transforming-growth-factor-beta and Histiocytosis--Langerhans-Cell

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

Topics: Adolescent; Adult; Aged; CD56 Antigen; CD8-Positive T-Lymphocytes; Child; Child, Preschool; Female; Forkhead Transcription Factors; Histiocytosis, Langerhans-Cell; Humans; Infant; Inflammation; Langerhans Cells; Male; Middle Aged; T-Lymphocytes, Regulatory; Transforming Growth Factor beta

Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are rare histiocytic disorders induced by somatic mutation of MAPK pathway genes.

Topics: Adult; Alleles; Antigens, CD; Antigens, CD1; Bone Marrow Cells; Cell Differentiation; Dendritic Cells; Diagnosis, Differential; Erdheim-Chester Disease; Female; Foam Cells; Gene Expression; Glycoproteins; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cells; Histiocytosis, Langerhans-Cell; Humans; Immunophenotyping; Lectins, C-Type; Lipopolysaccharide Receptors; Male; Mannose-Binding Lectins; Monocytes; Mutation; Proto-Oncogene Proteins B-raf; Receptors, Notch; Transforming Growth Factor beta

Langerhans cell histiocytosis (LCH) is a rare disease with an unknown etiology characterized by heterogeneous lesions containing CD207

Topics: Antigens, CD; Antigens, CD1; Child; Child, Preschool; Cytokines; Female; Histiocytosis, Langerhans-Cell; Humans; Infant; Lectins, C-Type; Male; Mannose-Binding Lectins; Thymic Stromal Lymphopoietin; Transforming Growth Factor beta

Langerhans cell histiocytosis (LCH) has a challenging and still unclear pathogenesis. A body of literature points to impaired maturation of the lesional dendritic cells, and to immune dysregulation in the form of increased FoxP3 cells. Various cytokine abnormalities such as expression of transforming growth factor (TGF)-β have been reported, as well as abnormalities in lipid content in LCH cells. Morphoproteomic techniques were applied to identify the signal transduction pathways that could influence histogenesis and immune regulation in osteolytic LCH. Five pediatric cases of osteolytic LCH were examined, using antibodies against CD1a, S100, CD68, CD8, FoxP3, phosphorylated (p)-STAT3 (Tyr705), protein kinase C (PKC)-α, phospholipase (PL)D1, fatty acid synthase (FASN), and zinc finger protein, Gli2. Positive and negative controls were performed. A FoxP3(+)/CD8(+) cell ratio was calculated by counting the FoxP3+ and CD8+ cells in 10 high power fields for each case. There is induction of sonic hedgehog (SHH) mediators consistent with TGF-β signaling pathway through Smad3-dependent activation of Gli2, findings supported by the plasmalemmal and cytoplasmic expression of PKC-α and PLD1, and nuclear expression of Gli2, in lesional cells. The FoxP3+/CD8+ cell ratio is increased, ranging from 1.7-7.94. There is moderate cytoplasmic expression of FASN in most of the Langerhans cells, a finding that supports previously published phospholipid abnormalities in LCH and is consistent with PKC-α/PLD1/TGF-β signaling. With our study, we strongly suggest that the TGF-β cell signaling pathway is a major player in the pathogenesis of LCH, leading to non-canonical induction of nuclear Gli2 expression, thereby contributing to osteoclastogenesis in LCH histiocytes. It could also cause a state of immune frustration in LCH, by inducing the transformation of CD4(+)CD25(-) cells into CD4(+)/FoxP3(+) cells. This coincides with the clinical evidence of a response to thalidomide in patients with osteolytic LCH, given its reported ability to reduce TGF-beta 1 and FoxP3 cells. Such TGF-β signaling in osteoclastogenesis and immune dysregulation, and the presence of FASN in the majority of cells, have additional therapeutic implications for osteolytic LCH.

Topics: Biomarkers; Cell Differentiation; Cell Membrane; Cell Nucleus; Child; Child, Preschool; Cytoplasm; Female; Histiocytosis, Langerhans-Cell; Humans; Kruppel-Like Transcription Factors; Male; Nuclear Proteins; Osteoclasts; Osteolysis; Proteomics; Signal Transduction; Thalidomide; Transforming Growth Factor beta; Zinc Finger Protein Gli2

To assess the expression of potential osteoclastogenic and osteolytic factors in osteolytic lesions from patients with Langerhans cell histiocytosis.. Paraffin-embedded biopsy sections from 5 such archival cases underwent immunohistochemical procedures with antibodies to detect the following antigens: CD(1a), S100 protein, interleukin 11, the latency-associated peptide of transforming growth factor beta(1), and angiotensin-converting enzyme.. Commonalities noted include (1) the presence of multinucleated osteoclast-like giant cells, (2) the expression of interleukin 11 and latency-associated peptide antigens in lesional Langerhans cells, and (3) plasmalemmal immunoreactivity for angiotensin-converting enzyme antigen on non-Langerhans cell histiocytes and, on occasion, osteoclast-like giant cells and endothelial cells.. These observations suggest a possible pathogenetic sequence for osteolysis in Langerhans cell histiocytosis that involves angiotensin II formation, leading to the activation of latent transforming growth factor beta(1) and, in turn, to the enhanced production of interleukin 11, resulting in both osteoclastogenesis and impaired remodeling of bone.

Topics: Adolescent; Adult; Antigens, CD1; Biopsy; Child; Endothelium; Female; Histiocytes; Histiocytosis, Langerhans-Cell; Humans; Interleukin-11; Langerhans Cells; Male; Osteoclasts; Osteolysis; Peptidyl-Dipeptidase A; S100 Proteins; Tissue Embedding; Transforming Growth Factor beta

Topics: Histiocytosis, Langerhans-Cell; Humans; Transforming Growth Factor beta