Inflammatory serum cytokines and chemokines increase associated with the disease extent in pediatric Langerhans cell histiocytosis

doi:10.1016/j.cyto.2017.05.026

Cytokine

Volume 97, September 2017, Pages 73-79

https://doi.org/10.1016/j.cyto.2017.05.026 Get rights and content

Highlights

•
The serum inflammatory cytokine/chemokine levels are remarkably high in LCH patients.
•
These values are associated with the disease extent.
•
The high serum IL-18 value may be associated with poor response to chemotherapy.
•
LCH cells with BRAF V600E mutation might produce higher amount of chemokines.

Abstract

Objective

Langerhans cell histiocytosis (LCH) is characterized by immature dendritic cell proliferation, infiltration of LCH lesions by various inflammatory cells, and a lesional cytokine storm. It is classified into three groups on the basis of disease extent, namely, multisystem with risk-organ involvement (MS+), multisystem without risk-organ involvement (MS−), and single-system (SS) disease. We comprehensively analyzed whether serum levels of cytokines/chemokines reflect the disease extent.

Methods

Serum samples from 52 children with LCH (eight, 25, and 19 with MS+, MS−, and SS, respectively) and 34 control children were analyzed quantitatively for 48 humoral factors. DNA samples extracted from biopsied LCH lesions from 12 patients were tested for BRAF V600E status.

Results

The LCH patients had significantly higher serum levels of IL-1Ra, IL-3, IL-6, IL-8, IL-9, IL-10, IL12, IL-13, IL-15, IL-17, IL-18, TNF-α, G-CSF, M-CSF, MIF, HGF, VEGF, CCL2, CCL3, CCL7, CXCL1, and CXCL9 than the controls by univariate analysis. Of these IL-9, IL-15 and MIF were significant by multivariate analysis; but not differed between MS and SS diseases. MS disease associated with significantly higher IL-2R, IL-3, IL-8, IL-18, M-CSF, HGF, CCL2, CXCL1, and CXCL9 levels than SS disease by univariate analysis. Of these, CCL2 and M-CSF were significant by multivariate analysis. IL-18 levels were significantly higher in MS+ disease than MS− disease. The LCH patients with BRAF V600E mutation had higher serum levels of CCL7.

Conclusion

Numerous inflammatory cytokines and chemokines play a role in LCH. Of those, more specific ones reflect the disease extent (MS vs. SS and MS+ vs. MS−) or the BRAF V600E mutation status. It is thought that the most responsible cytokines and chemokines involved in the poor outcome may become future candidate therapeutic targets in LCH.

Introduction

Langerhans cell histiocytosis (LCH) is a rare disorder characterized by the proliferation of CD1a-positive immature dendritic cells of LCH cells [1]. Its clinical features are quite variable and it is classified into three distinct groups on the basis of disease extent, namely, multisystem disease with risk-organ (liver, spleen, or hematopoietic system) involvement (MS+), multisystem disease without risk-organ involvement (MS−), and single-system (SS) disease. LCH has both inflammatory and neoplastic characteristics and is designated as “inflammatory myeloid neoplasm” [2]. It is hypothesized that LCH cells harboring oncogenic mutation proliferate and migrate to site of lesions, and recruit and activate various inflammatory cells [2].

LCH lesions not only contain LCH cells, they also bear various inflammatory cells, including T lymphocytes, macrophages, plasma cells, eosinophils, osteoclast-like multinucleated giant cells (MGCs), neutrophils, and natural killer (NK) cells [3]. The osteoclast-like MGCs are present not only in bone lesions but also in non-ostotic lesions, and osteoclast-derived enzymes are thought to play a major role in tissue destruction [4]. Within LCH lesions, these infiltrating cells produce abundant amounts of cytokines [e.g. granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-1α, IL-2, IL-3, IL-4, IL-5, IL-7, and IL-10] and thereby stimulate each other [5]. Moreover, LCH cells express the immature dendritic cell marker CC-chemokine receptor (CCR)6 and produce its ligand (CC-chemokine ligand (CCL)20) CCL20) as well as CCL5 and CXC-chemokine ligand (CXCL)11 [6]. These chemokine receptors and their ligand interactions may play a role in the hematogenous migration and dissemination of not only LCH cells but also the recruitment of eosinophils and T cells into the lesions. Several reports show that patients with LCH have elevated serum levels of IL-1 receptor antagonist (IL-1Ra), TNF-α, fms-like tyrosine kinase ligand, macrophage colony-stimulating factor (M-CSF), soluble IL-2 receptor (sIL-2R), CD40 ligand, receptor activator of NF-κB ligand (RANKL), osteoprotegerin, and IL-17A compared to controls [7], [8], [9], [10].

Mutually exclusive somatic mutations in mitogen-activated protein kinase pathway genes have been identified in patients with LCH, and BRAF V600E mutation accounts for about 50% of these mutations [11]. It is reported that in children with LCH, BRAF V600E mutation is associated with poor prognosis [12].

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis that is characterized by various manifestations that mimic LCH, including skeletal involvement, diabetes insipidus, interstitial lung disease, and central nervous system involvement [13]. However, the bone lesion of LCH is osteolytic whereas the bone lesion of ECD is characterized by bilateral and symmetrical osteosclerosis of the long bones. It has been reported that ECD associates with high serum cytokine and chemokine levels [14].

To date, however, it remains unknown whether the lesional “cytokine storm” is reflected in the serum and whether these serum cytokine levels can serve as markers of the extent of disease in the whole body. In addition, it is unknown whether BRAF V600E mutation affects the cytokine/chemokine production by LCH cells. In the present study, the serum levels of cytokines and chemokines in pediatric patients with various types of LCH and their correlations with disease extent and BRAF mutation status were assessed comprehensively.

Section snippets

Patients and controls

This study was approved by the ethics committee of Jichi Medical University School of Medicine. Blood samples and clinical information were obtained with informed consent from 52 newly diagnosed Japanese pediatric LCH patients (24 males and 28 females; median age, 2.6 [range, 0.4–14.3] years). Blood samples were also obtained from 34 pediatric patients with non-inflammatory diseases that were in a stable state, including inherited coagulopathy, thrombophilia, anemia, and resected benign tumor

LCV vs. Control

Comparison of the 52 patients with LCH with the 34 control group patients revealed that the two groups did not differ for mean ± SE age [4.5 ± 0.5 vs. 4.7 ± 0.7 years, p = 0.856]. With regard to the mean decadic logarithmic-transformed serum levels of humoral factors of the two groups (Table 2), the LCH patients had significantly higher levels of 23 of the 41 humoral factors that were analyzed than the control patients by univariate analysis. Of these 23 humoral factors, two were essentially found in

Discussion

This study is the first comprehensive analysis of numerous humoral factors in LCH patients. We found that the serum levels of various inflammatory cytokines and chemokines are significantly high in LCH patients, that more specific ones reflect the disease extent, and that these profile is little bit different from that of ECD. In addition, we found that the serum levels of an inflammatory chemokine is high in LCH patients with BRAF V600E mutation.

Of the 41 humoral factors, 23

Conclusion

The present comprehensive analysis of the serum cytokine/chemokine profiles of LCH patients revealed that these patients have prominent histio-monocytic immune responses, osteoclast activation, and chemotaxis of inflammatory cells for systemic recruitment. Of those, more specific ones reflect the disease extent (MS vs. SS), risk-organ involvement (MS+, MS−) or the BRAF V600E mutation status. These observations suggest that numerous inflammatory cytokines/chemokines play a major role in the

Declaration of interest

All of authors have indicated they have no potential conflicts of interest and no financial relationships relevant to this article to disclose.

Acknowledgments

The authors would like to thank the physicians who provided the patient information and samples and Ms. Yasuko Hashimoto for her excellent secretarial assistance. This work was supported by the Ministry of Health, Labor and Welfare, Japan (grant number: Research on Measures for Intractable Disease H24-General-076 and H-26-Gereral-068), the Ministry of Education, Culture, Sports, Science and Technology, Japan (grant numbers: Scientific Research 22591167 and 25461606), the Japan Agency for

References (41)

M.L. Berres et al.
Pathological consequence of misguided dendritic cell differentiation in histiocytic diseases
Adv. Immunol.
(2013)
G.I. Bechan et al.
Biology of Langerhans cells and Langerhans cell histiocytosis
Int. Rev. Cytol.
(2006)
R.M. Egeler et al.
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
Blood
(1999)
L. Arnaud et al.
Systemic perturbation of cytokine and chemokine networks in Erdheim-Chester disease: a single-center series of 37 patients
Blood
(2011)
T. Walzer et al.
Natural-killer cells and dendritic cells: “l'union fait la force”
Blood
(2005)
G. Conductier et al.
The role of monocyte chemoattractant protein MCP1/CCL2 in neuroinflammatory diseases
J. Neuroimmunol.
(2010)
G. Frendl
Interleukin 3: from colony-stimulating factor to pluripotent immunoregulatory cytokine
Int. J. Immunopharmacol.
(1992)
Y. Oh et al.
High serum osteopontin levels in pediatric patients with high risk Langerhans cell histiocytosis
Cytokine
(2014)
W. Zhang et al.
IL-18 upregulates the production of key regulators of osteoclastogenesis from fibroblast-like synoviocytes in rheumatoid arthritis
Inflammation
(2013)
A. Morimoto et al.
Recent advances in Langerhans cell histiocytosis
Pediatr. Int.
(2014)

C.E. da Costa et al.

Presence of osteoclast-like multinucleated giant cells in the bone and nonostotic lesions of Langerhans cell histiocytosis

J. Exp. Med.

(2005)

N.E. Annels et al.

Aberrant chemokine receptor expression and chemokine production by Langerhans cells underlies the pathogenesis of Langerhans cell histiocytosis

J. Exp. Med.

(2003)

D.A. Rosso et al.

Serum levels of interleukin-1 receptor antagonist and tumor necrosis factor-alpha are elevated in children with Langerhans cell histiocytosis

J. Pediatr. Hematol. Oncol.

(2003)

A. Rolland et al.

Increased blood myeloid dendritic cells and dendritic cell-poietins in Langerhans cell histiocytosis

J. Immunol.

(2005)

R. Ishii et al.

High serum values of soluble CD154, IL-2 receptor, RANKL and osteoprotegerin in Langerhans cell histiocytosis

Pediatr. Blood Cancer

(2006)

F. Coury et al.

Langerhans cell histiocytosis reveals a new IL-17A-dependent pathway of dendritic cell fusion

Nat. Med.

(2008)

C.E. Allen et al.

Biological and clinical significance of somatic mutations in Langerhans cell histiocytosis and related histiocytic neoplastic disorders

Hematol. Am. Soc. Hematol. Educ. Program

(2015)

S. Héritier et al.

BRAF Mutation correlates with high-risk Langerhans cell histiocytosis and increased resistance to first-line therapy

J. Clin. Oncol.

(2016)

J. Haroche et al.

Erdheim-Chester disease

Curr. Opin. Rheumatol.

(2012)

L. Ronceray et al.

Pulmonary involvement in pediatric-onset multisystem Langerhans cell histiocytosis: effect on course and outcome

J. Pediatr.

(2012)

Cited by (36)

Immune microenvironment associated with the severity of Langerhans cell histiocytosis in children
2023, Cytokine
The aim of this study is to investigate the clinical potential of immune microenvironment in peripheral blood for the severity and therapeutic efficacy of Langerhans cell histiocytosis (LCH). A total of 200 newly diagnosed children with LCH during 10 years was enrolled for analysis in this study. Peripheral blood samples were acquired from patients before treatment in our hospital and immune indicators were detected by a four-color flow cytometer. The levels of CD3 + CD8 + T cell, CD3 + CD4 + HLA-DR + T cell, CD3 + CD8 + HLA-DR + T cell, IL-4, IL-6, IL-10 and IFN-γ in peripheral blood were markedly elevated in LCH patients vs. healthy controls. Patients with multiple system with risk organ involvement (MS-RO + ) exhibited higher levels in IL-6, IL-10 and IFN-γ, CD3 + CD4 + HLA-DR + T cell and CD3 + CD8 + HLA-DR + T cell, compared to those in patients without risk organ involvement (RO-). Patients who responded effectively to initial chemotherapy showed significantly lower levels of IL-4, IL-10, IFN-γ, CD3 + CD4 + HLA-DR + T cell and CD3 + CD8 + HLA-DR + T cell in peripheral blood, compared to those in patients who did not respond to initial chemotherapy. Furthermore, univariate analyses were performed that the higher levels of CD3 + CD4 + HLA-DR + T cells, CD3 + CD8 + HLA-DR + T cells and IL-10 in peripheral blood were related to non-response in LCH after initial chemotherapy. Immune microenvironment in peripheral blood may be associated with the severity and treatment response of LCH. The levels of CD3 + CD4 + HLA-DR + T cells, CD3 + CD8 + HLA-DR + T cells and IL-10 may be biomarkers to predict treatment response of LCH patients.
Langerhans cell histiocytosis. Advances in pathogenesis and clinical practice
2022, Anales de Pediatria
La histiocitosis de células de Langerhans (HCL) es un tipo de neoplasia hematológica de origen mieloide, que puede afectar a diferentes órganos o tejidos, con gran variabilidad en la presentación clínica y comportamiento biológico, por lo que puede simular diferentes enfermedades. Se recomienda realizar diversas pruebas clínicas, analíticas y de imagen, para determinar la extensión de la afectación, que puede ser única o multisistémica, y la presencia o no de disfunción en órganos de riesgo como sistema hematopoyético, hígado y bazo. El diagnóstico se debe confirmar mediante biopsia y estudio histológico. Los estudios moleculares han permitido identificar mutaciones en la vía MAPK, lo que han ampliado las opciones terapéuticas. El diagnóstico es complejo y existe controversia en el manejo de ciertos casos. Las recomendaciones terapéuticas dependen de la localización de las lesiones y de la extensión de la afectación. Los estudios colaborativos internacionales han demostrado la efectividad de terapias prolongadas combinadas como vinblastina y prednisona en formas graves o multisistémicas y destaca el papel beneficioso de fármacos antiinflamatorios como indometacina y de otras combinaciones de citostáticos. La HCL representa un buen ejemplo de la importancia de la medicina de precisión y del beneficio de la identificación de dianas moleculares, comunes a diferentes neoplasias, para desarrollar nuevas terapias dirigidas. Los inhibidores de la vía MAPK representan una alternativa terapéutica en casos refractarios y en las formas neurodegenerativas de la HCL. Los estudios moleculares pueden contribuir en el pronóstico, el tratamiento y el seguimiento, especialmente en las formas graves.
Langerhans cell histiocytosis (LCH) is a type of myeloid neoplasia that can affect different organs or tissues and exhibits substantial variability in its clinical presentation and biological behaviour, so it may mimic different diseases. Performance of different clinical assessments and laboratory and imaging tests is recommended to determine the extent of involvement, which may be of a single location or multisystemic, and the presence or absence of dysfunction in risk organs, such as the haematopoietic system, liver and spleen. The diagnosis must be confirmed by histological examination of a biopsy sample. Molecular tests have identified mutations in the mitogen-activated protein kinase (MAPK) pathway, which has expanded treatment options. The diagnosis is complex and there is controversy regarding the management of certain cases. Treatment recommendations depend on the location of the lesions and the extent of involvement. International collaborative studies have demonstrated the effectiveness of prolonged combination therapies such as vinblastine and prednisone in severe or multisystemic forms, and anti-inflammatory drugs such as indomethacin and other cytostatic combinations have proven beneficial. LCH is a good example of the importance of precision medicine and the benefit of identifying molecular targets, common to different neoplasms, to develop new therapies. MAPK pathway inhibitors offer an alternative treatment option in refractory cases and neurodegenerative forms of LCH. Molecular testing can contribute to the prognosis, treatment and follow-up of LCH, especially in severe forms of disease.
Vemurafenib acts as a molecular on-off switch governing systemic inflammation in Langerhans cell histiocytosis
2022, Blood Advances
Citation Excerpt :
To understand which biological mechanisms coincide with these changes, we identified genes downregulated during therapy and performed pathway enrichment analysis (Figure 2E), which showed pathways associated with inflammation, but not cell cycle or cell division–related pathways. Among the top regulated genes in the bone marrow, we observed downregulation of amphiregulin (AREG), which is expressed in inflammatory conditions,26 and CXCL8 and IL1B, which both are upregulated in LCH,20,27 illustrating broad anti-inflammatory effects of vemurafenib on immune cells in LCH beyond CD1A+CD207+ cells in this patient (Figure 2F-G). Research on LCH has focused on CD1A+CD207+ cells, aiming to inhibit these “LCH cells” as a cure for patients with the disease.
Langerhans cell histiocytosis (LCH) is a neoplasm marked by the accumulation of CD1A⁺CD207⁺ cells. It is most commonly driven by a somatic, activating mutation in the BRAF serine-threonine kinase (BRAF^V600E). Multisystem disease with risk-organ involvement requires myelotoxic chemotherapy, making BRAF-inhibitors an attractive treatment option. Here, we present a comprehensive analysis of the course of an LCH patient treated with the combination of vemurafenib and salvage chemotherapy who achieved sustained clinical and molecular remission. We show that there is no relationship between peripheral blood BRAF^V600E levels and clinical presentation during treatment with vemurafenib, but that vemurafenib leads to a fast, efficient, but reversible inhibition of clinical manifestations of systemic inflammation. In line, serum levels of inflammatory cytokines exactly mirror vemurafenib administration. Genotyping analysis identified the BRAF^V600E mutation in multiple hematopoietic cell types, including NK cells and granulocytes. Single-cell transcriptome analyses of peripheral blood and bone marrow cells at time of diagnosis and during treatment indicate that RAF-inhibition abrogates the expression of inflammatory cytokines previously implicated in LCH such as IL1B and CXCL8. Together, our data suggest that while the CD1A⁺CD207⁺ histiocytes are the hallmark of LCH, other BRAF-mutated cell populations may contribute significantly to morbidity in patients with multisystem LCH.
Transcriptomic landscape of circulating mononuclear phagocytes in Langerhans cell histiocytosis at the single-cell level
2021, Blood
Citation Excerpt :
This pathology is underpinned by alterations in the MAPK pathway, with 50% to 60% of patients exhibiting the BRAFV600E mutation in lesions.2,3 Notably, LCH lesions are highly inflammatory, containing a variety of different cytokines such as tumor necrosis factor and SPP1,4-6 with high levels of proinflammatory cytokines often also detected in the blood of LCH patients.7-9 To date, front-line therapy for LCH patients with multisystem or multifocal disease has been standard oncologic chemotherapy (vinblastine and prednisone)10; however, the identification of BRAFV600E has paved the way for targeted therapies, with preliminary evidence showing promising responses to BRAF inhibitors in adults and children with LCH.11-16
Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm caused by aberrant activation of the mitogen-activated protein kinase (MAPK) pathway. Circulating myeloid cells from patients often carry disease-associated mutations and can be differentiated into langerin^high LCH-like cells in vitro, but their detailed immune-phenotypic and molecular profiles are lacking and could shed key insights into disease biology. Here we recruited 217 pediatric LCH patients and took blood and tissue samples for BRAF^V600E analysis. Immune-phenotyping of the circulating Lin⁻HLA-DR⁺ immune population in 49 of these patients revealed that decreased frequency of plasmacytoid dendritic cells was significantly linked to disease severity. By single-cell RNA sequencing of samples from 14 patients, we identified key changes in expression of RAS-MAPK-extracellular signal-regulated kinase (ERK) signaling-related genes and transcription factors in distinct members of the mononuclear phagocyte system in the presence of BRAF^V600E. Moreover, treatment of patients with the BRAF inhibitor dabrafenib resulted in MAPK cascade inhibition, inflammation prevention, and regulation of cellular metabolism within mononuclear phagocytes. Finally, we also observed elevated expression of RAS-MAPK-ERK signaling-related genes in a CD207⁺CD1a⁺ cell subcluster in skin. Taken together, our data extend the molecular understanding of LCH biology at single-cell resolution, which might contribute to improvement of clinical diagnostics and therapeutics, and aid in the development of personalized medicine approaches.
Foxp3<sup>+</sup> Tregs from Langerhans cell histiocytosis lesions co-express CD56 and have a definitively regulatory capacity
2020, Clinical Immunology
Citation Excerpt :
Moreover, Tregs were reported as increased in active LCH (AD) patient blood compared to controls [11], further suggesting a possible role in LCH pathogenesis. TGF-β and IL-10 are commonly produced by Tregs and were detected within blood [18,19] and lesions [10,11,13,20–22] from AD patients. Additionally, groups demonstrated that LCH cells produced TGF-β [14,21], and TGF-β was a driver of the LCH cell phenotype [18,23,24], while IL-10 was produced largely by macrophages [25] and LCH cells [10] within lesions.
Langerhans cell histiocytosis (LCH) lesions contain myeloid lineage ‘LCH’ cells. Regulatory T cells (Tregs) are also enriched within lesions, although their role in LCH pathogenesis is unknown. LCH cells are thought to produce the transforming growth factor beta (TGF-β) within lesions, however whether Tregs contribute is unestablished. Using flow cytometry, we analyzed relative frequencies of live Tregs from LCH patients and identified CD56 expression and TGF-β production by lesion Tregs. While CD56⁺ Tregs were enriched in lesions, overall CD56⁺ T cells were reduced in the blood from active LCH patients compared to non-active disease patients, and there was a negative correlation between CD8⁺CD56⁺ T cells and Tregs. We propose that inducing a Treg phenotype in T cells such as CD56⁺ T cells may be a mechanism by which LCH cells divert inflammatory T cell responses. Thus, Tregs within LCH lesions are likely an important component in LCH pathogenesis.
Serum and cerebrospinal fluid cytokines in children with acute encephalopathy
2020, Brain and Development
Citation Excerpt :
Samples were stored at −80 °C prior to analysis of the levels of 48 cytokines, as follows: interleukin (IL)-1α, IL-1β, IL-1 receptor antagonist, IL-2, IL-2 receptor α, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12p40, IL-12p70, IL-13, IL-15, IL-16, IL-17, IL-18, interferon (IFN)-α2, IFN-γ, tumor necrosis factor (TNF)-α, TNF-β, TNF-related apoptosis-inducing ligand, macrophage inhibitory factor (MIF), granulocyte-colony stimulating factor, macrophage-colony stimulating factor, granulocyte-macrophage colony-stimulating factor, stem cell factor, leukemia inhibitory factor (LIF), basic fibroblast growth factor, hepatocyte growth factor (HGF), nerve growth factor-β, vascular endothelial growth factor, platelet-derived growth factor-BB, stem cell growth factor-β, CC chemokine ligand (CCL)2, CCL3, CCL4, CCL5, CCL7, CCL11, CCL27, CXC chemokine ligand (CXCL)1, CXCL9, CXCL10, and CXCL12. Serum and CSF levels of these cytokines were determined with the Bio-Plex suspension array system (Bio-Rad Laboratories, Hercules, CA, USA), according to the manufacturer’s instructions, as described previously [10]. These assays were performed in single with 4-fold dilutions of samples.
The pathogenesis of acute encephalopathy (AE) remains unclear, and a biomarker has not been identified.
Levels of 49 cytokines and chemokines, including osteopontin (OPN), were measured in serum and cerebrospinal fluid (CSF) of children with AE (n = 17) or febrile convulsion (FC; n = 8; control group). The AE group included acute necrotizing encephalopathy (n = 1), acute encephalopathy with biphasic seizures and late reduced diffusion (AESD; n = 3), clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS; n = 4), and unclassified acute encephalopathy (UCAE; n = 9) that does not meet the criteria of syndrome classification. Five individuals with AE had neurological sequelae or death (poor prognosis), whereas 12 were alive without neurological sequelae (good prognosis).
The CSF:serum ratios of OPN, CC chemokine ligand (CCL)4, and interleukin (IL)-10 were significantly higher in AE than in FC. The CSF levels of macrophage inhibitory factor (MIF) and leukemia inhibitory factor (LIF) were significantly higher in the poor-prognosis group than in the good-prognosis group. The CSF:serum ratios of OPN were significantly higher in AESD and in MERS than in FC. The CSF:serum ratios of MIF and OPN were higher in MERS than in UCAE or FC.
Our results suggest that microglia-related cytokines and chemokines such as OPN, MIF, and LIF could be novel biomarkers of AE, in addition to the previously reported IL-10 and CCL4, and that MIF and LIF may be markers of poor prognosis.

View all citing articles on Scopus

View full text

Inflammatory serum cytokines and chemokines increase associated with the disease extent in pediatric Langerhans cell histiocytosis

Highlights

Abstract

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Patients and controls

LCV vs. Control

Discussion

Conclusion

Declaration of interest

Acknowledgments

Adv. Immunol.

Int. Rev. Cytol.

Blood

Blood

Blood

J. Neuroimmunol.

Int. J. Immunopharmacol.

Cytokine

Inflammation

Recent advances in Langerhans cell histiocytosis

Pediatr. Int.

Presence of osteoclast-like multinucleated giant cells in the bone and nonostotic lesions of Langerhans cell histiocytosis

J. Exp. Med.

Aberrant chemokine receptor expression and chemokine production by Langerhans cells underlies the pathogenesis of Langerhans cell histiocytosis

J. Exp. Med.

Serum levels of interleukin-1 receptor antagonist and tumor necrosis factor-alpha are elevated in children with Langerhans cell histiocytosis

J. Pediatr. Hematol. Oncol.

Increased blood myeloid dendritic cells and dendritic cell-poietins in Langerhans cell histiocytosis

J. Immunol.

High serum values of soluble CD154, IL-2 receptor, RANKL and osteoprotegerin in Langerhans cell histiocytosis

Pediatr. Blood Cancer

Langerhans cell histiocytosis reveals a new IL-17A-dependent pathway of dendritic cell fusion

Nat. Med.

Biological and clinical significance of somatic mutations in Langerhans cell histiocytosis and related histiocytic neoplastic disorders

Hematol. Am. Soc. Hematol. Educ. Program

BRAF Mutation correlates with high-risk Langerhans cell histiocytosis and increased resistance to first-line therapy

J. Clin. Oncol.

Erdheim-Chester disease

Curr. Opin. Rheumatol.

Pulmonary involvement in pediatric-onset multisystem Langerhans cell histiocytosis: effect on course and outcome

J. Pediatr.