Objective. Erdheim-Chester disease (ECD) is a rare form of non-Langerhans' cell histiocytosis (LCH) of unknown etiology, characterized by diffuse histiocyte infiltration of bones and soft tissue. The purpose of this study was to assess cell proliferation and expression of cytokines, chemokines, and chemokine receptors that may potentially be important in histiocyte accumulation in ECD lesions.Methods. Biopsies were performed on 3 patients with ECD. The diagnosis of the disease was based on clinical signs including typical radiologic osteosclerosis, and on the detection of foamy CD68؉,CD1a؊ nonLangerhans' cell histiocytes on histologic examination. The expression of the proliferation marker Ki-67 as well as of selected chemokine/chemokine receptor pairs and cytokines was analyzed by immunohistochemistry.Results. In all samples, Ki-67 was undetectable in CD68؉ histiocytes. Conversely, these cells expressed the chemokines CCL2 (monocyte chemotactic protein 1), CCL4/macrophage inflammatory protein 1 (MIP-1), CCL5/RANTES, CCL20/MIP-3␣, and CCL19/MIP-3, and their counter-receptors CCR1, CCR2, CCR3, CCR5, CCR6, and CCR7. Moreover, ECD histiocytes expressed interferon-␥-inducible 10-kd protein (CXCL10), which is specifically induced by interferon-␥, and interleukin-6 and RANKL, which are both implicated in bone remodeling. Finally, all cases showed a Th1-type lymphocyte infiltrate.Conclusion. Our data indicate that, similar to LCH, ECD lesions are characterized by a complex cytokine and chemokine network, which may orchestrate histiocyte activation and accumulation through an autocrine loop and contribute to the pathogenesis of the disease.Erdheim-Chester disease (ECD) is a rare form of systemic non-Langerhans' cell histiocytosis (LCH), with ϳ250 cases described so far. The disease represents a distinct pathologic entity characterized by nearly pathognomonic osteosclerosis, especially of the long bones, and frequently by extraskeletal involvement. Histologically, the lesions consist of diffuse infiltration of bones and soft tissue (kidney, retroperitoneal space, skin, brain, and lung) by foamy CD68ϩ,CD1aϪ nonLangerhans' cell histiocytes (1-3).The etiopathogenesis of the disease is unknown; in particular, at variance with LCH (4), attempts to demonstrate the clonality of histiocytes in ECD have shown inconclusive results (5). Moreover, the mechanisms leading to histiocyte accumulation in ECD lesions have not been elucidated. In this regard, it is well known that leukocyte migration to tissues may be driven by chemokines via interaction with their specific receptors
