Cleavage of Human IgE Mediated by <i>Schistosoma mansoni</i>

Abstract

Background: IgE-mediated mechanisms are important in protection against helminth parasites. However, schistosomes are long-lived in mammalian hosts, presumably as a result of immune evasion strategies. We sought evidence for one such strategy, namely specific cleavage of host IgE. Methods: Human IgE, IgA and IgG were incubated with extracts from cercarial and schistosomular stages of Schistosoma mansoni or with schistosomular culture supernatants. The resulting products were analysed by Western blotting with Ig-specific antibodies. Numerous protease inhibitors were assessed for ability to inhibit the observed cleavage of IgE by the extracts. Partial purification of the IgE-proteolytic activity from cercarial extract was achieved by gel filtration. To test IgE function, we compared the abilities of untreated and schistosomular-treated IgE to mediate rosette formation through interaction with Fcε receptors. Results: Cercarial and schistosomular extracts were found to cleave human, mouse and rat IgE but not human IgA1, IgA2 or IgG1. Schistosomular culture supernatants displayed similar proteolytic activity towards IgE. Immunoblotting suggested that cleavage occurred close to the Cε2/Cε3 domain interface of the IgE heavy chain. PMSF and elastatinal inhibited cleavage, suggesting that the protease involved is an elastase-like serine protease, particularly since porcine pancreatic elastase also cleaved IgE to give similar-sized products. Further, the chloromethyl ketone derivatized peptide MeO-Suc-Ala-Ala-Pro-Leu- CMK, known to specifically inhibit the schistosome elastase, prevented IgE cleavage. Cleavage of human IgE rendered the antibody molecule unable to interact with U937 cells expressing FcεRII. Conclusions: An elastase-like protease in S. mansoni is able to render IgE non-functional.

Helminth immunoregulation: The role of parasite secreted proteins in modulating host immunity

“…The same skin-stage schistosome ES directs DCs to drive Th2 responses in vivo [37]. This ES contains abundant proteases, including several elastases that facilitate parasite skin penetration [38], and can cleave host IgE antibodies [39]. The presence of multiple isoforms of cercarial elastase and a metalloprotease was confirmed by proteomics of cultured parasites [40,41], and by proteomic analysis of human skin traversed by invading cercariae [42].…”

Serine Proteases of Parasitic Helminths

“…This cleavage can be inhibited by serine protease inhibitors. This indicates that during the establishment of mature infections, an elastase-like serine protease helps the parasite to evade IgE-mediated protective reactions [ 46 ]. A recent study using a highly purified SmCE found that these SmCE cleave IgE at solvent-exposed interdomain regions of the IgE-Fc.…”

Schistosomiasis: Setting Routes for Drug Discovery

“…SmCE could have a role in immune evasion, as a highly purified SmCE was able to cleave IgE and other key molecules involved in immune regulation [101]. The use of serine protease inhibitors prevented IgE cleavage by cercariae and schistosomula extracts in a previous study, indicating that this could be a promising path for therapeutic strategies [102].…”