Extract of Nippostrongylus brasiliensis stimulates polyclonal type-2 immunoglobulin response by inducing de novo class switch

Infection with the nematode parasite Nippostrongylus brasiliensis induces a pronounced type-2 T-cell response that is associated with marked polyclona l immunoglobulin E (IgE) and IgG1 production in mice. To examine the differ ential roles of the infection and products produced by nematodes,,ve invest igated a soluble extract of N. brasiliensis for the ability to mediate this type-2 response. We found that the extract induced a marked increase in Ig E and IgG1 levels, similar to that induced by the infection. The extract di d not affect the level of IgG2a in serum, shelving that the effect was spec ific to IgE and IgG1 (type-2-associated immunoglobulin) rather than inducin g a nonspecific increase in all immunoglobulin isotypes. This response was also associated with increased interleukin-4 production in vitro. These res ults confirm that the extract, like infection, is a strong inducer of polyc lonal type-2 responses and a reliable model for investigating the regulatio n of nematode-induced responses. The extract induced the production of IgG1 when added to in vitro cultures of lipopolysaccharide-stimulated B cells. This provides evidence for the induction of class snitch. It did not induce upregulation of IgG1 in naive (unstimulated) B cells or expand B cells in in vitro cultures. Analysis of DNA from the spleens of mice treated with th e extract by digestion-circularization PCR demonstrated a marked increase i n the occurrence of gamma 1 switch region gene recombination in the cells i n vivo. These results provide strong evidence that soluble worm products ar e able to mediate the marked polyclonal gamma 1/epsilon response and that i nfection is not required to mediate this response. Furthermore, these data provide evidence that the soluble nematode extract induces this effect by c ausing de novo class switch of B cells and not by an expansion of IgG1 B ce lls or an increase in antibody production by IgG1 plasma cells.