Major link between mast cells and the idiopathic hypereosinophilic syndrome

The idiopathic hypereosinophilic syndrome (IHES) is characterized by sustained severe peripheral blood eosinophilia (more than 1500 eosinophils/mm³) and the presence of eosinophil-associated end-organ damage in a patient with no identifiable causes for the eosinophilia (eg, malignancy or infection). Despite the fact that IHES is a rare problem, the disease has received a significant amount of research attention, especially of late. Notably, the molecular basis for IHES (in a subset of patients) has recently been shown to involve an interstitial deletion in chromosome 4, which results in the generation of a fusion protein between the platelet-derived growth factor receptor α (PDGFRA) gene and a previously uncharacterized gene, FIP1L1 (Cools et al, N Engl J Med. 2003;348:1201-1214). Notably, the fusion protein is susceptible to imatinib (Gleevec) treatment; interestingly, this drug has recently been shown to be effective in a subset of patients with IHES. These results suggest that many cases of IHES are actually myeloproliferative clonal disorders. As such, these results challenge the conventional classification of hypereosinophilic syndromes that has historically distinguished IHES from eosinophilic leukemia.

In this issue Klion and colleagues (page 4660) extend these important observations in a landmark study that provides further evidence that this subset of patients has a myeloproliferative disease variant. In particular, the authors examine levels of serum tryptase, a mast cell–derived product that has been previously associated with myeloproliferative disorders and systemic mastocytosis. Notably, 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. Whereas the tryptase-positive IHES patients met minor criteria for systemic mastocytosis, the authors presented evidence that distinguished these patients from classic systemic mastocytosis (eg, lack of bone-marrow mast-cell clusters or abnormal mast-cell phenotypes). Indeed, mast-cell products (eg, TNF-α, IL-5, proteases, and eotaxin) activate eosinophils; conversely, eosinophil products (eg, major basic protein) activate mast cells. Although both cell types are involved in allergic diseases, previous studies have distinguished their lineage commitment. For example, mast cells are primarily c-Kit-ligand–dependent whereas eosinophils are primarily IL-5–dependent. These results implicate direct action between mast cells and eosinophils in the pathogenesis of severe disease pathology associated with IHES.

These results clearly open up several new major areas for research investigation. In particular, it will be critical to determine the molecular explanation for the association of tryptase with IHES. This association may be explained by the ability of aggressive eosinophils to stimulate mast cells, or alternatively, the FIP1L1-PDGFRA fusion protein may participate in multiple hematopoietic lineages, especially mast cells and eosinophils.

Before closing, a word of caution should be stated concerning nomenclature. While the authors refer to their patients as having “hypereosinophilic syndrome,” this categorization is fairly broad and nonspecific since numerous disease entities (eg, Churg-Strauss syndrome and eosinophilic gastroenteritis) may be considered to be hypereosinophilic syndromes. My own preference, consistent with Cools et al, calls these patients IHES rather than HES. As such, IHES patients have a strong male-sex predominance (9:1 male-female ratio), and a high probability of the FIP1L1-PDGFRA fusion event, and imatinib responsiveness. The strong male-sex predominance in tryptase-positive IHES patients suggests the importance of X-linked modifying genes. Clearly, this study represents a large step forward in understanding the pathogenesis of IHES. The authors are to be congratulated for making this important contribution.