Allen, CE, Li, L, Peters, TL, Leung, HC, Yu, A, Man, TK et al.. Cell-specific gene expression in Langerhans cell histiocytosis lesions reveals a distinct profile compared with epidermal Langerhans cells. J Immunol 184: 4557-4567
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Article: Allen, CE, Li, L, Peters, TL, Leung, HC, Yu, A, Man, TK et al.. Cell-specific gene expression in Langerhans cell histiocytosis lesions reveals a distinct profile compared with epidermal Langerhans cells. J Immunol 184: 4557-4567
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[Show abstract] [Hide abstract] ABSTRACT: Langerhans cell histiocytosis (LCH) is a clonal disorder with elusive etiology, characterized by the accumulation of CD207(+) dendritic cells (DCs) in inflammatory lesions. Recurrent BRAF-V600E mutations have been reported in LCH. In this study, lesions from 100 patients were genotyped, and 64% carried the BRAF-V600E mutation within infiltrating CD207(+) DCs. BRAF-V600E expression in tissue DCs did not define specific clinical risk groups but was associated with increased risk of recurrence. Strikingly, we found that patients with active, high-risk LCH also carried BRAF-V600E in circulating CD11c(+) and CD14(+) fractions and in bone marrow (BM) CD34(+) hematopoietic cell progenitors, whereas the mutation was restricted to lesional CD207(+) DC in low-risk LCH patients. Importantly, BRAF-V600E expression in DCs was sufficient to drive LCH-like disease in mice. Consistent with our findings in humans, expression of BRAF-V600E in BM DC progenitors recapitulated many features of the human high-risk LCH, whereas BRAF-V600E expression in differentiated DCs more closely resembled low-risk LCH. We therefore propose classification of LCH as a myeloid neoplasia and hypothesize that high-risk LCH arises from somatic mutation of a hematopoietic progenitor, whereas low-risk disease arises from somatic mutation of tissue-restricted precursor DCs.
- "However, recent discoveries question the model of LCH arising from transformed or pathologically activated epidermal Langerhans cells. The cell-specific gene expression signature in langerin + DCs within LCH lesions has been shown to be more consistent with immature myeloid DC precursors than epidermal Langerhans cells (Allen et al., 2010). Furthermore , mouse studies demonstrate that langerin is more promiscuous than previously appreciated (Ginhoux et al., 2007). "
[Show abstract] [Hide abstract] ABSTRACT: Hemorrhagic pustules with a "blueberry muffin" appearance accompanied by respiratory failure in a neonate present a challenging differential diagnosis that includes infections and neoplasms. We present a case of multiorgan, multisite Langerhans cell histiocytosis (LCH), positive for the oncogenic BRAF V600E mutation, in a preterm neonate. Infants with LCH pose a diagnostic challenge due to their heterogeneous presentations. This case is unusual in that the newborn presented with severe multiorgan involvement. Due to the rare incidence, wide spectrum of clinical manifestations, and high mortality rate, clinicians must maintain a high index of suspicion for LCH.
- "Laboratory tests upon diagnosis should include complete blood count, liver function tests, and cultures if infectious symptoms are present. Bone marrow aspiration and biopsy may be useful in the evaluation of cytopenias.15 Imaging should include a chest radiograph, and chest computed tomography should be obtained if pulmonary symptoms are present. "
[Show abstract] [Hide abstract] ABSTRACT: Langerhans cells (LCs) are professional antigen presenting cells (APCs) residing in the epidermis. Despite their high potential to activate T lymphocytes, current understanding of human LC biology is limited. Genome-wide comparison of the transcriptional profiles of human skin migratory CD1a+ LCs and CD11c+ dermal dendritic cells (DDCs) demonstrated significant differences between these 'dendritic cell' types, including preferential expression of 625 genes (P<0.05) in LC and 914 genes (P<0.05) in DDC. Analysis of the temporal regulation of molecular networks activated after stimulation with TNF-α confirmed the unique molecular signature of LCs. Although LCs conformed to the phenotype of professional APC, inflammatory signalling activated primarily genes associated with cellular metabolism and mitochondrial activation (e.g. CYB561, MRPS35), cell membrane re-organisation and antigen acquisition and degradation (CAV1, PSMD14) (P<0.05-P<0.0001). Conversely, TNF-α induced classical activation in DDCs with early down-regulation of surface receptors (MRC1, C-type lectins), and subsequent up-regulation of cytokines, chemokines (IL1a, IL1b, CCL18) and matrix metalloproteinases (MMP1, MMP3, MMP9), (P<0.05-P<0.0001). Functional interference of caveolin abrogated LCs superior ability to cross-present antigens to CD8+ T lymphocytes, highlighting the importance of these networks to biological function. Taken together these observations support the idea of distinct biological roles of cutaneous DC types.Journal of Investigative Dermatology accepted article preview online, 4 September 2013; doi:10.1038/jid.2013.375.
- "LC preferentially expressed a small number of receptors, including CD207 (langerin), lipoprotein receptors (LSR and LDLR), and only a handful of genes primarily involved in immune processes (CCL22, CD70, CLU, COTL1, HLA-DQA, and TAPBL; the full list of genes preferentially expressed in LCs and DDCs: Supplementary Table S2 online). Migratory skin DCs and trypsinized skin DCs demonstrate strongly matching transcriptomes To confirm the relevance of these findings to the in vivo situation, we also challenged our model system against whole transcriptome data from DCs rapidly isolated from skin using a trypsinization protocol (Santegoets et al., 2008; Allen et al., 2010; Hutter et al., 2012; Harman et al., 2013; Supplementary Table S3 online). Comparison of the genes differentially expressed in either LCs or DDCs revealed the same pattern of expression in both the migratory and trypsinized models (Supplementary Figure 2 online). "