Siglec-8 as mast cell selective target: developing paradigms amidst inconvenient truths

Abstract

Due to the limited efficacy of current drugs in treating systemic mast cell activation disease, there is an urgent need for more effective drugs selectively acting at mast cells. In the past, a large number of compounds have been claimed to be effective and mast cell selective on the basis of cell culture experiments and studies on blood leukocytes which could not be verified in organ and animal studies. Nevertheless, over time in review papers about potential mast cell targets mast cell selectivity of these targets has been no longer challenged. A recent example for such developing paradigms amidst inconvenient truths is the hype on the purported selective expression of the putative adhesion molecule sialic acid binding Ig-like lectin 8 (Siglec-8) in mast cells and eosinophils, although current data from different publically available databases/sources clearly demonstrate a widespread expression of Siglec-8 in the cells of most tissues. Two suggestions are presented: (1) In the specific case of Siglec-8, the limited mast cell selectivity should be kept in mind in the development and surveillance of Siglec-8-based mast cell- and eosinophil-targeted therapeutic strategies because of potential severe adverse effects in the Siglec-8-positive tissues. (2) In general, readers should always challenge reports about the selective expression of potential targets for drugs in a few cell types of the organism, even if they are published in highly renown journals.