Cell(s) of Origin of Langerhans Cell Histiocytosis

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Key points

  • Dendritic cells (DCs) are immune cells that arise from different lineages with a shared function of presenting antigen and activating adaptive immunity.

  • Langerhans cell histiocytosis (LCH) arises from myeloid DC precursors. Mitogen-activated protein kinase (MAPK) activation is a universal feature of CD1a+ langerin+ LCH cells. The clinical extent of LCH is related to the stage of development in which somatic MAPK mutations arise, either self-renewing progenitors or committed precursors.

  • Activating

The Histiocytoses

The spectrum of histiocytic diseases is characterized by collections of abnormal histiocytes or, literally, tissue cells related to myeloid cells of the mononuclear phagocyte system (MPS).1, 2, 3, 4 LCH is defined by the presence of a large pale-staining histiocyte with high expression of CD1a and langerin (CD207) and containing Birbeck granules (Fig. 1). These features, shared with Langerhans cells (LCs) of the epidermis, are the basis of classifying the disease as an LCH. Prior to this, LCH

Langerhans Cell Histiocytosis: The Debate

The fundamental nature of LCH as neoplastic versus reactive disorder has been an ongoing debate.6, 9 The granulomatous histology with quiescent histiocytes suggested potential autoimmune or infectious etiology10 but the unique appearance of LCH cells and destructive nature of lesions hinted at dysplastic development. Although Nezelof and Basset11 described LCs as the stem cell of LCH, they also acknowledged the prevailing view that elements of the MPS, including LCs, were continually

Branches of dendritic cell differentiation

The insight of Nezelof and Basset32 identified commonality between LCs and LCH but by their own reckoning could not fully explain the histogenesis of LCH. The identification of MAPK pathway mutations provides a genetic neoplastic etiology and an important investigational tool with which to track potential LCH precursor cells. The problem of understanding exactly how potential LCH precursors differentiate abnormally remains, however, unsolved.

Lineage Tracing Langerhans Cell Histiocytosis

Somatic mutations in LCH have provided a foothold with which to study the cell of origin of LCH. As discussed previously, it is evident that LCH cells could arise from more than 1 source. In an attempt to more precisely identify candidate precursor populations, the authors asked whether the mutation encoding BRAF V600E was present in circulating mononuclear cells in patients with active LCH. In the authors’ series of 100 patients, peripheral blood mononuclear cells with the BRAF V600E point

Summary/future directions

LCH is a complex disease with a fascinating history. Individual reports of highly variable intriguing presentations merged into eponymous classifications that were later unified as histiocytosis X, due to common histology. Subsequently, LCH shifted focus to the aberrant development of LCs. New data support a model that once again deconstructs this single diagnosis into its many facets, each caused by a repertoire of mutations acting at multiple stages of myeloid cell development. The common

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  • Cited by (0)

    The Texas Children’s Cancer Center Histiocytosis Program (C.E. Allen and K.L. McClain) is supported by the HistioCure Foundation. Grant support includes NIH R01 (CA154489) (C.E. Allen and K.L. McClain), NIH SPORE in Lymphoma (P50CA126752) (C.E. Allen), and the St. Baldrick’s Consortium Grant for the North American Consortium for Histiocytosis Research (C.E. Allen and K.L. McClain). M. Collin is supported by the Histiocytosis Research Trust (UK), the Leventis Foundation, and the Histiocytosis Association. V. Bigley is a Wellcome Trust Intermediate Fellow (WT088555MA).

    The authors have no conflicting financial interests.

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