Immunoglobulin E (IgE) containing complexes induce IL-4 production in human basophils: effect on Th1–Th2 balance in malaria

Abstract

Human basophils are potent producers of IL-4 following cross-linking of the high affinity receptor for IgE (FcεR1). Elevated levels of both total- and malaria-specific IgE have been demonstrated in sera from people living in malaria-endemic regions. Whether or not these IgE antibodies are pathogenic is unclear. Serum containing high IgE levels obtained from malaria individuals was used to establish whether IgE-immune complexes could induce IL-4 production in human basophils. The basophils, obtained from healthy donors, were primed with 10 ng/ml of IL-3 before being transferred to wells containing goat anti-human IgE or human antimalarial IgE-immune complexes. IL-4 was induced upon stimulation of human basophils by plate bound IgE-containing immune complexes. Basophils treated similarly but with goat anti-IgG/human antimalarial- IgG-immune complexes did not secrete IL-4. Similarly mononuclear cells depleted of basophils in parallel culture did not secrete IL-4. Thus, human basophils may contribute to the polarization of T-helper type 2 in the (Th2) responses in malaria hosts via IgE-induced IL-4 production.

Introduction

Parasite infections are often associated with increased levels of circulating basophils and eosinophils, markedly increased serum levels of IgE and increased numbers of mast cells and/or basophils in the affected tissue. Elevated serum levels of specific and polyclonal IgE are usually a hallmark of atopy and helminthic infection (Jarrett and Miller, 1982). We and others have shown that people living in malaria-endemic areas have elevated serum levels of both total- and anti-malarial-specific IgE (Desowitz, 1989, Perlmann et al., 1994). When examining serum samples from children and adults living in malaria-endemic areas in different African and Asian countries, 85% of the donors had significantly elevated levels of IgE and more than 60% of these had detectable anti-malarial specific IgE antibodies (Perlmann et al., 1994). However, the role of these IgE antibodies in malaria is unknown.

IgE interacts with IgE-receptors expressed on a variety of different cell types. There are two major types of IgE receptors. One form is the low-affinity receptor FcεRII (CD23) constitutively expressed on B cells and induced by IL-4 on macrophages (Vercelli et al., 1988), some T cells, human eosinophils and platelets (Delespesse et al., 1992). Cross-linking of CD23 on macrophages or other CD23-bearing effector cells by IgE-containing immune complexes is thought to play a pathogenic role, via TNF-mediated pathways (Perlmann et al., 1994, Dugas et al., 1995, Perlmann et al., 1999, Perlmann et al., 1997). Although these data seem to favour a pathogenic role of malarial induced IgE, they do not exclude other roles for this immunoglobulin isotype.

IgE also binds to the high affinity IgE receptor (FcεRI) present primarily on mast cells and/or basophils in both mice and humans. Upon cross-linking of the high affinity IgE receptors or in response to IL-3, basophils rapidly release cytokines such as IL-4 and IL-13 (Plaut et al., 1989, Brunner et al., 1993). The cytokine milieu is an important factor in the polarization of helper (Th) cells. This is for example evident in the murine P. chabaudichabaudi system where it has been shown that a population of IL-3 responsive IL-4 producing non-B non-T (NBNT) cells of basophil origin expand in the spleen and in the peripheral blood during acute infection (Poorafshar et al., 2000). This takes place at the same period when the Th cells switch from Th1 to Th2, needed for the complete resolution of the infection in this model (Helmby et al., 1998, Langhorne et al., 1990). However, a direct role of malaria-induced IgE in the activation of cells that express the high affinity receptors for IgE in humans is unknown. The aim of the present study was to determine whether IgE-containing malaria sera have the capacity to induce IL-4 in NBNT cells of basophil origin.