Importance of immunoglobulin E (IgE) in the protective mechanism against gastrointestinal nematode infection: looking at the intestinal mucosae

A importância de imunoglobulina E (IgE) na mucosa intestinal para a eliminação de nematódeos parasitos gastrointestinais

INVITED REVIEW

IMPORTANCE OF IMMUNOGLOBULIN E (IgE) IN THE PROTECTIVE MECHANISM AGAINST GASTROINTESTINAL NEMATODE INFECTION: LOOKING AT THE INTESTINAL MUCOSAE

Deborah NEGRÃO-CORRÊA(¹)

SUMMARY

This review discusses experimental evidences that indicate the IgE participation on the effector mechanisms that leads to gastrointestinal nematode elimination. Data discussed here showed that, for most experimental models, the immune response involved in nematode elimination is regulated by Th-2 type cytokines (especially IL-4). However, the mechanism(s) that result in worm elimination is not clear and might be distinct in different nematode species. Parasite specific IgE production, especially the IgE produced by the intestinal mucosae or associated lymphoid organs could participate in the intestinal elimination of Trichinella spiralis from infected rats. Intestinal IgE may also be important to the protective mechanism developed against other gastrointestinal nematodes that penetrate the murine duodenum mucosa tissue, such as Strongyloides venezuelensis and Heligmosomoides polygyrus. At least in Trichinella spiralis infected rats, the results indicated that intestinal IgE might work independently from mast cell degranulation for worm elimination.

KEYWORDS: Immunoglobulin E; Gastrointestinal nematodes; Rats; Intestinal immunity.

INTRODUCTION

Helminth infections are highly prevalent in human population, particularly in tropical and subtropical countries. Twenty-six species of helminth parasites have been reported to infect humans. Among these parasites, nematode species that colonize gastrointestinal tract are of concern in terms of overall morbidity. The four most prevalent species of nematodes: Ascaris lumbricoides, Trichuris trichiura, Necator americanus and Ancylostoma duodenale infect more than a billion people worldwide (CHAN, 1997).

The three hallmarks of the immune response triggered by gastrointestinal (GI) nematode infection are eosinophilia, intestinal mastocytosis and IgE production (JARRETT & MILLER, 1982; LOVE et al., 1976; RUITENBERG et al., 1979). These responses are regulated, in humans and mice, by cytokines produced by a T helper cell subset designated Th-2 (MOSMANN & COFFMAN, 1989). T lymphocytes bearing ab receptors represent > 90% of peripheral blood T cells and can be divided into two major populations, CD4+ and CD8+ cells. CD4+ T cells recognize specific antigens in association with MHC class II molecules and act predominantly as helper T cells (Th), while CD8+ T cells recognize specific antigens in association with MHC class I molecules and act primarily as cytotoxic effector cells (Tc). MOSMANN & COFFMAN (1989) subdivided the activated CD4+ T cells of mice into two classes, Th1 and Th2, based on the pattern of cytokines released upon stimulation.

The different cytokine patterns produced by Th1 and Th2 cells correspond to a functional separation of T helper cells. Th-1 subset produces mainly interferon-gamma (IFN-g), interleukin-2 (IL-2) and tumor necrosis factor-beta (TNF-b). These cytokines regulate cell-mediated immune response and delayed-type hypersensitivity reactions. Th-2 subset produces predominantly IL-4, IL-5, IL-9, IL-10 and IL-13, which regulate the humoral response, promoting B cell proliferation and immunoglobulin switching, predominantly to IgG1 (in mice) and IgE-producing plasma cells. Th-2 cytokines also induce growth and differentiation of mast cells and eosinophils (reviewed by ABBAS et al., 1996).

A Th1-like response appears critical to protective immunity developed against a variety of intracellular parasites. The protective function of Th1 response was first characterized in Leishmania major infected mice (LIEW et al., 1990) and subsequently confirmed in Toxoplasma, Eimeria and Cryptosporidium infected mice (FINKELMAN & URBAN, 1992). Th2 response is mainly induced by extracellular parasites such as helminthes. Recent evidence favors the idea that a protective role exists for Th2-like responses in helminth infection (URBAN et al., 1992; FINKELMAN et al., 1997). At least two independent studies of murine infection with Trichuris muris (ELSE et al., 1992) and Heligmosomoides polygyrus (URBAN et al., 1991) have directly demonstrated a protective role for Th2 response. In T. muris infection, mouse strains that produce predominantly Th-1 responses develop a chronic infection and are defined as susceptible strains for this parasite. Mouse strains capable of mounting a Th2 response against T. muris infection are able to eliminate worms before they mature into egg-producing adult worms, and are designated resistant strains. Susceptible mouse strains are able to cure chronic infection produced by T. muris if they are treated with IL-4 (ELSE et al., 1994). More recently, the essential role of Th-2 response in the protective mechanism against helminthic infection, but not the Th-1 response, was respectively demonstrated in IL-4 or IFN-g "knock-out" Trichinella spiralis infected mice (LAWRENCE et al., 1998).

Th2 immune response induced by IL-4 regulates antibody production and switching to IgG1 and IgE isotype (FINKELMAN et al., 1988) and mast cell activation (MADDEN et al., 1991). IL-4 may also have a direct effect on the intestinal mucosae that might contribute to worm elimination. In vitro, IL-4 stimulation produced a dose-dependent proliferation of a rat intestinal epithelial cell line - IEC-6 (McGEE & VITKUS, 1996). In addition, IL-4 stimulation resulted in a regulation of the ion transport and the expression of accessory molecules that mediated neutrophil adhesion displayed by the human gut epithelium (T84 cell line) monolayer (COLGAN et al., 1994). RAMASWAMY et al. (1994) reported an IgE transport mechanism in the intestine of T. spiralis infected rats, which is also IL-4 dependent. However, the exact mechanism by which IL-4 acts to control helminth infection is still unknown.

This review focus on the participation of the host IgE response in the protective immune response to helminthic infection, especially during a GI Nematode infection. To set the stage for a discussion some relevant aspects of IgE and the intestinal immune system are initially reviewed and then the relationship between IgE response with experimental models of GI Nematode parasite infections is analyzed.

BIOLOGICAL FEATURES OF IgE AND INTESTINAL IMMUNE SYSTEM

Immunoglobulin E (IgE) is one of the five classes of antibody recognized in humans. This immunoglobulin is only present in mammals and represents a very small fraction of the total antibody in serum. In humans, serum IgE concentrations range between 50 and 300 ng ml^-1, while IgG concentrations reach up to 10 mg ml^-1 (SUTTON & GOULD, 1993). In addition to the low concentration, IgE is catabolized at a greater rate than any other immunoglobulin. TADA et al. (1975) estimated that rat IgE has a half-life of 12 h in serum. However, when bound to mast cells, IgE has a half-life of 7 days. Studies on the metabolism of human IgE using ¹²⁵I- labeled IgE (IIO et al., 1978) indicated that the disappearance of IgE from the serum could only be explained by an extravascular catabolic mechanism. The extravascular catabolic process reported to IgE was undefined by the authors. RAMASWAMY et al. (1994) showed evidences of an IgE transport from the serum to the intestinal lumen in T. spiralis infected rats. In the same model, ¹²⁵I- labeled IgE had a half-life of 5 h in serum and only 3.25 min in the intestinal lumen of a 10 day infected rats (NEGRÃO-CORRÊA et al., 1996), demonstrating a rapid degradation rate of IgE in the intestine that could explain the extravascular metabolism of this immunoglobulin in T. spiralis infected rats.

B cells switch to IgE-producing plasma cells is regulated by IL-4 and require CD40 - CD40 ligand engagement (VERCELLI, 1993). The main source of IL-4 is thought to be T helper cells that after activation also express CD40 ligand. Therefore, IL-4 production by activated T cells seems essential for IgE production. The T cell dependence of serum IgE production has been investigated in vivo by reconstitution of X-irradiated mice with CD4+ plus CD4- spleen cells from the wild type or IL-4 "knock-out" mice. Mice reconstituted with T cells from IL-4 "knock-out" mice, do not produced serum IgE response, suggesting that IL-4 from T cells is sufficient to produce an IgE response in vivo (SCHMITZ et al., 1994).

However, non-T cells, such as mast cells and basophils (PLAUT et al., 1989) can also produce IL-4. Human mast cell and basophil cell line can also express CD40 ligand and, in the presence of IL-4, mast cells are able to stimulate IgE production in vitro (GAUCHAT et al., 1993). The biological relevance of the T-independent IgE production in vivo is unknown. Athymic rats infected by N. brasiliensis do produce up-regulation of IgE receptor and IgE occupancy on peritoneal mast cells, indicating that a T-independent IgE immune response might occur in vivo. However, the response is considerably smaller than that observed in euthymic rats and mast cell degranulation was not achieved (CHEN & ENERBACK, 1996). JANKOVIC et al. (1997) demonstrated that FceRI "knock-out" mice are unable to trigger IL-4 production from non-B and non-T cell after Schistosoma mansoni infection, however T cells from FceRI "knock-out" mice do produce normal IL-4 level and the serum IgE production was not altered.

Due to the low concentration of circulating IgE, its function is normally related to the cell-bound receptor to which IgE binds. "The high affinity" receptor for IgE, FceRI, is expressed in high density by basophils and mast cells. Immediate hypersensitivity, the principal known function of IgE in vivo, requires binding of IgE to FceRI on mast cell and basophils. The cross-linking of IgE on mast cells by the antigen triggers mast cell degranulation, resulting in release of preformed mediators such as histamine, heparin, citokines and protease (SCHWARTZ, 1994). These preformed mediators induce the characteristic symptoms observed in an allergic reaction and contribute to the chronic eosinophilic inflammation that can appear in the surrounding tissue. FceRI has also been detected, in lower density, on Langerhans cells (WANG et al., 1992; BIEBER et al., 1992), on eosinophils of some hypereosinophilic patients (GOUNNI et al., 1994), on monocytes of patients with some atopic disorders (MAURER et al., 1994), and on circulating dendritic cells (GRABBE et al., 1993; MAURER et al., 1996) and platelets (JOSEPH et al., 1997). The function of IgE on either of these cell types is still unknown. On eosinophils, IgE binding to FceRI can lead to an antibody-dependent cellular cytotoxity (ADCC) reaction which has been associated with killing of schistosomula of Schistosoma mansoni (GOUNNI et al., 1994). It is important to notice that the FceRI cell distribution in human and rodents is not the same and the differences may provide a molecular basis for the differences observed between rat and mouse regarding IgE-mediated anti-parasite immunity. FceRI receptor was identified on human macrophages and eosinophils, and more recently on rat eosinophils and macrophages (DOMBROWICZ et al., 2000), however the receptor was not yet identified on mouse eosinophils (DE ANDRES et al., 1997). There are experimental evidences that FceRI expressed by human monocytes, Langerhans and dendritic cells do not express the b chain (ag₂ instead of abg₂), which would implicate in different functions or regulation, for instance IgE-mediated antigen presentation (KINET, 1999).

IgE also has a low affinity receptor, FceRII (CD23), present on a variety of cell types such as platelets, lymphocytes, eosinophils (CAPRON & JOSEPH, 1991) and enterocytes (KAISERLIAN et al., 1993). IgE also binds to epsilon-binding proteins (eBP) detected on the surface of enterocytes (BRASSART et al., 1992), eosinophils and neutrophils (TRUONG et al., 1993a and b), mast cells and macrophages (FRIGERI & LIU, 1992). IgE-dependent cell functions in vivo for most of these cell types have not been established. In vitro, there is some evidence that the association of IgE with FceRII in B cells might increase antigen presenting function to T cells (PIRRON et al., 1990), and on monocytes, IgE bound to FceRII may mediate phagocytosis of immune complexes (YOKOTA et al., 1992). The data discussed above illustrate how much of the IgE response is still unknown and give us an idea of how difficult is to understand the IgE role on helminthic infection.

In addition to the unknown functions of IgE, it is important to remember that the intestinal mucosae is associated to a very peculiar immune system. The diffuse lymphocyte population present in lamina propria (LPL) and epithelial tissue (IEL) constitutes the largest and more complex lymphocyte population in the body. In normal adult humans, the lamina propria of the small and large intestine contains a large number of plasma cells, most of which are sIgA+ (TSENG, 1983). IgE producing cells in the mucosae-associated lymphoid tissue is observed after helminthic infection or allergic reaction, and there are some experimental evidences suggesting that IgE+ cells in the mucosa of nematode infected rodents are also mostly, but not all, mast cells (MAYRHOFER et al., 1976; ALIZADEH et al., 1986; ISHIZAKA et al., 1976).

The T cell population makes up half of the lymphocytes in the lamina propria. The majority of these T cells in both the small and large intestine are CD4+ (SELBY et al., 1983), and bear ab T cell receptor (TCR). In contrast, IELs are predominantly T lymphocytes CD8+ with both TCR ab+ and gd+ cells. CD4+CD8+ (double positive) and CD4-CD8- (double negative) cells are also found in the IEL population. Some of these T cell populations have an alternative or extrathymic pathway for T cell differentiation which is regulated in the intestine environment (ROCHA et al., 1991; GUY-GRAND et al., 1991). Functionally, the IEL population is also complex and not fully understood. Regulation of IEL populations and their antigen recognition patterns probably differ from those of peripheral lymphocyte populations. PORCELLI et al. (1992) describe a CD1b-dependent, non-MHC class II-associated antigen recognition process. Therefore, the intestine can initiate and regulate T cell development independently of the thymus and the rest of the peripheral immune system (POUSSIER et al., 1992).

Many authors have demonstrated important differences between local and systemic immune responses. For example, local (intestinal) IgA response in N. brasiliensis infected rats (SINSKI & HOLMES, 1977) or in Haemonchus contortus infected sheep (CHARLEY-POULAIN et al., 1984) is not similar to the IgA response observed in the serum. Also, the intestinal IgE response during T. spiralis infection in rats is stronger and appeared earlier than the serum IgE response (NEGRÃO-CORRÊA et al., 1996). Local differences in cytokines levels were also observed between spleen and mesenteric lymph node or gut cells after T. spiralis infection in mice (LAWRENCE et al., 1998). However, the consequence of the local response in the GI nematode infection outcome has been poorly explored.

IgE AND HELMINTH INFECTION

IgE response has been strongly associated with helminth infections and allergic diseases, but the role of IgE in protective immunity against helminth infection has been difficult to establish. During an helminth infection, IgE levels in serum may increase 100-fold (JARRETT & BAZIN, 1974), which is proportionately greater than the response of any other immunoglobulin isotype. However, the absolute concentration of IgE in serum is still very low when it is compared with IgG subclasses. Although IgE levels are elevated during the infection, only a small proportion of the serum IgE pool is parasite specific (TURNER et al., 1979). For type I hypersensitivity and ADCC, two mechanisms that have been related to protection against helminthes, an excess of non-specific IgE might block the development of the host-protective mechanism. It has been proposed that the presence of disproportionately high levels of non-parasite specific IgE would saturate IgE receptors on effector cells and prevent activation of the effector mechanisms (PRITCHARD, 1993). Another interpretation for the high levels of non-specific IgE found in serum is a reduction in the risk of anaphylaxis (HAGAN, 1993), even though the response may still be sufficient to eliminate the parasite.

While the mechanism by which IgE participates in protective immunity is still unclear, IgE has been indirectly associated with protection in many infection models. OGILVIE (1964) reported the first correlation of IgE response with protection against helminthes. Based on results of N. brasiliensis infection in rats and S. mansoni infection in monkeys, the author suggested that "it may well be that reagin-like antibodies are responsible for immunity to helminthes in many species of animals". Since OGILVIE, many studies reported a positive correlation between specific IgE levels and protection against infection with different species of helminthes, such as Taenia taeniformis (MUSOKE et al., 1978), Trichinella spiralis (DESSEIN et al., 1981; NEGRÃO-CORRÊA et al., 1999), Brugia malayi (KURNIAWAN et al., 1993), Strongyloides ratti (KORENAGA et al., 1986). A positive correlation of parasite-specific IgE level and protection is also reported in human populations infected with Schistosoma mansoni and S. hematobium (HAGAN, 1993; DUNNE et al., 1992), Necator americanus (PRITCHARD et al., 1995) and Ascaris lumbricoides (McSHARRYet al., 1999). However, most of the evidences of IgE participation on protective mechanism of helminthic infection are indirect and inconclusive.

A more detailed discussion about IgE involvement in protective immunity will be explored in Trichinella spiralis infection of rats. In this experimental model, it has been described structural damage to the adult worms, loss of fecundity and expulsion of adult worms from the intestine within 10 - 20 days of infection (WAKELIN & DEHAM, 1983). The loss of fecundity and worm expulsion is also demonstrated, with a different kinetics, in several mice strains infected with T. spiralis (BELL, 1992). Upon challenge, immune rats are able to eliminate up to 90% of T. spiralis larvae within 1 - 2 h in a response called rapid expulsion (BELL & McGREGOR, 1979).

Although the mechanism responsible for worm elimination is not fully understood, many points have been elucidated. Experiments performed in nude mice (PERRUDET-BADOUX et al., 1980) and using adoptive cell transfer showed that worm elimination mechanism is promoted by thymus-derived (T) lymphocytes. Immune T cells do not act directly against the worm, since adoptive transfer of immune T cells to prior irradiated recipients (rats or mice) abolishes their ability to expel the worms (WAKELIN & DENHAM, 1983). Instead of acting directly, immune T cells produce different cytokines that induce many intestinal alterations, like eosinophilia and mastocytosis, observed during T. spiralis infection (RUITENBERG et al., 1979; FINKELMAN et al., 1997). The most accepted theory postulates that the T-dependent intestinal inflammation, denominated as allergic inflammation (LARSH & RACE, 1975), would induce alterations in the intestine mucosae which create an unsuitable environment for the worm (WAKELIN, 1993). Recently, this hypothesis has been largely discussed (reviewed by BELL, 1998). The results presented by LAWRENCE et al. (1998), using T. spiralis infected knockout mice (IL-4, IFNg and TNF receptor deficient animals), indicated that worm elimination and enteropathy would be independent. Therefore the IL-4 – dependent protective response against the parasite operates by mechanisms other than the degradation of the parasite's environment produced by the immune enteropathy.

Immune T cells and their cytokines are also essential for the formation of parasite specific antibodies, such as IgG1 and IgE (FINKELMAN et al., 1988). Larvae specific IgG antibody alone has been shown to mediate the rapid expulsion phenomenon in T. spiralis infected newborn rats (APPLETON & McGREGOR, 1987; APPLETON et al., 1988), while in adult rats, immune serum combined to lymphocytes mediates parasites rapid expulsion (BELL & McGREGOR, 1980; AHMAD et al., 1991a; BELL et al., 1992). Experimental evidences have demonstrated antibody participation, especially of the IgE isotype, on the T. spiralis worm elimination during primary infection and rapid expulsion (reviewed by BELL, 1998). It has been shown (AHMAD et al.,1991a and b) that parasite specific IgE, when transferred to rats primed with immune CD4+ OX22- T cells, was able to eliminate most of the T. spiralis infective larvae within hours after infection. These results also suggested that parasite specific IgE might mediate rejection even after infective larvae had penetrated the gut epithelium, since IgE could be transferred up to 6 h after the infection. Furthermore, larvae elimination appeared to be independent of intestinal mastocytosis, since the transfer of protective T cells plus IgE did not induce mastocytosis (WANG et al., 1990). In addition, the significance of IgE in the intestine during T. spiralis infections was reinforced by RAMASWAMY et al. (1994) who demonstrated a selective transport of IgE to the intestine lumen occurred in T. spiralis infected rats and in CD4+ OX22- immune T cells recipients rats, but not in non-infected animals.

Based on these previous results, we explored the importance of local (intestine) IgE in T. spiralis worm elimination. The comparison of IgE levels in serum and intestinal lumen of rats during a primary T. spiralis infection showed a powerful IgE response in the intestinal lumen in addition to that already recognized in serum (NEGRÃO-CORRÊA et al., 1996). The uniqueness of intestinal IgE was first evidenced by comparing the kinetics of the serum and the intestinal response during the infection. Intestinal IgE elevation occurred earlier in the infection than did the serum IgE response, peaking around 10 dpi. Furthermore, the intestinal IgE level dropped sharply after worm elimination, while in serum total IgE level reached a plateau after 14 dpi. IgE turnover studies indicated that IgE measured in the intestine at 10 dpi could not be explained by serum leakage or transport. At this point in the infection, the total amount of IgE in the intestine reached 2.57 mg/day, while the serum IgE level was only around 5 mg/day. These numbers suggested that the majority of the IgE response observed during the enteral phase of a primary T. spiralis infection in rats was produced and metabolized in the intestine associated lymphoid tissue and it is largely secretory (NEGRÃO-CORRÊA et al., 1996).

Comparison of T. spiralis specific IgE levels confirmed the independence of serum IgE with respect to intestinal IgE production. Parasite specific IgE isolated from the intestinal wash of T. spiralis infected rats had a higher titer, appeared earlier in the infection, and most importantly, had a different specificity than serum IgE. At 14 dpi, over 60% of intestinal IgE and only 10% of serum IgE reacted against larvae and/or adult T. spiralis antigens (NEGRÃO-CORRÊA & BELL, 1996; NEGRÃO-CORRÊA, 1997). The low proportion of parasite specific IgE observed in serum of helminth infected animals has been used as an argument against the participation of IgE in protective immunity (PRITCHARD, 1993). However, our result suggests that, at least in T. spiralis infections, serum IgE response does not reflect true responsiveness at the infection site, and therefore, may not be appropriate for studying protective mechanisms involved in gastrointestinal nematode infection. We further investigated T. spiralis adult specific IgE response in infection of different rat strains. The results demonstrated an association between the earlier detection of intestinal IgE reactive with adult metabolic antigen and faster elimination of the parasite as observed in LEWIS rats. In PVG infected rats, a rat strain that eliminated the intestinal parasite few days later than LEWIS rats, adult specific intestinal IgE response also appeared later (NEGRÃO-CORRÊA et al., 1999), indicating that intestinal IgE would have an important role in the worm elimination from the intestinal mucosae.

The mechanism by which specific IgE participates in worm elimination within the gut mucosae is still being investigated. Our data (Fig. 1) showed that intestinal IgE purified from 14 dpi infected rats, but not serum IgE, was able to block adult worm invasion of IL-4 stimulated gut epithelial cell lines in vitro (NEGRÃO-CORRÊA, 1997). The in vitro blockage of worm invasion using intestinal IgE suggests that IgE might directly mediate elimination from the epithelium. The continued presence of T. spiralis worms in the gut epithelial layer requires constant movement of the worms as they invade new epithelial cells. It is possible that an antibody that can block or neutralize any factor essential for this activity will result in worm elimination. We may also hypothesize that activated enterocytes have an important role in the mechanism of worm elimination, so cross-linking of parasite specific IgE bound to IL-4 stimulated enterocytes might produce alteration that leads to worm elimination (BELL, 1998).

Finally, it is important to consider that although Th2-regulated immune response is considered to have a central role in protection against helminthic infections (FINKELMAN et al., 1997), experiments with different species of gastrointestinal nematode parasites indicated that different effector mechanism(s) could be responsible for worm elimination in each infection model. Direct evidence of such diversity is observed in concurrent infections with Strongyloides ratti and Nippostrongylus brasiliensis in nude mice. In these infected mice, multiple administration of recombinant IL-3 resulted in elimination of S. ratti worms, but not N. brasiliensis (ABE et al., 1992; HORII et al., 1993; NAWA et al., 1994). IL-3 treatment in nude mice restores mast cell response normally observed in the intestine of infected mice, indicating that S. ratti protection, but not N. brasiliensis, is due to a mast cell-dependent mechanism. Differences are also observed for worm elimination in S. ratti and N. brasiliensis infected mast cell deficient W/W^v mice. Although the W/W^v mice showed a delayed rejection of both parasites, the rejection response and intestinal mastocytosis could be restored by bone marrow grafting in mice infected with S. ratti but not in mice infected with N. brasiliensis (CROWLE, 1983; NAWA et al., 1985; ISHIKAWA et al., 1994). Goblet cell hyperplasia and modifications in terminal sugars of goblet cell mucins, which are thought to be T-dependent effects, are associated with the protective mechanism against N. brasiliensis (ISHIKAWA et al., 1993). These results have demonstrated that the mucosal defense mechanisms operating against Strongyloides spp are distinct from those operating against N. brasiliensis and also that protection is parasite specific rather than just a non-specific inflammatory process. Differences were also observed in the intestinal IgE response after nematode infection. Intestinal IgE response reported in T. spiralis infected rats were not induced by all the intestinal nematode parasites that were tested. An intestinal IgE response was observed during infection with T. spiralis and H. polygyrus in rats. More recently, we also identified IgE response in intestinal and bronchoalveolar lavage of Strongyloides venezuelensis infected rats (unpublished results). However, infection with N. brasiliensis, a nematode that parasitizes the upper portion of the rat small intestine but, unlike the other nematode species tested, does not penetrate the intestinal mucosa, did not produce an intestinal IgE response (NEGRÃO-CORRÊA & BELL, 1999). These results reinforce the idea that different mechanisms may be involved in protective immunity that develops against individual gastrointestinal nematodes. These data are also consistent with the view that mucosal penetration by the nematode worm is essential for the induction of an intestinal secretory IgE response that may locally participate on worm elimination.

FINAL REMARKS

Gastrointestinal nematodes include many different parasite species that have a complex life cycle, with some species showing a systemic migration and other species directly establishing at the gastrointestinal site. It is also known that each nematode species may occupy different regions on the intestinal tract (stomach, small intestine, large intestine). Even at the same intestinal portion, different nematode species may localize at the lumen, epithelial layer or inside the mucosae tissue. Therefore, it is not surprising that the immune response to a GI nematode infection would have different effector mechanisms at distinct infection site or against different parasite stage even though the systemic response show many common elements.

Although experimental systems have demonstrated that the host protection is a CD4 + T cell–dependent process and IL-4 secreted by these cells has an essential or very important role in the process (FINKELMAN et al., 1997; LAWRENCE et al., 1998), the steps from IL-4 secretion to worm elimination are still not clear. The literature review indicates that multiple and not excludent mechanisms might be involved on immune response against nematode infections. Eosinophilia, mastocytosis, and IgE stimulation are the three main immune alterations observed during a nematode infection and are controlled by Th2 lymphocytes. Activated eosinophils plus immune serum has been able to kill helminthes larvae in vitro and also in some experimental models, specially in parasites that have a systemic migration in the life cycle (reviewed in CARA et al., 2000). However, IL-5 knockout mice showed that the eosinophil mediated mechanism is not essential to the protection (CARA et al., 2000). Similarly, mastocytosis reported at the intestinal site of nematode infected animals would be an important element to the protective immunity against S. ratti but not against N. brasiliensis (NAWA et al., 1994). Finally, there is a positive correlation between IgE levels and protection against helminthic infection in many experimental models or human population studies tested. In most cases, the protective role of IgE has been associated to mast cell degranulation and the consequent allergic inflammation induced at the infection site. However, some experimental data indicated that IgE would also participate in the protective mechanism independently of mast cells (WANG et al., 1990; KING et al., 1997).

Our previous experience with T. spiralis infection in rats indicated that antibody response, specially IgE, induced at the intestinal mucosae would be involved in the protective mechanism that leads to worm elimination (reviewed BELL, 1998). The intestinal IgE response appeared earlier, showed different specificity against the parasite antigens and was more intense than the serum IgE response (NEGRÃO-CORRÊA et al., 1996; NEGRÃO-CORRÊA & BELL, 1996). These elements and the results obtained with the in vitro system for testing worm invasion of intestinal epithelial monolayers suggested that IgE would participate in T. spiralis elimination independently of mast cell or eosinophils degranulation. Induction of intestinal IgE response was also demonstrated in rats infected with H. polygyrus (NEGRÃO-CORRÊA et al., 1999) and S. venezuelensis (unpublished results), but not N. brasiliensis (NEGRÃO-CORRÊA et al., 1999).

Therefore, the experimental data discussed here support the idea that the protective immune response against a nematode infection is a multifactorial and redundant mechanism, whose effector elements will depend on the infection site and nematode species. At the intestinal site, local IgE production would be a very important element to worm elimination in nematode species that penetrate the mucosa tissue. The mechanism by which IgE would lead to worm elimination from the intestine is still unknown, however, based on the high quantity of parasite specific IgE in the intestinal wash of rats infected with T. spiralis and on the possibility that this intestinal IgE block worm invasion to IEC-6 monolayer, we hypothesize that intestinal IgE would directly interfere with the worm ability to establish in the enterocytes layer (NEGRÃO-CORRÊA, 1997; BELL, 1998).

RESUMO

A importância de imunoglobulina E (IgE) na mucosa intestinal para a eliminação de nematódeos parasitos gastrointestinais

Esta revisão pretende discutir as evidências experimentais indicando que IgE tem participação no processo que resulta na eliminação de nematódeos parasitos gastrointestinais. Os dados da literatura revelam que, na maioria dos modelos experimentais de infecção em murinos, a resposta imune que induz a eliminação de nematódeos é controlada por citocinas Th-2 (especialmente IL-4). Entretanto, o exato mecanismo(s) responsável pelo fenômeno ainda não foi completamente esclarecido e, provavelmente, varia em diferentes espécies de nematódeos. A produção de IgE específica contra antígenos do parasito, especialmente a IgE produzida localmente (mucosa intestinal ou órgãos linfáticos associados), tem grande importância para eliminação de T. spiralis do intestino de ratos infectados. IgE intestinal pode também estar envolvida na eliminação de vermes adultos de outros nematódeos que penetram na mucosa intestinal da região duodenal, como S. venezuelensis e H. polygyrus. No caso da infecção de T. spiralis em ratos, os resultados obtidos sugerem ainda que IgE intestinal pode participar da eliminação dos vermes intestinais através de mecanismos que independem de mastócitos.

ACKNOWLEDGEMENTS

This work has been financially supported by CNPq (PADCT) and FAPEMIG. I would like to thank Dr. Ary Corrêa Jr. and Dr. Mauro Martins Teixeira for comments on the manuscript. The author is also grateful to Sra. Vera Ribeiro for reviewing the text.

Received: 12 February 2001

Accepted: 20 July 2001

Correspondence to: Deborah Negrão-Corrêa, Department of Parasitology, Federal University of Minas Gerais, Av. Antônio Carlos 6627, 31270-901 Belo Horizonte, MG, Brazil. Phone [phone], Fax: [phone]. E-mail: [e-mail]

• 1. ABBAS, A.K.; MURPHY, K.M. & SHER, A. - Functional diversity of helper T lymphocytes. Nature (Lond.), 383: 787-793, 1996.
• 2. ABE, T.; SUGAYA, H.; YOSHIMURA, K. & NAWA, Y. - Induction of the expulsion of Strongyloides ratti and retention of Nippostrongylus brasiliensis in athymic nude mice by repetitive administration of recombinant IL-3. Immunology, 76: 10-14, 1992.
• 3. AHMAD, A.; BELL, R.G.; WANG, C.H. & SACUTO, F.R. - Characterization of the thoracic duct T helper cells that co-mediate, with antibody, the rapid expulsion of Trichinella spiralis in adult rats. Paras. Immunol., 13: 147-159, 1991a.
• 4. AHMAD, A.; WANG, C.H. & BELL, R.G. - A role for IgE in intestinal immunity. Expression of rapid expulsion of Trichinella spiralis in rats transfused with IgE and thoracic duct lymphocytes. J. Immunol., 146: 3563-3570, 1991b.
• 5. ALIZADEH, H.; URBAN Jr., J.F.; KATONA, I.M. & FINKELMAN, F.D. - Cells containing IgE in the intestinal mucosa of mice infected with the nematode parasite Trichinella spiralis are predominantly of a mast cell lineage. J. Immunol., 137: 2555-2560, 1986.
• 6. APPLETON, J.A. & McGREGOR, D.D. - Characterization of the immune mediator of rapid expulsion of Trichinella spiralis in suckling rats. Immunology, 62: 477-484, 1987.
• 7. APPLETON, J.A.; SCHAIN, L.R. & McGREGOR, D.D. - Rapid expulsion of Trichinella spiralis in suckling rats: mediation by monoclonal antibodies. Immunology, 65: 487-492, 1988.
• 8. BELL, R.G. - Variation in responsiveness to Trichinella spiralis infection in inbred rat strains. Parasitology, 105: 125-130, 1992.
• 9. BELL, R.G. - The generation and expression of immunity to Trichinella spiralis in laboratory rodents. Advanc. Parasit., 41: 149217, 1998.
• 10. BELL, R.G. & McGREGOR, D.D. - Trichinella spiralis: expression of rapid expulsion in rats exposed to an abbreviated enteral infection. Exp. Parasit., 48: 42-50, 1979.
• 11. BELL, R.G. & McGREGOR, D.D. - Requirement for two discrete stimuli for induction of the intestinal rapid expulsion response against Trichinella spiralis in rats. Infect. Immunol, 29: 186-193, 1980.
• 12. BELL, R.G.; APPLETON, J.A.; NEGRĂO-CORRĘA, D.A. & ADAMS, L.S. - Rapid expulsion of Trichinella spiralis in adult rats mediated by monoclonal antibodies of distinct IgG isotypes. Immunology, 75: 520-527, 1992.
• 13. BIEBER, T.; de la SALLE, H.; WOLLENBERG, A. et al - Human epidermal Langerhans cells express the high affinity receptor for immunoglobulin E (Fc episilon RI). J. exp. Med., 175: 1285-1290, 1992.
• 14. BRASSART, D.; KOLODZIEJCZYK, E.; GRANATO, D. et al. - An intestinal galactose-specific lectin mediates the binding of murine IgE to mouse intestinal epithelial cells. Europ. J. Biochem., 203: 393-396, 1992.
• 15. CAPRON, M. & JOSEPH, M. - The low affinity receptor for IgE on eosinophils and platelets. In: GORDON, J., ed. CD23: a novel multifunctional regulator of the immune system that binds IgE. Basel, Karger, 1991. (Monogr. Allergy, 29: 63-75, 1991).
• 16. CARA, D.C.; NEGRĂO-CORRĘA, D. & TEIXEIRA, M.M. - Mechanisms underlying eosinophil trafficking and their relevance in vivo Histol. Histopath, 15: 899-920, 2000.
• 17. CHAN, M-S. - The global burden of intestinal nematode infections. Fifty years on. Parasit. today, 13: 438-443, 1997.
• 18. CHARLEY-POULAIN, J.; LUFFAU, G. & PERY, P. - Serum and abomasal antibody response of sheep to infections with Haemonchus contortus Vet. Parasit., 14: 129-141, 1984.
• 19. CHEN, X-J. & ENERBACK, L. - Immune responses to a Nippostrongylus brasiliensis infection in athymic and euthymic rats: surface expression of IgE receptors, IgE occupancy and secretory ability of mast cells. Int. Arch. Allergy Immunol, 109: 250-257, 1996.
• 20. COLGAN, S.P.; RESNICK, M.B.; PARKOS, C.A. et al - IL-4 directly modulates function of a model human intestinal epithelium. J. Immunol., 153: 2122-2129, 1994.
• 21. CROWLE, P.K. - Mucosal mast cell reconstitution and Nippostrongylus brasiliensis rejection by W/W^v mice. J. Parasit., 69: 66-69, 1983.
• 22. DE ANDRES, B.; RAKASZ, E.; HAGEN, M. et al - Lack of Fc-epsilon receptors on murine eosinophils: implications for the functional significance of elevated IgE and eosinophils in parasitic infections. Blood, 89: 3826-3836, 1997.
• 23. DESSEIN, A.J.; PARKER, W.L.; JAMES, S.L. & DAVID, J.R. - IgE antibody and resistance to infection. I. Selective suppression of the IgE antibody response in rats diminishes the resistance and the eosinophil response to Trichinella spiralis infection. J. exp. Med., 153: 423-436, 1981.
• 24. DOMBROWICZ, D.; QUATANNENS, B.; PAPIN, J.P.; CAPRON, A. & CAPRON, M.J. - Expression of a functional Fc epsilon RI on rat eosinophils and macrophages. J. Immunol., 165: 1266-1271, 2000.
• 25. DUNNE, D.W.; BUTTERWORTH, A.E.; FULFORD, A.J.C. et al - Immunity after treatment of human schistosomiasis: association between IgE antibodies to adult worm antigens and resistance to reinfection. Europ. J. Immunol., 22: 1483-1494, 1992.
• 26. ELSE, K.J.; HULTER, L. & GRENCIS, R.K. - Cellular immune responses to the murine nematode parasite Trichuris muris. II. Differential induction of Th-cell subsets in resistant versus susceptible mice. Immunology, 75: 232-237, 1992.
• 27. ELSE, K.J.; FINKELMAN, F.D.; MALISZEWSKI, C.R. & GRENCIS, R.K. - Cytokine-mediated regulation of chronic intestinal helminth infection. J. exp. Med., 179: 347-351, 1994.
• 28. FINKELMAN, F.D. & URBAN Jr., J.F. - Cytokines: making the right choice. Parasit. today, 8: 311-315, 1992.
• 29. FINKELMAN, F.D.; KATONA, I.M. & URBAN Jr., J.F. - IL-4 is required to generate and sustain in vivo IgE responses. J. Immunol, 141: 2335-2341, 1988.
• 30. FINKELMAN, F.D.; SHEA-DONOHUE, T.; GOLDHILL, J. et al. - Cytokine regulation of host defense against parasitic gastrointestinal nematodes: lessons from studies with rodent models. Ann. Rev. Immunol., 15: 505-533, 1997.
• 31. FRIGERI, L.G. & LIU, F.-T. - Surface expression of functional IgE binding protein and endogenous lectin on mast cells and macrophages. J. Immunol., 148: 861-867, 1992.
• 32. GAUCHAT, J.-F.; HENCHOZ, S.; MAZZEI, G. et al. - Induction of human IgE synthesis in B cells by mast cells and basophils. Nature (Lond.), 365: 340-343, 1993.
• 33. GOUNNI, A.S.; LAMKHIOUED, B.; OCHIAI, K. et al. - High-affinity IgE receptor on eosinophils is involved in defence against parasites. Nature (Lond.), 367: 183-186, 1994.
• 34. GRABBE, J.; HAAS, N. & HAMANN, K. - Demonstration of high-affinity IgE receptor on human Langerhans cells in normal and diseased skin. Brit. J. Derm., 129: 120-123, 1993.
• 35. GUY-GRAND, D.; CERF-BENSUSSAN, N.; MALISSEN, B. et al - Two gut intraepithelial CD8+ lymphocyte populations with different T cell receptors: a role for the gut epithelium in T cell differentiation. J. exp. Med., 173: 471-481, 1991.
• 36. HAGAN, P. - IgE and protective immuntiy to helminth infections. Paras. Immunol., 15: 1-4, 1993.
• 37. HAGAN, P.; BLUMENTHAL, U.J.; DUNN, D.; SIMPSON, A.J.G. & WILKINS, H.A. - Human IgE, IgG4 and resistance to reinfection with Schistosoma haematobium. Nature (Lond.), 349: 243-245, 1991.
• 38. HORII, Y.; KHAN, A.I. & NAWA, Y. - Persistent infection of Strongyloides venezuelensis and normal expulsion of Nippostrongylus brasiliensis in Mongolian gerbils, Meriones unguiculatus, with reference to the cellular responses in the intestinal mucosa. Paras. Immunol., 15: 175-179, 1993.
• 39. IIO, A.; WALDMANN, T.A. & STROBER, W. - Metabolic study of human IgE: evidence for an extravascular catabolic pathway. J. Immunol., 120: 1696-1701, 1978.
• 40. ISHIKAWA, N.; HORII, Y. & NAWA, Y. - Immune-mediated alteration of the terminal sugars of goblet cell mucins in the small intestine of Nippostrongylus brasiliensis-infected rats. Immunology, 78: 303-307, 1993.
• 41. ISHIKAWA, N.; HORII, Y. & NAWA, Y. - Reconstitution by bone marrow grafting of the defective protective capacity at the migratory phase but not at the intestinal phase of Nippostrongylus brasiliensis infection in W/W^v mice. Paras. Immunol., 16: 181-186, 1994.
• 42. ISHIZAKA, T.; URBAN Jr., J.F. & ISHIZAKA, K. - IgE formation in rat following infection with Nippostrongylus brasiliensis I. Proliferation and differentiation of IgE-bearing cells. Cell. Immunol., 22: 248-261, 1976.
• 43. JANKOVIC, D.; KULLBERG, M.C.; DOMBROWICZ, D. et al - Fc epsilon RI-deficient mice infected with Schistosoma mansoni mount normal Th2-type responses while displaying enhanced liver pathology. J. Immunol., 159: 1868-1875, 1997.
• 44. JARRETT, E.E.E. & BAZIN, H. - Elevation of total serum IgE in rats following helminth infection. Nature (Lond.), 251: 613-614, 1974.
• 45. JARRETT, E.E.E. & MILLER, H.R.P. - Production and activities of IgE in helminth infections. Prog. Allergy, 31: 178-233, 1982.
• 46. JOSEPH, M.; GOUNNI, A.S.; KUSNIERZ, J.P. et al. - Expression and functions of the high-affinity IgE receptor on human platelets and megakaryocyte precursors. Europ. J. Immunol., 27: 2212-2218, 1997.
• 47. KAISERLIAN, D.; LACHAUX, A.; GROSJEAN, I.; GRABER, P. & BONNEFOY, J-Y. - Intestinal epithelial cells express the CD23/FceRII molecule: enhanced expression in enteropathies. Immunology, 80: 90-95, 1993.
• 48. KINET, J.-P. - The high-affinity IgE receptor (FCeRI): from physiology to pathology. Ann. Rev. Immunol, 17: 931-972, 1999.
• 49. KING, C.L.; XIANLI, J.; MALHOTRA, I. et al. - Mice with a targeted deletion of the IgE gene have increased worm burdens and reduced granulomatous inflammation following primary infection with Schistosoma mansoni J. Immunol., 158: 294-300, 1997.
• 50. KORENAGA, M.; NAWA, Y. & TADA, I. - IgE response in Strongyloides ratti-infected rats with special reference to the life cycle of the parasite. Z. Parasitenk., 72: 213-220, 1986.
• 51. KURNIAWAN, A.; YAZDANBAKHSH, M.; VAN REE, R. et al - Differential expression of IgE and IgG4 specific antibody responses in asymptomatic and chronic human filariasis. J. Immunol., 150: 3941-3950, 1993.
• 52. LAKE, A.M.; BLOCH, K.J.; SINCLAIR, K.J. & WALKER, W.A. - Anaphylactic release of intestinal goblet cell mucus. Immunology, 39: 173-178, 1980.
• 53. LARSH, J.E. & RACE, G.J. - Allergic inflammation as a hypothesis for the expulsion of worms from tissue: a review. Exp. Parasit., 37: 251-266, 1975.
• 54. LAWRENCE, C.E.; PATERSON, J.C.M.; HIGGINS, L.M. et al - IL-4-regulated enteropathy in an intestinal nematode infection. Europ. J. Immunol., 28: 2672-2684, 1998.
• 55. LIEW, F.Y.; LI, Y. & MILLOTT, S. - TNF-a synergizes with IFN-g in mediating killing of Leihmania major through induction of nitric oxide. J. Immunol., 145: 4306-4310, 1990.
• 56. LOVE, R.J.; OGILVIE, B.M. & MCLAREN, D.J. - The immune mechanism which expels the intestinal stage of Trichinella spiralis from rats. Immunology, 30: 7-15, 1976.
• 57. MADDEN, K.B.; URBAN Jr., J.F.; ZILTENER, H.J. et al. - Antibodies to IL-3 and IL-4 suppress helminth-induced intestinal mastocytosis. J. Immunol., 147: 1387-1391, 1991.
• 58. MAURER, D.; FIEBIGER, E.; REININGER, B. et al. - Expression of functional high affinity immunoglobulin E receptors (Fc epsilon RI) on monocytes of atopic individuals. J. exp. Med., 179: 745-750, 1994.
• 59. MAURER, D.; FIEBIGER, E.; EBNER, C. et al - Peripheral blood dendritic cells express Fc epsilon RI as a complex composed of Fc epsilon RI alpha- and Fc epsilon RI gamma-chains and can use this receptor for IgE-mediated allergen presentation. J. Immunol., 157: 607-616, 1996.
• 60. MAYRHOFER, G.; BAZIN, H. & GOWANS, J. L. - Nature of cells binding anti-IgE in rats immunized with Nippostrongylus brasiliensis: IgE synthesis in regional nodes and concentration in mucosal mast cells. Europ. J. Immunol., 6: 537-545, 1976.
• 61. McGEE, D.W. & VITKUS, S.J.D. - IL-4 enhances IEC-6 intestinal epithelial cell proliferation yet has no effect on IL-6 secretion. Clin. exp. Immunol., 105: 274-277. 1996.
• 62. McSHARRY, C.; XIA, Y.; HOLLAND, C.V. & KENNEDY, M.W. - Natural immunity to Ascaris lumbricoides associated with immunoglobulin E antibody to ABA-1 allergen and inflammation indicators in children. Infect. Immun., 67: 484-489, 1999.
• 63. MOSMANN, T.R. & COFFMAN, R.L. - Th1 and Th2 cells: different patterns of lymphokine secretion lead to different functional properties. Ann. Rev. Immunol., 7: 145-173, 1989.
• 64. MUSOKE, A.J.; WILLIAMS, J.F. & LEID, R.W. - Immunological response of the rat to infection with Taenia taeniaeformis VI. The role of immediate hypersensitivity in resistance to reinfection. Immunology, 34: 565-570, 1978.
• 65. NAWA,Y.; KIYOTA, M.; KORENAGA, M. & KOTANI, M. - Defective protective capacity of W/W^v mice against Strongyloides ratti infection and its reconstitution with bone marrow cells. Paras. Immunol., 7: 429-438, 1985.
• 66. NAWA, Y.; ISHIKAWA, N.; TSUCHIYA, K. et al. - Selective effector mechanism for the expulsion of intestinal helminths. Paras. Immunol., 16: 333-338, 1994.
• 67. NEGRĂO-CORRĘA, D. - The intestinal IgE response to infection with Trichinella spiralis in rats. Cornell, 1997. (Tese de Doutoramento, Cornell University).
• 68. NEGRĂO-CORRĘA, D. & BELL, R.G. - The dynamics of IgE production during Trichinella spiralis infection in rats. Quantitative significance of transport to the intestine versus serum. In: ORTEGA-PIERRES, G.; GAMBLE, R.; VANKNAPEN, F. & WAKELIN D. Trichinellosis. INTERNATIONAL CONFERENCE ON TRICHINELLOSIS, 9., 1996. Proceedings. p. 361-368.
• 69. NEGRĂO-CORRĘA, D.; ADAMS, L.S. & BELL, R.G. - Intestinal transport and catabolism of IgE: a major blood-independent pathway of IgE dissemination during a Trichinella spiralis infection of rats. J. Immunol., 157: 4037-4044, 1996.
• 70. NEGRĂO-CORRĘA, D.; ADAMS, L.S. & BELL, R.G. - Variability of the intestinal immunoglobulin E response of rats to infection with Trichinella spiralis, Heligmosomoides polygyrus or Nippostrongylus brasiliensis Paras. Immunol., 21: 287-297, 1999.
• 71. OGILVIE, B.M. - Reagin-like antibodies in animals immune to helminth parasites. Nature (Lond.), 204: 91-94, 1964.
• 72. PERRUDET-BADOUX, A.; BOUSSAC-ARON, Y.; RUITENBERG, E.J. & ELGERSMA, A. - Preliminary studies on the course of a Trichinella spiralis infection in athymic, nude rats. J. Parasit., 66: 671-673, 1980.
• 73. PIRRON, U.; SCHLUNCK, T.; PRINZ, J.C. & RIEBER, E.P. - IgE-dependent antigen focusing by human B lymphocytes is mediated by the low affinity receptor for IgE. Europ. J. Immunol., 20: 1547-1551, 1990.
• 74. PLAUT, M.; PIERCE, J.H.; WATSON, C.J. et al - Mast cell lines produce lymphokines in response to cross-linkage of FceRI or to calcium ionophores. Nature (Lond.), 339: 64-67, 1989.
• 75. PORCELLI, S.; MORITA, C.T. & BRENNER, B. - CD1b restricts the response of human CD4-8- T lymphocytes to a microbial antigen. Nature (Lond.), 360: 593-597, 1992.
• 76. POUSSIER, P.; EDOUARD, P.; LEE, C.; BINNIE, M. & JULIUS, M. - Thymus-dependent development and negative selection of T cells expressing T cell receptor alpha/beta in the intestinal epithelium: evidence for distinct circulation patterns of gut- and thymus derived T lymphocytes. J. exp. Med., 176: 187-199, 1992.
• 77. PRITCHARD, D.I. - Immunity to helminths: is too much IgE parasite- rather than host-protective? Paras. Immunol., 15: 5-9, 1993.
• 78. PRITCHARD, D.I.; QUINNELL, R.J. & WASH, E.A. - Immunity in humans to Necator americanus: IgE, parasite weight and fecundity. Paras. Immunol., 17: 71-75, 1995.
• 79. RAMASWAMY, K.; HAKIMI, J. & BELL, R.G. - Evidence for an interleukin 4-inducible immunoglobulin E uptake and transport mechanism in the intestine. J. exp. Med., 180: 1793-1803, 1994.
• 80. RAMASWAMY, K.; NEGRĂO-CORRĘA, D. & BELL, R.G. - Local intestinal immune response to infections with Trichinella spiralis: real time, continuous assay of cytokines in the intestinal afferent and efferent thoracic duct lymph of rats. J. Immunol., 156: 4328-4337, 1996.
• 81. ROCHA, B.; VASSALLI, P. & GUY-GRAND, P. - The Vb repertoire of mouse gut homodimeric alpha CD8+ intraepithelial T cell receptor alpha/beta+ T lymphocytes reveals a major extrathymic pathway of T cell differentiation. J. exp. Med., 173: 483-486, 1991.
• 82. RUITENBERG, E.J.; ELGERSMA, A. & KRUIZINGA, W. - Intestinal mast cell and globule leukocytes: role of the thymus on their presence and proliferation during a Trichinella spiralis infection in the rat. Int. Arch. Allergy, 60: 302-309, 1979.
• 83. SCHMITZ, J.; THIEL, A.; KUHN, R. et al - Induction of interleukin 4 (IL-4) expression in T helper (Th) cells is not dependent on IL-4 from non-Th cells. J. exp. Med., 179: 1349-1353, 1994.
• 84. SCHWARTZ, L.B. - The molecular and cell biology of mast cells and basophils. In: LEVINSON, A.I. & PATERSON, Y., ed. Molecular and cellular Biology of the allergic response. New York, Marcel Dekker, 1994. p. 281-330.
• 85. SELBY, W.S.; JANOSSY, G.; BONFILL, M. & JEWELL, D.P. - Lymphocyte subpopulation in the human small intestine. The findings in normal mucosa and in the mucosa of patients with coelic disease. Clin. exp. Immunol., 52: 219-224, 1983.
• 86. SINSKI, E. & HOLMES, P.H. - Nippostrongylus brasiliensis: systemic and local IgA and IgG immunoglobulin responses in parasitized rats. Exp. Parasit., 43: 382-389, 1977.
• 87. SUTTON, B.J. & GOULD, H.J. - The human IgE network. Nature (Lond.), 366: 421-428, 1993.
• 88. TADA, T.; OKUMURA, K.; PLATTEAU, B.; BECKERS, A. & BAZIN, H. - Half-lifes of two types of rat homocytotropic antibodies in circulation and in the skin. Int. Arch. Allergy, 48: 116-131, 1975.
• 89. TRUONG, M.J.; GRUART, V. & KUSNIERZ, J.P. - Human neutrophils express immunoglobulin E IgE-binding proteins Mac-2-epsilon BP of the S-type lectin family: role in IgE-dependent activation. J. exp. Med., 177: 243-248, 1993a.
• 90. TRUONG, M.J.; GRUART, V.; LIU, F.T. et al - IgE-binding molecules (Mac-2-epsilon BP) expressed by human eosinophils. Implication in IgE-dependent eosinophil cytotoxicity. Europ. J. Immunol., 23: 3230-3235, 1993b.
• 91. TSENG, J. - Expression of immunoglobulin isotypes by lymphoid cells isolated from lamina propria. Cell. Immunol., 73: 324, 1983.
• 92. TURNER, K.J.; FEDDEMA, L. & QUINN, E.H. - Non-specific potentiation of IgE by parasitic infection in man. Int. Arch. Allergy, 58: 232-236, 1979.
• 93. URBAN Jr., J.F.; KATONA, I.M.; PAUL, W.E. & FINKELMAN, F.D. - Interleukin 4 is important in protective immunity to a gastrointestinal nematode infection in mice. Proc. nat. Acad. Sci. (Wash.), 88: 5513-5517, 1991.
• 94. URBAN Jr., J.F.; MADDEN, K.B.; SVETIC, A. et al. - The importance of Th2 cytokines in protective immunity to nematodes. Immunol. Rev., 127: 205-220, 1992.
• 95. URBAN Jr., J.F.; MALISZEWSKI, C.R.; MADDEN, K.B.; KATONA, I.M. & FINKELMAN, F.D. - IL-4 treatment can cure established gastrointestinal nematode infections in immunocompetent and immunodeficient mice. J. Immunol., 154: 4675-4684, 1995.
• 96. VERCELLI, D. - Regulation of IgE synthesis. Allergy Proc., 14: 413-416, 1993.
• 97. WAKELIN, D. - Allergic inflammation as a hypothesis for the expulsion of worms from tissues. Parasit. today, 9: 115-116, 1993.
• 98. WAKELIN, D. & DEHAM, D.A. - The immune response. In: CAMPBELL, W.C., ed. Trichinellosis and Trichinosis. New York, Plenum Press, 1983. p. 265-308.
• 99. WANG, B.; RIEGER, A.; KILGUS, O. et al - Epidermal Langerhans cells from normal human skin bind monomeric IgE via FceRI. J. exp. Med., 175: 1353-1365, 1992.
• 100. WANG, C.H.; KORENAGA, M.; GREENWOOD, A. & BELL, R.G. - T helper subset function in the gut of rats: differential stimulation of eosinophils, mucosal mast cells and antibody-forming cells by OX8- OX22- and OX8- OX22+ cells. Immunology, 71: 166-175, 1990.
• 101. YOKOTA, A.; YUKAWA, K.; YAMAMOTO, A. et al. - Two forms of the low-affinity Fc receptor for IgE differentially mediate endocytosis and phagocytosis: identification of the critical cytoplasmic domains. Proc. nat. Acad. Sci. (Wash.), 89: 5030-5034, 1992.

(1

) Department of Parasitology, Federal University of Minas Gerais/UFMG, Belo Horizonte, MG, Brazil

Publication Dates

• Publication in this collection
  31 Oct 2001
• Date of issue
  Oct 2001

History

• Accepted
  20 July 2001
• Received
  12 Feb 2001