The role of eosinophils in the pathobiology of Hodgkin's disease

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Abstract
Background Even though the presence of a prominent tissue eosinophilia represents a common histopathologic feature of Hodgkin's disease (HD), eosinophils have been mainly regarded as ‘innocent’ bystanders recruited and activated during the cellular reaction typical of HD. To evaluate the putative role of eosinophils or eosinophil-derived cytokines on tumor-cell regulation in HD, we have analyzed these cells for the functional expression of surface ligands (L) of the tumor necrosis factor (TNF) superfamily, whose specific receptors are known to transduce proliferation signals at the surface of Hodgkin (H) and Reed-Sternberg (RS) cells. Materials and methods Eosinophils from peripheral blood of healthy donors and patients with HD, primary hypereosinophilic syndrome (HES), or secondary hypereosinophilia (HE), were purified by density gradient centrifugation and immunomagnetic depletion of residual granulocytes. Results By immunostaining and mRNA analysis, we were able to show that eosinophils from normal donors and patients with HD, HES, and HE express a number of receptors and ligands of the TNF superfamily, including CD40, CD40L, CD30L, CD95/Fas, CD95/FasL and 4-1BB. In addition, we provide evidence that cytokines regulating eosinophil proliferation and activation, i.e., interleukin (IL)-5, IL-3, and granulocyte-macrophage colony-stimulating factor, are able to enhance the cellular density of several TNF superfamily ligands and/or receptors at the surface of cultured eosinophils. Finally, we have shown that native CD40L and CD30L at the surface of purified eosinophils are functionally active and able to transduce proliferative signals on CD40+ and CD30+ target cells, including cultured H-RS cells. Conclusions Our data suggest that eosinophils may act as important elements in the pathology of HD by providing cellular ligands for TNF-superfamily receptors (CD40, CD30, CD95/Fas) able to transduce proliferation and antiapoptotic signals at the surface of H-RS cells. The presence on eosinophils of receptors for TNF ligands expressed by activated T cells (i.e., OX40L, FasL, CD40L, 4-1BBL), also suggest that eosinophils may contribute to the deregulated network of interactive signals between H-RS cells, T cells, and other surrounding reactive cells.