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Nature Reviews. Disease Primers Oct 2021The historic term 'histiocytosis' meaning 'tissue cell' is used as a unifying concept for diseases characterized by pathogenic myeloid cells that share histological... (Review)
Review
The historic term 'histiocytosis' meaning 'tissue cell' is used as a unifying concept for diseases characterized by pathogenic myeloid cells that share histological features with macrophages or dendritic cells. These cells may arise from the embryonic yolk sac, fetal liver or postnatal bone marrow. Prior classification schemes align disease designation with terminal phenotype: for example, Langerhans cell histiocytosis (LCH) shares CD207 antigen with physiological epidermal Langerhans cells. LCH, Erdheim-Chester disease (ECD), juvenile xanthogranuloma (JXG) and Rosai-Dorfman disease (RDD) are all characterized by pathological ERK activation driven by activating somatic mutations in MAPK pathway genes. The title of this Primer (Histiocytic disorders) was chosen to differentiate the above diseases from Langerhans cell sarcoma and malignant histiocytosis, which are hyperproliferative lesions typical of cancer. By comparison LCH, ECD, RDD and JXG share some features of malignant cells including activating MAPK pathway mutations, but are not hyperproliferative. 'Inflammatory myeloproliferative neoplasm' may be a more precise nomenclature. By contrast, haemophagocytic lymphohistiocytosis is associated with macrophage activation and extreme inflammation, and represents a syndrome of immune dysregulation. These diseases affect children and adults in varying proportions depending on which of the entities is involved.
Topics: Erdheim-Chester Disease; Histiocytosis, Langerhans-Cell; Histiocytosis, Sinus; Humans; Inflammation; Xanthogranuloma, Juvenile
PubMed: 34620874
DOI: 10.1038/s41572-021-00307-9 -
Blood Apr 2020Langerhans cell histiocytosis (LCH) is caused by clonal expansion of myeloid precursors that differentiate into CD1a+/CD207+ cells in lesions that leads to a spectrum of... (Review)
Review
Langerhans cell histiocytosis (LCH) is caused by clonal expansion of myeloid precursors that differentiate into CD1a+/CD207+ cells in lesions that leads to a spectrum of organ involvement and dysfunction. The pathogenic cells are defined by constitutive activation of the MAPK signaling pathway. Treatment of LCH is risk-adapted: patients with single lesions may respond well to local treatment, whereas patients with multisystem disease require systemic therapy. Although survival rates for patients without organ dysfunction is excellent, mortality rates for patients with organ dysfunction may reach 20%. Despite progress made in the treatment of LCH, disease reactivation rates remain above 30%, and standard second-line treatment is yet to be established. Treatment failure is associated with increased risks for death and long-term morbidity, including LCH-associated neurodegeneration. Early case series report promising clinical responses in patients with relapsed and refractory LCH treated with BRAF or MEK inhibitors, although potential for this strategy to achieve cure remains uncertain.
Topics: Animals; Histiocytosis, Langerhans-Cell; Humans; MAP Kinase Signaling System; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf
PubMed: 32106306
DOI: 10.1182/blood.2019000934 -
International Journal of Molecular... Oct 2020Psoriasis is an immune cell-mediated inflammatory skin disease. The interleukin (IL)23/IL17 axis plays an important role in the development of psoriasis. The... (Review)
Review
Psoriasis is an immune cell-mediated inflammatory skin disease. The interleukin (IL)23/IL17 axis plays an important role in the development of psoriasis. The effectiveness of biologic treatments such as tumor necrosis factor (TNF)α inhibitors (infliximab, adalimumab, certolizumab pegol), IL23 inhibitors (ustekinumab, guselkumab, tildrakizumab, risankizumab), and IL17 inhibitors (secukinumab, ixekizumab, brodalumab) have verified these findings. Immune-related cells such as dendritic cells (DCs) and macrophages, in addition to Toll-like receptors and cytokines such as interferon (IFN)α, TNFα, IFNɤ, IL12, IL22, IL23, and IL17, are related to the pathogenesis of psoriasis. Here, we first review new insights regarding the pathogenesis of psoriasis, as it relates to DCs, Langerhans cells, macrophages, the signal transducer and activator of transcription 3 pathway, and aryl hydrocarbon receptor in cutaneous vascular endothelial cells. Based on these findings, we summarize currently available oral treatments and biologics. Furthermore, we describe a new treatment option including Janus kinase inhibitor, tyrosine kinase 2 inhibitor, modulator of sphingosine 1-phosphate receptor 1, and Rho-associated kinase 2 inhibitor.
Topics: Animals; Biomarkers; Dendritic Cells; Disease Management; Disease Susceptibility; Humans; Molecular Targeted Therapy; Psoriasis; Signal Transduction
PubMed: 33050592
DOI: 10.3390/ijms21207488 -
Immunology Jun 2020The skin is the outermost layer of the body with an extensive surface area of approximately 1·8 m , and is the first line of defence against a multitude of external... (Review)
Review
The skin is the outermost layer of the body with an extensive surface area of approximately 1·8 m , and is the first line of defence against a multitude of external pathogens and environmental insults. The skin also has important homeostatic functions such as reducing water loss and contributing to thermoregulation of the body. The structure of the skin and its cellular composition work in harmony to prevent infections and to deal with physical and chemical challenges from the outside world. In this review, we discuss how the structural cells such as keratinocytes, fibroblasts and adipocytes contribute to barrier immunity. We also discuss specialized immune cells that are resident in steady-state skin including mononuclear phagocytes, such as Langerhans cells, dermal macrophages and dermal dendritic cells in addition to the resident memory T cells. Ageing results in an increased incidence of cancer and skin infections. As we age, the skin structure changes with thinning of the epidermis and dermis, increased water loss, and fragmentation of collagen and elastin. In addition, the skin immune composition is altered with reduced Langerhans cells, decreased antigen-specific immunity and increased regulatory populations such as Foxp3 regulatory T cells. Together, these alterations result in decreased barrier immunity in the elderly, explaining in part their increased susceptiblity to cancer and infections.
Topics: Adipocytes; Aging; Disease Susceptibility; Fibroblasts; Humans; Immunity, Cellular; Incidence; Keratinocytes; Langerhans Cells; Macrophages; Microbiota; Skin; Skin Diseases, Infectious; Skin Neoplasms; Water Loss, Insensible
PubMed: 31709535
DOI: 10.1111/imm.13152 -
The Journal of Investigative Dermatology Apr 2021As global life expectancy continues to rise, we are challenged with maintaining health into old age. One strategy is to target the chronic low-level inflammation... (Review)
Review
As global life expectancy continues to rise, we are challenged with maintaining health into old age. One strategy is to target the chronic low-level inflammation associated with aging, termed inflammaging. This is characterized by increased levels of circulating proinflammatory cytokines and a shift toward cellular senescence, changes that are believed to drive many age-associated conditions, including dementia, arthritis, and type 2 diabetes. As with other organs, the skin undergoes functional decline during aging, becoming more fragile and susceptible to infection; however, the contribution of inflammaging is not well-understood. This review article describes the evidence for inflammaging in the skin, its relationship with senescence, and how this relates to declining skin structure and function.
Topics: Cellular Senescence; Cytokines; Fibroblasts; Healthy Aging; Humans; Immunosenescence; Inflammation; Keratinocytes; Langerhans Cells; Skin; Skin Aging; T-Lymphocytes
PubMed: 33358020
DOI: 10.1016/j.jid.2020.11.006 -
Hematological Oncology Jun 2021Children with Langerhnans cell histiocytosis (LCH) develop granulomatous lesions with characteristic clonal CD207+ dendritic cells that can arise as single lesions or... (Review)
Review
Children with Langerhnans cell histiocytosis (LCH) develop granulomatous lesions with characteristic clonal CD207+ dendritic cells that can arise as single lesions or life-threatening disseminated disease. Despite the wide range of clinical presentations, LCH lesions are histologically indistinguishable based on severity of disease, and uncertain classification as an immune versus neoplastic disorder has historically challenged the development of optimal clinical strategies for patients with LCH. Recently, activating somatic mutations in MAPK pathway genes, most notably BRAFV600E, have been discovered in almost all cases of LCH. Further, the stage of myeloid differentiation in which the mutation arises defines the extent of disease and risk of developing LCH-associated neurodegeneration. MAPK activation in LCH precursor cells drives myeloid differentiation, inhibits migration, and inhibits apoptosis, resulting in accumulation of resilient pathologic dendritic cells that recruit and activate T cells. Recurrent somatic mutations in MAPK pathway genes have also been identified in related histiocytic disorders: juvenile xanthogranuloma, Erdheim-Chester disease, and Rosai-Dorfman disease. New insights into pathogenesis support reclassification of these conditions as a myeloid neoplastic disorders. Continued research will uncover opportunities to identify novel targets and inform personalized therapeutic strategies based on cell of origin, somatic mutation, inherited risk factors, and residual disease.
Topics: Amino Acid Substitution; Cell Differentiation; Cell Movement; Dendritic Cells; Histiocytosis, Langerhans-Cell; Humans; MAP Kinase Signaling System; Mutation, Missense; Precision Medicine; Proto-Oncogene Proteins B-raf; T-Lymphocytes
PubMed: 34105821
DOI: 10.1002/hon.2857 -
Annual Review of Immunology Apr 2021Dendritic cells (DCs) possess the ability to integrate information about their environment and communicate it to other leukocytes, shaping adaptive and innate immunity....
Dendritic cells (DCs) possess the ability to integrate information about their environment and communicate it to other leukocytes, shaping adaptive and innate immunity. Over the years, a variety of cell types have been called DCs on the basis of phenotypic and functional attributes. Here, we refocus attention on conventional DCs (cDCs), a discrete cell lineage by ontogenetic and gene expression criteria that best corresponds to the cells originally described in the 1970s. We summarize current knowledge of mouse and human cDC subsets and describe their hematopoietic development and their phenotypic and functional attributes. We hope that our effort to review the basic features of cDC biology and distinguish cDCs from related cell types brings to the fore the remarkable properties of this cell type while shedding some light on the seemingly inordinate complexity of the DC field.
Topics: Animals; Cell Lineage; Dendritic Cells; Humans; Immunity, Innate; Mice
PubMed: 33481643
DOI: 10.1146/annurev-immunol-061020-053707 -
Lancet (London, England) Jul 2021Histiocytoses constitute a heterogeneous group of rare disorders, characterised by infiltration of almost any organ by myeloid cells with diverse macrophage or dendritic... (Review)
Review
Histiocytoses constitute a heterogeneous group of rare disorders, characterised by infiltration of almost any organ by myeloid cells with diverse macrophage or dendritic cell phenotypes. Histiocytoses can start at any age. Diagnosis is based on histology in combination with appropriate clinical and radiological findings. The low incidence and broad spectrum of clinical manifestations often leads to diagnostic delay, especially for adults. In most cases, biopsy specimens infiltrated by histiocytes have somatic mutations in genes activating the MAP kinase cell-signalling pathway. These mutations might also be present in blood cells and haematopoietic progenitors of patients with multisystem disease. A comprehensive range of investigations and molecular typing are essential to accurately predict prognosis, which can vary from spontaneous resolution to life-threatening disseminated disease. Targeted therapies with BRAF or MEK inhibitors have revolutionised salvage treatment. However, the type and duration of treatment are still debated, and the prevention of neurological sequelae remains a crucial issue.
Topics: Adult; Delayed Diagnosis; Histiocytes; Histiocytosis, Langerhans-Cell; Humans; MAP Kinase Kinase Kinases; Macrophages; Mutation; Rare Diseases
PubMed: 33901419
DOI: 10.1016/S0140-6736(21)00311-1 -
Frontiers in Immunology 2022Psoriasis is a chronic inflammatory skin disease characterized by scaly indurated erythema. This disease impairs patients' quality of life enormously. Pathological... (Review)
Review
Psoriasis is a chronic inflammatory skin disease characterized by scaly indurated erythema. This disease impairs patients' quality of life enormously. Pathological findings demonstrate proliferation and abnormal differentiation of keratinocytes and massive infiltration of inflammatory immune cells. The pathogenesis of psoriasis is complicated. Among immune cells, dendritic cells play a pivotal role in the development of psoriasis in both the initiation and the maintenance phases. In addition, it has been indicated that macrophages contribute to the pathogenesis of psoriasis especially in the initiation phase, although studies on macrophages are limited. In this article, we review the roles of dendritic cells and macrophages in the pathogenesis of psoriasis.
Topics: Dendritic Cells; Humans; Macrophages; Psoriasis; Quality of Life; Skin
PubMed: 35837394
DOI: 10.3389/fimmu.2022.941071