Dendritic Cell Disorders: Matters of Lineage and Clinical Drug Testing in Rare Diseases

It is often said that lineage means everything. Whether born to royalty or rags, lineage affects the lives of people. Lineage also matters in terms of cells and the mutations they acquire during their journey to neoplasia. Those cells that populate the mononuclear phagocytic system are no exception. Identification of the lineage origins of dendritic cells begins with their close relatives, the macrophages and monocytes, on the basis of the simple but seminal observations in Metchnikov’s descriptions in the latter part of the 19th century, of the tissue remodeling and phagocytic function of these cells. The earliest descriptions of epidermal dendritic cells by the then medical student Paul Langerhans, also in the second half of the 19th century, provided more members to this cellular family. Although Langerhans considered these cells with branching extensions (from which they acquired their name, dendrites, from the Greek) to be of neuronal origin, the true nature of their function would not be revealed for more than a century. The description of the function of these key cellular regulators of tissue remodeling and host defense established their central role in what Aschoff called the reticuloendothelial system. Although a myriad of different cell types has been included in this family of immune orchestrators, multiple studies have elegantly helped to define their embryonic and tissue origins. Such studies have demonstrated that fetal yolk sack progenitors (macrophages) give rise to epidermal Langerhans cells that in turn self-renew independently of bone marrow– derived hematopoiesis. In contrast, fetal liver and, later, bone marrow progenitors give rise to blood monocytes, tissue macrophages, and dermal dendritic cells. Under special physiologic circumstances, such as inflammatory conditions, many of these proprietary rules of lineage break down to allow for the replacement of these key cell types. Significant advances and some roadblocks have arisen from the work to define the immune functions, origins, and phenotypic characteristics of cells that comprise the reticuloendothelial system. In retrospect, this is what we might expect from these immunologic cell chameleons. The importance of this historic evolution is well illustrated by experimental observations that have led to our current understanding of, and possible therapeutic approaches for, Langerhans cell histiocytosis (LCH) and Erdheim-Chester Disease (ECD), both of which are the focus of the report by Haroche et al that accompanies this article. On the basis of morphologic characteristics and cellular markers, such as expression of CD1a, CD207, and S100, the historical names, including Hand-Christian-Shuller disease, Abt-Letterer-Siwe disease, eosinophilic granuloma, and histiocytosis X, were all eventually replaced by the more biologically relevant name LCH. However, the cell of origin for LCH has recently come into question on the basis of transcriptional and lineage observations that suggest that it may be more accurately designated a dermal dendritic cell. Similarly, on the basis of morphology and a variety of cell markers, ECD, which expresses CD68 but not CD1a or usually S100, is considered a separate disorder from LCH. Pathologically, LCH and ECD also differ considerably: LCH characteristically shows a granulomatous, inflammatory background of CD1a dendritic cells, lymphocytes, eosinophils, and multinucleated giant cells, whereas ECD demonstrates an accumulation of xanthogranulomatosis histiocytes, proliferating fibroblasts, and fibrosis, along with Touton giant cells. Furthermore, the clinical spectrum of the two disorders is different in terms of age distribution, organ involvement, responses to conventional treatment, and prognosis. Thus, these two diseases have been considered to represent separate entities, although they are part of the family of histiocytic disorders that result from immuneor metabolically mediated dysfunction. But the unusual patients in whom both LCH and ECD are clearly present raise the question of whether there could be a potentially common cellular precursor for both diseases? Furthermore, the observations linking molecular clonality, dysregulated oncogene expression, and, most recently, common mutations involving the RAS-RAF-MEK-ERK (mitogen-activated protein kinase) pathway have solidified the conclusion that these disorders are oncogene-driven neoplasms that seem to share more than was previously thought. Approximately 50% to 60% of lesions from patients with LCH have BRAF mutations. This seems to be the case regardless of the extent of organ involvement and has been observed from infants to the elderly. Importantly, the observation that the mutations involve a single allele is consistent with the BRAF mutation being a dominant, activating oncogenic signal. Furthermore, the initial report by Badalian-Very et al indicated that in patients in whom a BRAF mutation was not identified, evidence for activation at the protein level of the RAS-RAF-MEK-ERK pathway was present. This suggested that additional mutations possibly existed that involved this signaling pathway, which has subsequently been shown to be the case. The identification of BRAF mutations in 50% to 100% of patients with ECD has further linked these two clinically disparate disorders. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L