Erdheim-Chester disease: An in vivo human model of Mϕ activation at the crossroad between chronic inflammation and cancer

Abstract

Erdheim-Chester disease (ECD) is a rare histiocytosis characterized by infiltration of multiple tissues by CD68 + foamy M s (or 'histiocytes'). Clinical manifestations arise from mass-forming lesions or from tissue and systemic inflammation. ECD histiocytes harbor oncogenic mutations along the MAPK-kinase signaling pathway (BRAF V600E in more than half of the patients), and secrete abundant pro-inflammatory cytokines and chemokines. Based on these features, ECD is considered an inflammatory myeloid neoplasm, and is accordingly managed with targeted kinase inhibitors or immunosuppressive and cytokine-blocking agents. Evidence is emerging that maladaptive metabolic changes, particularly up-regulated glycolysis, represent an additional, mutation-driven feature of ECD histiocytes, which sustains deregulated and protracted proinflammatory activation and cytokine production. Besides translational relevance to the management of ECD patients and to the development of new therapeutic approaches, recognition of ECD as a natural human model of chronic, maladaptive M activation instructs the understanding of M dysfunction in other chronic inflammatory conditions.

Identification and characterization of stromal-like cells with CD207+/low CD1a+/low phenotype derived from histiocytic lesions – a perspective in vitro model for drug testing

“…Moreover, its expression was upregulated during different histiocytoses, e.g. LCH [ 18 , 42 ] and Erdheim-Chester disease [ 43 ]. Additionally, the mesenchymal stromal cells (MSCs) themselves are also capable of expressing HLA DR [ 44 , 45 ].…”

A Patient With Erdheim-Chester Disease Presenting With Intestinal Obstruction as the Initial Symptom: A Case Report

“…( 1 ) reported that ECD histiocytes harbor oncogenic mutations in genes involved in the MAPK, signaling pathway (BRAF V600E in more than half of the patients) and secrete abundant proinflammatory cytokines, such as interleukin (IL)-1, IL-6, and TNF-α, as well as chemokines. Based on these features, ECD is considered an inflammatory myeloid neoplasm ( 1 , 6 ). In recent years, ECD was added to the classification of histiocytic and dendritic cell neoplasms ( 7 ).…”

“…Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis. ECD is considered an inflammatory myeloid neoplasm whose pathogenesis is related to BRAF V600E mutation or other mutations in the MAPK pathway ( 1 ). It is a multisystem disease involving all organs, and intestinal involvement is even rarer.…”

3D Models as a Tool to Assess the Anti-Tumor Efficacy of Therapeutic Antibodies: Advantages and Limitations

“…The system was suitable to investigate the impact of drugs, including therapeutic mAbs. Specifically, 3D cultures of tissue biopsies derived from patients affected by Erdheim Chester Disease (ECD), a rare inflammatory myeloid neoplasm driven by MAPK mutations (particularly the BRAF V600E mutation) [ 107 , 108 ], allowed to unveil immune-metabolic mechanisms underlying disease pathogenesis and to compare the efficacy of IFX versus the specific BRAF-inhibitor vemurafenib in dampening inflammation [ 103 ]. Culture in bioreactor of fresh tissue explants (organotypic culture) allows assessment of the dynamic evolution of tumor angiogenesis through serial sampling followed by histological and image analysis of tumor features (e.g., nuclei, stroma and angiogenic CD34 + vessels).…”