanisms by which mutant histiocytes control the initiation and progression of PLCH are unknown. To address this critical gap, we previously developed a novel preclinical model that recapitulates hallmark features of PLCH. We showed that cigarette smoke (CS) exposure of mice expressing an inducible CD11c cre driven BRAFV600E mutation exhibit peribronchiolar inflammation, neoplasm formation, and airspace enlargement accompanied by cyst-like formations. These structural changes are accompanied by alterations in dendritic cell (DC) homeostasis, including increased expression of and responsiveness to CCL20, and the production of CCL7. Based on these findings, we hypothesize that PLCH pathogenesis is driven by a combination of RAS pathway mutations along with CS exposure to amplify CCL20 driven histiocyte accumulation and recruitment of inflammatory cells via CCL7. We are developing BMDCs expressing mutant BRAF to further investigate their role in PLCH. Funding Sources Funded by support from the NIH (HL162662, HL119538, U54HL127672, F31CA284547) and the Veterans Administration (I01BX002347). Other support and resources provided by the Center for Environmental Genetics (NIH/National Institute of Environmental Health Sciences, P30 ES006096), and the Center for Clinical and Translational Science and Training (NIH, 5UL1TR001425). Topic Categories Immune Mechanisms of Human Disease (HUM)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkaf283.816

Authors: Joey Emery Breckenridge, Huan Liu, Andrew Osterburg, Nick Balzarini, Michael Borchers

Institutions: Cincinnati Children's Hospital Medical Center, University of Cincinnati

Language: English

Topic: Histiocytic Disorders and Treatments

Subfield: Physiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: bronze

OpenAlex ID: W4416447140