Nippocystatin, a cysteine protease inhibitor from Nippostrongylus brasiliensis, inhibits antigen processing and modulates antigen-specific immune response

During infection, parasites evade the host immune system by modulating or e xploiting the immune system; e.g., they suppress expression of major histoc ompatibility complex class II molecules or secrete cytokine-like molecules. However, it is not clear whether helminths disturb the immune responses of their hosts by controlling the antigen-processing pathways of the hosts. I n this study, we identified a new cysteine protease inhibitor, nippocystati n, derived from excretory-secretory (ES) products of an intestinal nematode , Nippostrongylus brasiliensis. Nippocystatin, which belongs to cystatin fa mily 2, consists of 144 amino acids and is secreted as a 14-kDa mature form . In vivo treatment of ovalbumin (OVA)-immunized mice with recombinant nipp ocystatin (rNbCys) profoundly suppressed OVA-specific proliferation of sple nocytes but not non-antigenspecific proliferation of splenocytes. OVA-speci fic cytokine production was also greatly suppressed in rNbCys-treated mice. Although the serum levels of both OVA-specific immunoglobulin G1 (IgG1) an d IgG2a were not affected by rNbCys treatment, OVA-specific IgE was prefere ntially downregulated in rNbCys-treated mice. In vitro rNbCys inhibited pro cessing of OVA by lysosomal cysteine proteases from the spleens of mice. Mi ce with anti-nippocystatin antibodies became partially resistant to infecti on with N. brasiliensis. Based on these findings, N. brasiliensis appears t o skillfully evade host immune systems by secreting nippocystatin, which mo dulates antigen processing in antigen-presenting cells of hosts.