New insights into the molecular pathogenesis of langerhans cell histiocytosis

Abstract

Langerhans cell histiocytosis (LCH) is a rare proliferative disorder characterized by an accumulation of cells sharing the major phenotypic features of cutaneous Langerhans cells. Given its variable clinical evolution, ranging from self-limiting lesions to multisystemic forms with a poor prognosis, in the last decades it has been debated whether LCH might not have a neoplastic rather than an inflammatory nature. However, although the fundamental events underlying the pathogenesis of LCH are still elusive, recent advances have strikingly improved our understanding of the disease. In particular, the identification of multiple interplays between LCH cells and their tumor microenvironment, along with the recognition of the lesional cytokine storm as a key determinant of LCH progression, has substantiated new opportunities for devising targeted therapeutic approaches. Strikingly, the detection of the rapidly accelerated fibrosarcoma isoform B(V600E) gain-of-function mutation as a genetic alteration recurring in more than 50% of patients has fueled the paradoxical picture of LCH as a tumor of the antigen-presenting cells that can evade rejection by the immune system. Thus, new evidence regarding the ontogeny of LCH cells, as well as a better understanding of the putative immune system frustrating strategy in LCH, may help to define the precise pathogenesis.

Keywords: BRAF kinases; Bone marrow; Cancer microenvironment; Interleukin-17; Langerhans cell histiocytosis; Vemurafenib.

Figure 1.

Development of monocytes, macrophages, and dendritic cells. In the bone marrow, hematopoietic stem cells produce myeloid and lymphoid precursors. Myeloid precursors give rise to monocytes/macrophages and dendritic cell (DC) progenitors that in turn generate monocytes and common DC precursors. DC precursors give rise to preclassical dendritic cells that circulate in the blood and enter lymphoid tissues as classical dendritic cells and nonlymphoid tissues as mucosal DCs in the lamina propria. Epidermal Langerhans cells replicate in situ and are independent from the bone marrow because they derive from an embryonic precursor invading the epidermis before birth and subsequently proliferate in situ to create a pool of Langerhans cells. Monocytes derived from monocytes/macrophages and dendritic cell progenitors give rise to macrophages, both in a steady state and during infection, and inflammatory monocyte-derived DCs. A contribution of lymphoid precursors to DC development cannot be excluded in view of their intrinsic myeloid potential (dashed line). Abbreviations: cDC, classical dendritic cell; CDP, common dendritic cell precursor; DCP, dendritic cell precursor; HSC, hematopoietic stem cell; LCs, Langerhans cells; LP, lymphoid precursor; lpDCs, dendritic cells in the lamina propria; MØ, macrophage; MDP, monocytes/macrophages and dendritic cell progenitors; moDCs, monocyte-derived dendritic cells; MP, myeloid precursor; Pre-c DC, preclassical dendritic cell.

Figure 2.

IL-10 prevents maturation of Langerhans cell histiocytosis (LCH) cells. LCH cells express CD40 at higher levels than normal Langerhans cells. When cocultured with CD40L-transfected fibroblasts, they become mature cells and express high levels of membrane MHC class II molecules that link antigens presented by T cells through both T-cell receptor and CD86, the costimulatory molecule binding CD28 for full activation. IL-10 produced by intralesional macrophages downregulates the expression of both molecules on the surface of LCH cells. Abbreviations: IL10, interleukin 10; iLCH, immature Langerhans cell histiocytosis; MØ, macrophage; MHCII, major histocompatibility complex II; mLCH, mature Langerhans cell histiocytosis; T-reg, regulatory T cells; TCR, T-cell receptor; TH, T helper.

Figure 3.

The BRAF^V600E mutated protein and its pathogenic role in LCH. (A): In normal LCs, the binding of ligands such as hormones, cytokines, and growth factors to the cell-surface RTK leads to dimerization and autophosphorylation. Activation of RTK induces formation of the active RAS-GTP complex, which binds and activates BRAF that, in turn, triggers the phosphorylation of both MEK and ERK. By altering the levels and activities of nuclear trascription factors, ERK drives the transcription of genes involved in cell survival, proliferation, motility, and differentiation. (B): In LCH, the BRAF^V600E mutated gene constitutively activates the MEK-ERK pathway that reinforces cell survival, proliferation, motility, and differentiation. (C): In normal melanocytes, the expression of a BRAF^V600E mutated protein can lead to senescence after an initial phase of naevus growth, as confirmed by the intense activity of the stress marker SA-β-Gal and the increased levels of the tumor suppressor p16^INK4a. Abbreviations: BRAF, rapidly accelerated fibrosarcoma isoform B; ERK, extracellular signal-regulated kinase; LC, Langerhans cell; LCH, Langerhans cell histiocytosis; MEK, mitogen-activated protein kinase kinase; RAS, Rat Sarcoma; RTK, receptor tyrosine kinase.

Figure 4.

The cytokine storm: possible interplays with the LCH microenvironment. The LCH microenvironment plays a critical role in the disease progression, both by inducing a local state of immune system frustration and by enhancing the proliferation of pathological LCH cells. Arrows indicate stimulating effects, whereas lines designate inhibitory effects. Abbreviations: CAT K, cathepsin K; Eo, eosinophils; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; LCH, Langerhans cell histiocytosis; MØ, macrophage; MØ M2, macrophages M2 phenotype; M-CSF, macrophage colony-stimulating factor; MGC, multinucleated giant cell; MMP, metalloproteinases; T reg, T regulatory cell; TGF, transforming growth factor; Th17, T helper 17; TNF, tumor necrosis factor; TRAP, tartrate resistant acid phosphatase; VNR, vitronectin receptor.