Major link between mast cells and the idiopathic hypereosinophilic syndrome

Abstract

The idiopathic hypereosinophilic syndrome (IHES) is characterized by sustained severe peripheral blood eosinophilia (>1500 einophils/mm3) and the presence of eosinophil-associated end-organ damage in a patient with no identifiable cause for the eosinophilia. The molecular basis for IHES (in a subset of patients) has recently been shown to involve an interstitial deletion in chromosome 4, resulting in the generation of a fusion protein between the platelet-derived growth factor receptor α gene (PDGFRA) and the previously uncharacterized gene FIP1L1 (Cools et al. N Engl J Med 2003;348:1201-14). Notably, the fusion protein is susceptible to imatinib (Gleevec) treatment. In the present study, the authors extend these important observations by providing further evidence that this subset of patients has a myeloproliferative disease variant. In particular, the authors examined levels of serum tryptase, a mast cell–derived product that has been previously associated with myeloproliferative disorders and systemic mastocytosis. Significantly, the investigators found that 9 of 15 patients with classic IHES had elevated levels of serum tryptase. Importantly, this tryptase-positive subset of patients had a markedly worse disease course, including extensive end-organ damage and a higher mortality rate. Of even greater interest, all tryptase-positive patients harbored the FIP1L1-PDGRFA gene fusion and all responded to imatinib therapy. Although the tryptase-positive patients with IHES met minor criteria for a diagnosis of systemic mastocytosis, the authors present evidence that distinguishes these patients from patients with classic systemic mastocytosis. The results implicate direct action between mast cells and eosinophils in IHES and raise the possibility that the fusion protein is active in both cell lineages.