Conditions where eosinophils are overproduced lead to detrimental effects for the host. One such condition, HES is defined by the presence of more than 1.5 × 10 6 eosinophils/mL blood during a time period of at least 6 months, organ involvement and with no other etiology identified. One form of HES, the myeloproliferative form, is caused by an 800 bp deletion on chromosome 4 during the haematopoiesis in the bone marrow, resulting in a fusion between the gene FIP1L1 and the PDGFRA gene [110] . A fusion protein is produced which constitutively phosphorylates tyrosine residues leading to malignant expansion of eosinophils. Another form of HES is a clonal lymphocytic variant (L-HES) where aberrant cytokine production by malignant lymphocytes causes HES. For other cases the cause of the overproduction of the eosinophils is unknown but HES is associated with high levels of ECP in plasma and serum, of up to 0.2 μg/mL [111, 112] . It is not know however whether theses high levels of the protein are pathological. A few in vitro studies might relate to the etiologies of HES. Eosinophil infiltration of the skin of HES patients is the most common clinical manifestation [113] . Some of these patients present with erosive and ulcerative lesions and ECP was found both deposited and taken up by cells in those lesions [114] . ECP's ability to cause ulcerations in the skin has been analysed by injecting the protein intradermally into guinea pig skin, where it was found that the protein can persist there for two weeks [64] which is possibly attributed to its high stability [28] . Injections of high levels of ECP (48 and 190 μg/mL/2.5 and 10 μM) caused ulcerations which were most severe after seven days [114] . Inflammatory cells were found infiltrating the inflamed area and ECP was found taken up by cells within 48 hr. Injection of poly-lysine, other basic granule proteins MBP, EPO and the basic ribonuclease onconase showed that the severity of the lesions was not directly correlated with level of basicity. ECP and EDN were found to be more potent in lesion formations than MBP and EPO. Addition of RNase inhibitor or obliteration of the RNase activity by carboxymethylation of the RNase site of ECP reduced the ulcerations by 60 percent suggesting RNase activity is important, but not wholly responsible for the activity [114] . Some studies have shown that patients with HES have an slightly elevated risk for thrombosis formation systemically [115] and in the cardiac ventricle [116] . ECP has been shown to shortened the coagulation time for plasma which was dependent on an interaction with coagulation factor XII [117] . Eosinophils also infiltrate the endomyocardium of some patients and this has been suggested to be the cause of development of scaring in the ventricle [116] . High levels of ECP (16.25 μg/mL) degrade the muscle protein component, the myosin heavy chain in vitro [118] but it is not known whether ECP directly interacts with muscle fibres of the heart. The final stage is endomyocardial fibrosis in which eosinophils and ECP have been postulated to participate [119] by their influence on fibroblast function. Although a rare finding, a few patients with the myeloid form of HES have been reported to have central nervous system (CNS) manifestation [113, 120] . It is not known whether ECP can reach the brain but ECPs effect on the CNS has been assayed by direct intracerebral injection. Guinea-pigs injected with ECP, showed with doses of 0.1 μg and up, cerebral symptoms up until the end of the experiment at day 16 [121] . Purkinje cells in the brain were decimated in this model, suggesting that the circulating ECP could affect the CNS of some HES patients if the protein reached the brain.