Abstract

Langerhans cell histiocytosis (LCH) can present in several clinical forms with expected response to therapy categorized by the organ systems involved. Low Risk patients (unifocal bone, skin, or lymph nodes disease) are nearly always cured of the disease, patients with multifocal bone involvement are more likely to have relapses, and High Risk patients (involving liver, lung, spleen, or bone marrow) have only a 50% chance of cure. The etiology of LCH is unknown and controversy exists whether this is purely an immunologic dysfunction or a neoplastic disease since the Langerhans cells have been identified as a clonal proliferation. Understanding interaction of Langerhans cells (LC) with T lymphocytes and macrophages in the lesions of Langerhans cell histiocytosis (LCH) is critical to elucidating LCH pathophysiology. We have used laser capture microdissection to isolate CD1a+ LC and CD3+ T cells from frozen LCH lesions. RNA from the dissected cells was enzymatically amplified, hybridized to a cytokine/growth factor array and analyzed for quantity of gene expression after normalizing to b-actin. A complex expression profile has emerged:

Gene Expression in LCH Clinical Groups

Low RiskMultifocal BoneHigh Risk
* to ***= low to high expression of a gene, VEGF:vascular endothelial growth factor, FGF: fibroblast growth factor 
CD1a Cytokines IL-9**, -11***, -17**, Leptin*,TGF- β IL-10**, IL-11**,TGF- β IL-9*,11*,Leptin** 
CD1a Growth Factors FGF-6*, VGEF*** FGF-6**, VEGF** FGF-6***, VEGF* 
CD3 Cytokines IL-9**, Lymphotoxin- α IL-9*,-10 IL-9*** Lymphotoxin- α** 
CD3 Growth Factors GM-CSF* GM-CSF** FGF-5* GM-CSF*** FGF-5** 
Low RiskMultifocal BoneHigh Risk
* to ***= low to high expression of a gene, VEGF:vascular endothelial growth factor, FGF: fibroblast growth factor 
CD1a Cytokines IL-9**, -11***, -17**, Leptin*,TGF- β IL-10**, IL-11**,TGF- β IL-9*,11*,Leptin** 
CD1a Growth Factors FGF-6*, VGEF*** FGF-6**, VEGF** FGF-6***, VEGF* 
CD3 Cytokines IL-9**, Lymphotoxin- α IL-9*,-10 IL-9*** Lymphotoxin- α** 
CD3 Growth Factors GM-CSF* GM-CSF** FGF-5* GM-CSF*** FGF-5** 

Growth factor and cytokine interactions from these LCH patients with different clinical presentations illustrates the importance of both LC and T-cells as well as the known influence of macrophages on the type of LCH. Although previous studies have shown TNF-a is an important factor, our data illustrates that other cytokines and growth factors may play critical roles, because of their relative higher gene expression when compared with TNF-a. These data will facilitate development of in vitro systems to test our hypotheses that a combination of cytokines/growth factors may be important in varying LCH clinical presentations.

Supported by:Histiocytosis Association of America, Families Conquering Histiocytosis, and The Texas Children’s Cancer Center

Author notes

Corresponding author