A filarial nematode-secreted phosphorylcholine-containing glycoprotein uncouples the B cell antigen receptor from extracellular signal-regulated kinase-mitogen-activated protein kinase by promoting the surface Ig-mediated recruitment of Src homology 2 domain-containing tyrosine phosphatase-1 and Pac-1 mitogen-activated kinase-phosphatase

Unraveling the molecular mechanisms by which filarial nematodes, major huma n pathogens in the tropics, evade the host immune system remains an elusive goal. We have previously shown that excretory-secretory product-62 (ES-62) , a homologue of phosphorylcholine-containing molecules that are secreted b y human parasites and which is active in rodent models of filarial infectio n, is able to polyclonally activate certain protein tyrosine kinase and mit ogen-activating protein kinase signal transduction elements in B lymphocyte s. Such activation mediates desensitization of subsequent B cell Ag recepto r (BCR) ligation-induced activation of extracellular signal-regulated kinas e-mitogen-activated protein (ErkMAP) kinase and ultimately B cell prolifera tion. We now show that the desensitization is due to ES-62 targeting two ma jor regulatory sites of B cell activation. Firstly, pre-exposure to ES-62 p rimes subsequent BCR-mediated recruitment of SHP-1 tyrosine phosphatase to abolish recruitment of the RasErkMAP kinase cascade via the Ig alpha beta - ShcGrb2Sos adaptor complex interactions. Secondly, any ongoing ErkMAP kinas e signaling in ES-62-primed BCR.