Blockade of either alpha-4 or beta-7 integrins selectively inhibits intestinal mast cell hyperplasia and worm expulsion in response to Nippostrongylus brasiliensis infection.

Mast cells are known to express high levels of alpha4 integrins including alpha4beta7 and are found in increased numbers in mucosal inflammation. Mast cell accumulation is particularly prominent in the intestine following nematode infection. The adhesion molecule requirements for this process have not yet been defined. The role of alpha4 and beta7 integrin chains in the intestinal mast cell hyperplasia following infection of rats with the nematode parasite Nippostrongylus brasiliensis was examined in this study. Rats were infected with N. brasiliensis larvae and treated with either anti-alpha4 (TA-2), anti-beta7 or isotype-matched control antibodies. The initial mast cell hyperplasia in response to N. brasiliensis infection was significantly inhibited by either anti-alpha4 or anti-beta7 treatment. In contrast, the intestinal eosinophil response to N. brasiliensis infection was not reduced at day 14 or day 16. Elevations in serum IgE levels due to N. brasiliensis infection were also not inhibited by anti-alpha4 or anti-beta7 antibody treatment. Anti-alpha4 antibody but not anti-beta7 antibody treatment also induced a small but significant decrease in the numbers of mast cells in tongue tissue. These data suggest a role for alpha4 integrins, in particular alpha4beta7, in the regulation of mast cell precursor migration to the intestine.

Mast cell Fc epsilonRI expression in the rat intestinal mucosa and tongue is enhanced during Nippostrongylus brasiliensis infection and can be up-regulated by in vivo administration of IgE.

The activation of rodent and human mast cells can occur through the cross-linking of tetrameric IgE receptors each containing single alpha- and beta- and two gamma-subunits. However, the factors that regulate the in vivo expression of Fc epsilonRI are poorly understood. We have examined the expression of the Fc epsilonRI beta-subunit in the Nippostrongylus brasiliensis (Nb)-induced mode l of rat intestinal inflammation. We developed a double-staining technique for mast cell granules (Alcian blue) and the beta-subunit of Fc epsilonRI. The intensity of immunohistochemical staining per mast cell was quantified using an image analysis system. Jejunal and tongue mast cells of Lewis rats were visible by Alcian blue staining before Nb infection, but they expressed very low levels of beta-subunit as assessed by immunohistochemical staining. These levels were increased by day 11 postinfection and reached a maximum at day 14. Since serum IgE levels correlated well with the degree of beta-subunit expression, we investigated whether the observed enhancement of receptor expression might occur through the stabilization of receptor complexes by IgE. Therefore, Lewis rats were treated with myeloma IgE, and beta-subunit expression was examined. In both tongue and jejunal tissue, a significant rise in beta-subunit expression was observed in response to IgE injection, although levels of beta-subunit expression were not as high as those observed in Nb-infected animals. The increase in beta-subunit expression was accompanied by an increase in the amount of mast cell-associated IgE. These observations may have important implications for the regulation of IgE receptor expression during disease.

Accelerated elimination of N. brasiliensis from the small intestine after auto-anti-IgE induction.

Immunization of rats with a purified IgE myeloma (IR2) induced an auto-anti-IgE response. Such treatment inhibited total IgE levels in the serum of conventional IgE-producing rats (Marshall & Bell, 1985) and increased the number of mucosal mast cells (MMC) in the intestine. The present study has investigated the ability of auto-anti-IgE induction to influence the course of a Nippostrongylus brasiliensis infection, to modify IgE synthesis, or to affect the number of MMC in the intestine following infection. Auto-anti-IgE induction was found to have a surprising effect on worm elimination. IR2-immunized rats were able to rid themselves of this nematode with an accelerated tempo--a small but significant effect after primary infection, but a substantial enhancement of worm loss after reinfection. Auto-anti-IgE induction was not able to prevent the typical increase in IgE that accompanies an N. brasiliensis infection, nor did it alter the helminth-induced intestinal mastocytosis. When MMC degranulation was measured by assaying the serum levels of a specific rat mast protease (RMCP II) following secondary infection, the amount of RMCP II released was less in auto-anti-IgE-producing rats. These findings have implications for the importance of IgE, MMC and other cells of inflammation in an anti-parasitic response.