Pathological Consequence of Misguided Dendritic Cell Differentiation in Histiocytic Diseases

Abstract

Histiocytic disorders represent a group of complex pathologies characterized by the accumulation of histiocytes, an old term for tissue-resident macrophages and dendritic cells. Langerhans cell histiocytosis is the most frequent of histiocytosis in humans and has been thought to arise from the abnormal accumulation of epidermal dendritic cells called Langerhans cells. In this chapter, we discuss the origin and differentiation of Langerhans cells and dendritic cells and present accumulated evidence that suggests that Langerhans cell histiocytosis does not result from abnormal Langerhans cell homeostasis but rather is a consequence of misguided differentiation programs of myeloid dendritic cell precursors. We propose reclassification of Langerhans cell histiocytosis, juvenile xanthogranuloma, and Erdheim–Chester disease as inflammatory myeloid neoplasias.

Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis

“…5,38,39 Similarly, JXG has been associated with neurofibromatosis and juvenile myelomonocytic leukemia, diseases defined by MAPK hyperactivity, as was observed in a case in this series (reviewed in Berres et al 9 ). The increasingly frequent recognition of patients with lesions with distinct phenotypes (ECD in bone lesion and LCH in skin, for example) or with mixed LCH/JXG phenotype in a single lesion supports a common cell of origin with potential to differentiate into a range of terminal phenotypes.…”

“…A model is emerging in which clinical manifestations may be defined by both the specific mutation as well as the cell in which an ERK-activating genetic lesion arises. 9 We previously observed that BRAFV600E confers a relative increase in risk of initial treatment failure using current therapies 1 (note that most LCH patients were analyzed in both studies). Although the relatively small number of patients with MAP2K1 mutations, retrospective data collection, and heterogeneous patient population and treatment history limit the ability to generalize these findings, a novel observation in this cohort is the lack of increase in risk in initial treatment failure associated with MAP2K1 mutations compared with the aggregate, but a relative decrease in risk compared with BRAF-V600E ( Figure 5B).…”

“…The high frequency of BRAF mutations in LCH, the presence of the mutation in myelomonocytic precursors in patients with high-risk LCH, and the ability of enforced expression of BRAFV600E in mice to recapitulate an LCH-like phenotype support a model in which LCH is a myeloid neoplasm that arises as the result of MAPK pathway activation at critical stages in myeloid differentiation. 4,9 However, the mechanisms by which BRAF hyperactivation drives LCH pathogenesis remain to be established.…”

How I treat Langerhans cell histiocytosis

“…9 However, the origin of LCH cells from the epidermal LC lineage has recently been challenged. Langerin expression is more widespread than previously appreciated: blood-derived CD207…”

Association of both Langerhans cell histiocytosis and Erdheim-Chester disease linked to the BRAFV600E mutation

“…[3][4][5][6][7] The cells involved are either dendritic cells or macrophages, and they can be characterized by immunohistochemical methods with CD1a and PS100 antibodies. 3,7 In LCH, tissues are infiltrated by CD1a 1…”