Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019621 (Langerhans cell histiocytosis)
 3,250 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pathogenesis of Langerhans cell histiocytosis (LCH) remains poorly understood. To further elucidate LCH pathogenesis, we analyzed the expression of 10 cytokines relevant to cellular recruitment and activation at the protein level in 14 patients and identified the lesional cells responsible for cytokine production in situ by immunohistochemistry. The cytokines investigated included the hematopoietic growth factors interleukin-3 (IL-3), IL-7, and granulocyte-macrophage colony-stimulating factor (GM-CSF); the lymphocyte regulatory cytokines IL-2, IL-4, and IL-10; the inflammatory regulators IL-1alpha and tumor necrosis factor-alpha (TNF-alpha); and the effector cell-activating cytokines IL-5 and interferon-gamma (IFN-gamma). In all specimens, CD1a(+) histiocytes (LCH cells) and CD3(+) T cells produced large amounts of cytokines, creating a true cytokine storm. IL-2, IL-4, IL-5, and TNF-alpha were produced exclusively by T cells, whereas only IL-1alpha was produced by LCH cells. Equal numbers of LCH cells, T cells, and macrophages produced GM-CSF and IFN-gamma. Equal numbers of LCH cells and macrophages produced IL-10, whereas IL-3 was produced by T cells and macrophages. IL-7 was only produced by macrophages. Eosinophils, present in some specimens, were partially responsible for the production of IL-5, IFN-gamma, GM-CSF, IL-10, IL-3, and IL-7. Expression of all cytokines, abundant in most biopsies, was irrespective of age, gender, or site of biopsy. These findings emphasize the role of T cells in LCH. The juxtaposition of T cells and LCH cells suggests that both cells interact in a cytokine amplification cascade, resulting from stimulation of autocrine and paracrine stimulatory loops. This cascade can be linked directly to the development of LCH through recruitment, maturation, and proliferation of LCH cells. The cytokines studied are known to be involved in the development of other characteristic features of LCH, such as fibrosis, necrosis, and osteolysis.
 ...
PMID:Differential In situ cytokine profiles of Langerhans-like cells and T cells in Langerhans cell histiocytosis: abundant expression of cytokines relevant to disease and treatment. 1059 64

The pathogenesis of Langerhans cell histiocytosis (LCH) is obscure, partly because the events leading to activation of Langerhans-like lesional cells (LCH cells) and associated T cells, and the excessive cytokine production by these cells are unknown. The interaction between CD40 on antigen-presenting cells (APC) like Langerhans cells and CD40 ligand (CD40L) (CD154) expressed by activated CD4+ T cells, is essential for the activation of both the APC and the T cells and results in upregulation of APC functions and initiation of immunoreactivity. The effects of CD40-CD40L interaction include increased expression of co-stimulatory and adhesion molecules, proliferation, and production of pro-inflammatory cytokines and proteolytic enzymes, all features of LCH. Using immunohistochemistry, we analysed the in situ presence of the co-stimulatory molecules CD40 and CD40L in 15 fresh frozen biopsies of LCH lesions in children. The cells producing these molecules were identified by double staining for CD1a on LCH cells and CD3 on T cells. Prominent expression of CD40 by LCH cells and CD40L by T cells was found in all 15 specimens regardless of the source of specimen or characteristics of the patient. The findings of high expression of CD40 and CD40L in all specimens imply a key role for the CD40-CD40L adhesion pathway in the pathogenesis of LCH. Since this interaction is an accessible and realistic target for immunotherapy, these findings prompt speculation on the use of blocking antibodies to CD40 or to CD40L in the treatment of LCH.
 ...
PMID:Abundant expression of CD40 and CD40-ligand (CD154) in paediatric Langerhans cell histiocytosis lesions. 1104 48

Bronchoalveolar lavage (BAL) has become a standard diagnostic procedure for the majority of patients with interstitial disease. The technique is safe, minimally invasive, and reveals specific information in some disorders such as pulmonary alveolar proteinosis, Langerhans cell histiocytosis, alveolar hemorrhage, malignant infiltrates, or dust exposure. Here BAL can often replace lung biopsy. The results of BAL cell differentials with a lymphocytic, a neutrophilic, an eosinophilic, or a mixed cellular pattern can be used as an adjunct to diagnosis. If a BAL finding is compatible with the suspected diagnosis in the context of an appropriate disease history and clinical and radiologic findings, this can then be sufficient for disease confirmation. Recent research focused on the pathogenesis of various types of interstitial lung disorders. In this regard, BAL findings contributed to the characterization of idiopathic pulmonary fibrosis (IPF) as a condition with a predominant T-helper-2 (Th2) cytokine profile, whereas BAL findings in sarcoidosis and hypersensitivity pneumonitis are characterized by a Th1-dominant profile. The clinical value of BAL to assess the activity of disease processes and to provide prognostic information is still under debate. The routine performance of serial BAL is not recommended at present.
 ...
PMID:Bronchoalveolar lavage in interstitial lung disease. 1158 73

Langerhans cell histiocytosis is a rare condition that can affect any organ of the body. Patients of all ages may present to the dermatologist and it is important to make the diagnosis as quickly as possible, because time from presentation to diagnosis is of prognostic importance in adults with the disease. Langerhans cell histiocytosis is now classified as a class I histiocytosis and research into this disease has been very active over the past 10 years. We now know that the disease represents a clonal expansion of a Langerhans cell, which shows phenotypic evidence of activation. The tissue damage induced by the disease appears to be related to local cytokine release. In single system disease, Langerhans cell histiocytosis is responsive to local therapy but, in resistant single system disease or in multisystem disease, etoposide is the most effective monochemotherapy. Some patients will need maintenance treatment with azathioprine or 6-mercaptopurine with or without methotrexate. In such cases, physicians who are used to treating chronic and relapsing diseases and who have experience with these drugs, such as dermatologists, are the most appropriate to manage patients with Langerhans cell histiocytosis.
 ...
PMID:Langerhans cell histiocytosis. 1190 53

The authors describe a girl with multisystem Langerhans cell histiocytosis (LCH) who developed central precocious puberty (CPP). At the age of 19 months she presented with otorrhea and polypoid formations in the ear canal; polyps were removed and LCH suspected. She subsequently developed diabetes insipidus with a documented lesion of the pituitary stalk; she received chemotherapy and began therapy with l-desamino-8-D-argininevasopressin. Growth hormone deficiency was diagnosed at the age of 4.4 years and GH replacement therapy started. The patient has been off therapy for LCH since the age of 6. Signs of pubertal development appeared at 7.5 years (bone age 8 years) and gonadotropin-releasing hormone analog (GnRHa) treatment was started. During the observation period she developed central hypothyroidism. Development of CPP during LCH is extremely rare; to the authors 'knowledge, no patient has been described so far. The authors believe that CPP was secondary to LCH and did not represent a casual finding, even in the absence of hypothalamic-pituitary axis involvement. The presence of preceding lesions producing excessive cytokine levels, with damage on the neurosecretory apparatus that inhibits the GnRH pulse generator, represents the most intriguing hypothesis. The possibility of CPP development should be considered during the follow-up of these patients.
 ...
PMID:Central precocious puberty in multisystem Langerhans cell histiocytosis: a case report. 1205 95

Critical to the function of Ag-presenting dendritic cells (DCs) is their capacity to migrate to lymphoid organs and to sites of inflammation. A final stage of development, termed maturation, yields DCs that are strong stimulators of T cell-mediated immunity and is associated with a remodeling of the cell surface that includes a change in the levels of expression of many molecules, including chemokine receptors. We show in this study that CCR3, a chemokine receptor initially discovered on eosinophils, is also expressed by human DCs that differentiate from blood monocytes, DCs that emigrate from skin (epidermal and dermal DCs), and DCs derived from CD34+ hemopoietic precursors in bone marrow, umbilical cord blood, and cytokine-elicited peripheral blood leukapheresis. Unlike other chemokine receptors, such as CCR5 and CCR7, the expression of CCR3 is not dependent on the state of maturation. All DC subsets contain a large intracellular pool of CCR3. The surface expression of CCR3 is not modulated following uptake of particulate substances such as zymosan or latex beads. CCR3 mediates in vitro chemotactic responses to the known ligands, eotaxin and eotaxin-2, because the DC response to these chemokines is inhibited by CCR3-specific mAbs. We postulate that expression of CCR3 may underlie situations where both DCs and eosinophils accumulate in vivo, such as the lesions of patients with Langerhans cell granulomatosis.
 ...
PMID:Expression of a functional eotaxin (CC chemokine ligand 11) receptor CCR3 by human dendritic cells. 1221 6

The liver can be involved directly, by infiltration, and indirectly--by remote effects--in the histiocytoses of childhood. Langerhans cell disease, the most well recognized of these, infiltrates the liver directly but has a remarkable selectivity for the bile ducts. Early involvement is by Langerhans cell histiocytosis (LCH) infiltration leading to a sclerosing cholangitis and, eventually, biliary cirrhosis. Gamma glutamyl transpeptidase is a sensitive indicator of liver infiltration in a child with LCH. The indirect effects on the liver of LCH elsewhere in the body are mediated through an accompanying macrophage activation syndrome that is most likely responsible for hepatomegaly and hypoalbuminemia but without direct infiltration. These indirect effects are completely reversible. Juvenile xanthogranuloma/xanthoma disseminatum, a related dendritic cell disorder that can have systemic manifestations, has a strikingly different pattern, with a predominantly portal infiltrate spilling over into the adjacent lobule but sparing the biliary tree. The biology of the liver lesions is not clear but regression has been documented. Myeloproliferative disorders and myeloid leukemias can express CD1a and/or S100 protein, mimicking LCH but distinguished by their sinusoidal pattern. The primary macrophage histiocytoses such as the familial hemophagocytic syndromes can lead to severe liver damage. Although a portal lymphohistiocytic infiltrate is most characteristic, it is probably cytokine-mediated hepatocellular damage that can cause substantial functional impairment or even hepatic failure as a presenting feature. Liver involvement in other, more unusual histiocytic disorders, is also illustrated.
 ...
PMID:Liver involvement in the histiocytic disorders of childhood. 1502 67

Some immunologic diseases are characterized by profound loss or primary dysfunction of a given population of cells. The atypical cellular disorders discussed here all bear some similarities in that abnormal proliferations of lymphocytes and macrophages or dendritic cells result in lymphadenopathy, skin rashes, bone lesions and infiltrations of nearly any other organ system. What are the similarities and the differences between Langerhans cell histiocytosis (LCH), sinus histiocytosis with massive lymphadenopathy (SHML) or Rosai-Dorfman disease, and Castleman's disease (CD)? Studies on LCH have some advantages since it was described before the others, and organized clinical trials have been done since the 1980s. The understanding of SHML benefited from a registry maintained by Drs. Rosai and Dorfman. CD was described fifty years ago and for one subtype has the most clearly defined etiology (HHV-8 infection) of the three atypical cellular disorders discussed here. In Section I, Dr. Kenneth McClain examines the unanswered question of whether LCH is a malignant clonal disorder or an inflammatory response triggered by aberrant cytokine expression or a virus. Advocates of the malignant proliferation theory rest their case primarily on the following two points: Clonality of the CD1a+ Langerhans cells was demonstrated by analysis of the human androgen receptor in patients with single bone lesions (Low Risk) or multisystem disease including spleen, liver, bone marrow, or lung (High Risk). Although no consistent chromosomal abnormalities have been reported, loss of heterozygosity (LOH) has been defined by comparative genomic hybridization. Those in the "inflammatory response" camp note that non-clonal proliferation of Langerhans cells in adult pulmonary LCH also have LOH by the same method. The pathologic cells have not been successfully grown in culture or immune-deficient mice and don't have a "malignant" morphology. While the basic scientific arguments continue, important advances in the treatment of LCH have been made by international collaborations of the Histiocyte Society. Risk groups have been clearly defined and the response to therapy after the initial 6 weeks is known to be the strongest prognostic variable for outcome. In Section II, Dr. Yasodha Natkunam reviews the features of SHML, which most often presents as painless cervical lymphadenopathy, although many patients can have extranodal involvement as well. These sites include the skin, respiratory tract, bone, lung, gastrointestinal tract, and brain. The diagnosis rests on finding intact lymphocytes in the cytoplasm of activated macrophages as well as accumulation of mature plasma cells. Hemolytic or non-hemolytic anemias, hypergammaglobulinemia, and elevated erythrocyte sedimentatin rate (ESR) are often found with SHML. An intriguing finding of human herpesvirus (HHV)-6 viral proteins in SHML has been reported in several patients, but needs further study. SHML associated with lymphoproliferations triggered by defects in apoptosis are discussed since this mechanism may provide a clue to the etiology. Therapy for SHML varies greatly in reported case series. Many patients have spontaneous regression or resolution after surgical removal of isolated node groups. Others with systemic involvement may benefit from chemotherapy, but no clinical trials have been done. In Section III, Dr. Steven Swerdlow clarifies key features of the four types of CD. Localized cases are divided into the hyaline vascular type and plasma cell type. Both are usually cured by surgical excision and have symptoms mainly of a mass lesion, although the latter often also has constitutional symptoms. The two types are distinguished largely by the nature of the follicles and the number of interfollicular plasma cells. Interleukin (IL)-6 expression is increased in the plasma cell type. Multicentric CD of the plasmablastic type is most often found in HIV-positive patients with coincident HHV-8 infection. Many have lymphomas or Kaposi sarcomas. Other cases of multicentric CD are also most like the plasma cell type, however, with disseminated disease and constitutional symptoms. A wide variety of anti-neoplastic drugs, radiation therapy, anti-IL-6 and rituximab or atlizumab have been used with varying success in patients with multicentric CD. Clinical trials are needed for SHML and CD and registration of adult and pediatric patients on current LCH trials are encouraged.
 ...
PMID:Atypical cellular disorders. 1556 88

Langerhans cell histiocytosis (LCH) commonly involves the oral and maxillofacial region, and comes to the attention of dental practitioners when a patient presents with orofacial pain and a bony or soft tissue lesion. This is a relatively rare entity, which has made it difficult to investigate the clinical, biologic, and molecular aspects of the disease. Treatment protocols are not well defined, particularly in adults. During the past decade, the Histiocyte Society has formulated various LCH categories, based on risk stratification, and treatment protocols for the pediatric population. Adult trials are currently available through the Histiocyte Society. Although there has been considerable controversy, the neoplastic nature of LCH has been established by demonstrating clonality. LCH symptoms and the development and persistence of LCH lesions have been ascribed to a "chemokine/cytokine storm" due to autocrine and paracrine mechanisms. Discovery of biologic, cytogenetic, and molecular abnormalities in LCH have already affected treatment by providing novel therapeutic targets.
 ...
PMID:Langerhans cell histiocytosis: current insights in a molecular age with emphasis on clinical oral and maxillofacial pathology practice. 1603 92

Langerhans cell histiocytosis (LCH) is characterized by an accumulation of dendritic Langerhans cells in granulomatous lesions in the bone, skin, and other sites in the body. The pathogenesis of the disease remains unknown. We measured serum levels of the decoy receptor osteoprotegerin (OPG), an important regulator of bone metabolism as well as immune responses, in 18 children with single system (SS) or multi-system (MS) forms of LCH and 20 pediatric controls. OPG levels were significantly increased in LCH patients at diagnosis when compared with controls, and pretreatment levels of OPG were elevated in MS compared with SS patients. Moreover, OPG levels in LCH patients were elevated in patients with involvement of risk organs (liver, lungs, hematopoietic system, or spleen) when compared with patients without risk organ involvement, indicative of an association between OPG values and disease severity. We also observed a positive correlation between serum levels of OPG and tumor necrosis factor (TNF)-alpha, a pro-inflammatory cytokine, at the time of onset of disease. These findings show, for the first time, that serum OPG levels are elevated in LCH patients, and suggest that OPG may play a role in the pathogenesis of this enigmatic disease.
 ...
PMID:Elevated serum levels of the decoy receptor osteoprotegerin in children with Langerhans cell histiocytosis. 1643 93


<< Previous 1 2 3 4 Next >>