What is the pathophysiology of Langerhans cell histiocytosis (LCH)?

Updated: Jun 12, 2020
  • Author: Christopher R Shea, MD; Chief Editor: William D James, MD  more...
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The pathogenesis of Langerhans cell histiocytosis (LCH) is unknown. It has been debated whether LCH is a reactive or neoplastic process, although the latter is now more commonly accepted. Arguments supporting the reactive nature of LCH include the occurrence of spontaneous remissions, the extensive elaboration of multiple cytokines by dendritic cells and T-cells (the so-called cytokine storm) in LCH lesions, and the good survival rate in patients without organ dysfunction. [6] Furthermore, a rigorous investigation of potential chromosomal aberrations in LCH via analysis of ploidy, karyotype, single-nucleotide polymorphism arrays, and array-based comparative genomic hybridization did not reveal consistent abnormalities; these findings were considered to support the idea of LCH as a reactive process. [7]

On the other hand, the infiltration of organs by a monoclonal population of aberrant cells, the possibility of lethal evolution, and the cancer-based modalities of successful treatment are all consistent with a neoplastic process. [8, 9] In addition, the demonstration, by use of X chromosome–linked DNA probes, of LCH as a monoclonal proliferation supports a neoplastic origin for this proliferation; however, the presence of this finding in distinct subtypes with different evolutions demands further investigations to elucidate its significance. A breakthrough was made when genomic studies demonstrated activating, somatic BRAF V600E mutations in approximately half of human specimens. The mutation was also found in CD34+ hematopoietic cell progenitors and mature dendritic cells of patients, with mouse models, demonstrating that BRAF V600E mutation is sufficient to develop an LCH phenotype. [10] Other studies found mutations in MAPK, with both BRAF and MAPK acting through a common MEK/ERK pathway. [11, 12] These studies further supported the concept of LCH as a myeloid neoplasm.

A 2010 study comparing gene expression of cells expressing CD207 (a marker of Langerhans cells) in LCH lesions with epidermal CD207+ control cells identified differential expression of more than 2000 genes between these 2 subsets. These differences were found in genes involved in cell cycle regulation, apoptosis, cell signaling, metastasis, and myeloid differentiation. [13] Interestingly, this analysis found no differences in expression of proliferation markers between these subsets of CD207+ cells, consistent with the hypothesis that LCH may be a disease of abnormal cellular accumulation.

The extensive variability in gene expression between these 2 cellular populations has prompted speculation that LCH cells develop from a population of cells distinct from epidermal Langerhans cells. Specifically, it is hypothesized that "misguided" blood-derived myeloid dendritic cells are recruited to specific anatomic sites and their subsequent stimulation of T-cell trafficking and local immunomodulation is responsible for the characteristic lesions of LCH. [13]

Evidence suggests a role for immune dysfunction in the pathogenesis of LCH, through the creation of a permissive immunosurveillance system. Specifically, findings from immunohistochemical and immunofluorescence analyses of LCH biopsy specimens have led to the hypothesis that semimature LCH cells stimulate the expansion of a polyclonal population of regulatory T cells. These regulatory T cells may, in turn, inhibit the immune system (in part via the elaboration of interleukin (IL)–10 and prevent it from effectively resolving LCH lesions. [14] These T cells generate transforming growth factor-β, but do not produce inflammatory cytokines. [12] In active LCH patients, the increase in regulatory T cells in active lesions is accompanied by the decrease of CD8+CD56+ T cells elsewhere in the blood. [12] These findings support that regulatory T cells may, in turn, inhibit the immune system and prevent it from effectively resolving LCH lesions.

Detection of high serum levels of the proinflammatory cytokine IL-17A in patients with LCH has given rise to speculation that IL-17A is also involved in the pathogenesis of the disease. Further investigation into this phenomenon has led to the proposal that IL-17A induces dendritic cell/Langerhans cell fusion into multinucleated giant cells that in turn recruit other inflammatory cells and cause local tissue destruction, creating the characteristic lesions of LCH. [15] However, these findings have not been independently reproduced, and the role of IL-17A in the pathogenesis of LCH remains controversial. [16]

Some studies have also indicated that expression of vascular endothelial growth factor (VEGF); Bcl-2 family proteins; and FADD, FLICE, and FLIP proteins in the Fas signaling pathway may be involved in the pathogenesis of LCH. [17, 18, 19] The E-cadherin-beta-catenin-Wnt signaling pathway has also been implicated in LCH, and down-regulation of E-cadherin may be associated with disease dissemination. [3, 20]  More recently, the expression of CSF1 receptor has been found to be essential in the differentiation and migration of Langerhans cells. [21]

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