Dendritic cells (DCs), monocytes, and macrophages are leukocytes with critical roles in immunity and tolerance. The DC network is evolutionarily conserved; the homologs of human tissue CD141(hi)XCR1⁺ CLEC9A⁺ DCs and CD1c⁺ DCs are murine CD103⁺ DCs and CD64⁻ CD11b⁺ DCs. In addition, human tissues also contain CD14⁺ cells, currently designated as DCs, with an as-yet unknown murine counterpart. Here we have demonstrated that human dermal CD14⁺ cells are a tissue-resident population of monocyte-derived macrophages with a short half-life of <6 days. The decline and reconstitution kinetics of human blood CD14⁺ monocytes and dermal CD14⁺ cells in vivo supported their precursor-progeny relationship. The murine homologs of human dermal CD14⁺ cells are CD11b⁺ CD64⁺ monocyte-derived macrophages. Human and mouse monocytes and macrophages were defined by highly conserved gene transcripts, which were distinct from DCs. The demonstration of monocyte-derived macrophages in the steady state in human tissue supports a conserved organization of human and mouse mononuclear phagocyte system.

PURPOSE: Off-label use of vemurafenib (VMF) to treat BRAF^V600E mutation–positive, refractory, childhood Langerhans cell histiocytosis (LCH) was evaluated. PATIENTS AND METHODS: Fifty-four patients from 12 countries took VMF 20 mg/kg/d. They were classified according to risk organ involvement: liver, spleen, and/or blood cytopenia. The main evaluation criteria were adverse events (Common Terminology Criteria for Adverse Events [version 4.3]) and therapeutic responses according to Disease Activity Score. RESULTS: LCH extent was distributed as follows: 44 with positive and 10 with negative risk organ involvement. Median age at diagnosis was 0.9 years (range, 0.1 to 6.5 years). Median age at VMF initiation was 1.8 years (range, 0.18 to 14 years), with a median follow-up of 22 months (range, 4.3 to 57 months), whereas median treatment duration was 13.9 months (for 855 patient-months). At 8 weeks, 38 complete responses and 16 partial responses had been achieved, with the median Disease Activity Score decreasing from 7 at diagnosis to 0 ( P < .001). Skin rash, the most frequent adverse event, affected 74% of patients. No secondary skin cancer was observed. Therapeutic plasma VMF concentrations (range, 10 to 20 mg/L) seemed to be safe and effective. VMF discontinuation for 30 patients led to 24 LCH reactivations. The blood BRAF^V600E allele load, assessed as circulating cell-free DNA, decreased after starting VMF but remained positive (median, 3.6% at diagnosis, and 1.6% during VMF treatment; P < .001) and was associated with a higher risk of reactivation at VMF discontinuation. None of the various empirical therapies (hematopoietic stem-cell transplantation, cladribine and cytarabine, anti-MEK agent, vinblastine, etc) used for maintenance could eradicate the BRAF^V600E clone. CONCLUSION: VMF seemed safe and effective in children with refractory BRAF^V600E-positive LCH. Additional studies are needed to find effective maintenance therapy approaches.

Key Points: Diverse patient groups with GATA2 mutation develop mononuclear cytopenia and elevated Flt3 ligand. Progressive cytopenias, rising Flt3 ligand, and terminal differentiation of lymphoid cells accompany clinical progression.

Key Points: Bone marrow progenitors, monocytes, and myeloid DCs contain BRAFV600E alleles in adults with LCH and ECD. Mutant allele distribution is not disease specific, but precursors have distinct LCH-like and macrophage differentiation capacities.

Langerin is a C-type lectin expressed at high level by LCs of the epidermis. Langerin is also expressed by CD8+/CD103+ XCR1+ cross-presenting DCs of mice but is not found on the homologous human CD141high XCR1+ myeloid DC. Here, we show that langerin is expressed at a low level on DCs isolated from dermis, lung, liver, and lymphoid tissue and that langerin+ DCs are closely related to CD1c+ myeloid DCs. They are distinguishable from LCs by the level of expression of CD1a, EpCAM, CD11b, CD11c, CD13, and CD33 and are found in tissues and tissue-draining LNs devoid of LCs. They are unrelated to CD141high XCR1+ myeloid DCs, lacking the characteristic expression profile of cross-presenting DCs, conserved between mammalian species. Stem cell transplantation and DC deficiency models confirm that dermal langerin+ DCs have an independent homeostasis to LCs. Langerin is not expressed by freshly isolated CD1c+ blood DCs but is rapidly induced on CD1c+ DCs by serum or TGF-β via an ALK-3-dependent pathway. These results show that langerin is expressed outside of the LC compartment of humans and highlight a species difference: langerin is expressed by the XCR1+ “DC1” population of mice but is restricted to the CD1c+ “DC2” population of humans (homologous to CD11b+ DCs in the mouse).

Purpose of review This article summarizes recent research on the ontogeny of Langerhans cells and regulation of their homeostasis in quiescent and inflamed conditions. Recent findings Langerhans cells originate prenatally and may endure throughout life, independently of bone marrow-derived precursors. Fate-mapping experiments have recently resolved the relative contribution of primitive yolk sac and fetal liver hematopoiesis to the initial formation of Langerhans cells. In postnatal life, local self-renewal restores Langerhans cell numbers following chronic or low-grade inflammatory insults. However, severe inflammation recruits de-novo bone marrow-derived precursors in two waves; a transient population of classical monocytes followed by uncharacterized myeloid precursors that form a stable self-renewing Langerhans cell network as inflammation subsides. Human CD1c⁺ dendritic cells have Langerhans cell potential in vitro, raising the possibility that dendritic cell progenitors provide the second wave. Langerhans cell development depends upon transforming growth factor beta receptor signaling with distinct pathways active during differentiation and homeostasis. Langerhans cell survival is mediated by multiple pathways including mechanistic target of rapamycin and extracellular signal-regulated kinase signaling, mechanisms that become highly relevant in Langerhans cell neoplasia. Summary The study of Langerhans cells continues to provide novel and unexpected insights into the origin and regulation of myeloid cell populations. The melding of macrophage and dendritic cell biology, shaped by a unique habitat, is a special feature of Langerhans cells.