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

The pathogenesis of Langerhans cell histiocytosis (LCH) remains poorly unde rstood. To further elucidate LCH pathogenesis, we analyzed the expression o f 10 cytokines relevant to cellular recruitment and activation at the prote in level in 14 patients and identified the lesional cells responsible for c ytokine production in situ by immunohistochemistry. The cytokines investiga ted included the hematopoietic growth factors interleukin-3 (IL-3), IL-7, a nd granulocyte-macrophage colony-stimulating factor (GM-CSF); the lymphocyt e regulatory cytokines IL-2, IL-4, and IL-10; the inflammatory regulators I L-1 alpha and tumor necrosis factor-alpha (TNF-or); and the effector cell-a ctivating 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-or were produced exclusively by T cells, whereas only IL-2 was produced by LC H cells. Equal numbers of LCH cells, T cells, and macrophages produced GM-C SF 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 produ ced 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 irrespec tive of age, gender, or site of biopsy. These findings emphasize the role o f T cells in LCH. The juxtaposition of T cells and LCH cells suggests that both cells interact in a cytokine amplification cascade, resulting from sti mulation 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 invol ved in the development of other characteristic features of LCH, such as fib rosis, necrosis, and osteolysis. (C) 1999 by The American Society of Hemato logy.