Importance of homoeostatic immune regulation

It may seem paradoxical that mucosal disorders, such as inflammatory bowel disease (IBD) and coeliac disease, appear to depend, at least initially, on putative Th1-cell-driven pathogenic mechanisms (Scott et al., 1997; Brandtzaeg et al., 1999d), while atopic (IgE-mediated) allergy originates from Th2-cell responses (Brandtzaeg, 1997b; Corry and Kheradmand, 1999), which generate the essential cytokines IL-4 and IL-13 (early phase) as well as IL-3, IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) (late phase). According to the 'hygiene hypothesis', the increasing incidence of allergy in Westernized societies may to some extent be explained by a reduced microbial load early in infancy, resulting in too little Th1-cell activity and therefore an insufficient level of IFN-7 to cross-regulate Th2-cell responses optimally (Rook and Stanford, 1998; Erb, 1999; Kirjavainen and Gibson, 1999). In this context, an appropriate composition of the commensal bacterial flora (Isolauri et al.,

2000) and exposure to food-borne and orofaecal microbes (Herz et al., 2000; Matricardi et al., 2000) most probably exert an important homoeostatic impact, both by enhancing the SIgA-mediated barrier function (see above) and by promoting oral tolerance through a shift from a predominant Th2-cell activity in the newborn period (Prescott et al., 1998) to a more balanced cytokine profile later on (Fig. 14.5). Thus, the intestinal microflora of young children in Sweden was found to contain a relatively large number of Clostridium spp., whereas high levels of Lactobacillus spp. and Eubacterium spp. were detected in an age-matched population from Estonia (Sepp et al., 1997). Perhaps this difference could explain the lower incidence of allergy in the Baltic countries compared with Scandinavia. Interestingly, the intestinal microflora of children in Estonia was deemed to be somewhat similar to that of Swedish children in the 1960s. Also, the intestinal microflora of Estonian children with allergy appeared to differ from that of their healthy counterparts, particularly by containing fewer lac-tobacilli (Bjorksten et al., 1999). A recent Finnish study likewise reported that atopic infants had more clostridia and tended to have fewer bifidobacteria in their stools than non-atopic controls (Kalliomaki et al., 2001b).

Such observations make a good case for studying the potential clinical benefits of prebiotics and probiotic bacterial strains from the indigenous gut flora (Collins and Gibson, 1999; Kirjavainen and Gibson, 1999; Isolauri et al.,

2001). Similarly, there is some hope that immunization with mycobacterial antigens might skew the cytokine profile towards Th1 and thereby, through cross-regulation, dampen Th2-dependent allergic (atopic) symptoms (von Reyn et al., 1997; Hopkin et al., 1998). Newborns are in fact able to mount a Th1-type immune response when appropriately stimulated (Marchant et al., 1999). Also notably, the bacterial endotoxin or LPS receptor CD14, together with the Tolllike receptor (TLR) 4 on APCs, as well as other TLRs that recognize microbial products (e.g. lipoproteins and peptidoglycans) as danger signals or pathogen-associated molecular patterns (PAMPs), are in this respect an important link between innate and specific immunity (Fig. 14.6). This link operates via the nuclear factor kappa B (NFkB) activation pathway to release pro-inflammatory cytokines (Modlin, 2000; Kaisho and Akira, 2001), including the Th1-inducing IL-12 and IL-18 (McInnes et al., 2000; Manigold et al., 2000). Even certain CpG motifs of bacterial DNA have been shown to promote Th1-cell activity through interaction with TLR9 (Klinman et al., 1996; Kadowaki et al., 2001; Peng et al., 2001). Subepithelial intestinal APCs most probably express TLRs, although this has not yet been studied properly in the human gut (MacDonald and Pettersson, 2000). However, low levels of CD14 are normally present on these cells, and its expression is enhanced, together with that of B7.1 and B7.2, by pro-inflammatory factors (Rugtveit et al., 1997; Brandtzaeg, 2001).

Altogether, it appears that the human intestinal immune system preferentially responds with a dominating Th1 profile (Nilsen et al., 1998), even against various food antigens in the seemingly normal state (Nagata et al., 2000). This appears to be true for T-cells also in the duodenal mucosa of children with cow's milk hypersensitivity (Hauer et al., 1997) and might, to some extent, reflect a high expression level of the Thl-promoting cytokine IL-12 observed for putative APCs situated below the FAE of Peyer's patches in children (MacDonald and Monteleone, 2001). The strong bias towards Th1-cell responses in the human gut could thus contribute to the fact that the majority of food-allergic children outgrow their problems (Bischoff et al., 2000). This is in contrast to respiratory atopic allergy, which tends to persist and even increase in severity (Hattevig et al., 1993; Brandtzaeg et al., 1996). Most probably, danger signals from an established intestinal bacterial flora, as well as the environmental microbial exposure, exert an important drive towards an adequate Th1 skewing in the gut, thus counterbalancing excessive Th2 responses (Fig. 14.6). Nevertheless, allergen-specific mucosal Th2 cells have been detected in patients with (presumably) cow's-milk-induced gastroenteritis (Beyer et al., 2001).

Although the immune system in the airways also responds to antigen stimulation in the presence of danger signals (infection or inflammation) with a Th1 profile (Holt and Stumbles, 2000), an increasingly prominent Th2 profile generally develops as the basis for IgE-mediated (atopic) respiratory allergy (Hattevig et al., 1993; Holt et al., 1999) in individuals with a hereditary predisposition (Anderson and Cookson, 1999; Barnes, 2000). This skewing towards Th2-cell responses may be influenced by the so-called 'lymphoid' DC type, recently named plasmacytoid DCs (P-DCs), which can be identified by their high level of IL-3 receptor (CD123) in allergic nasal mucosa (Jahnsen et al., 2000). In vitro, P-DCs have been shown to drive naive T-cells towards a Th2 response, with IL-4 and IL-5 production (Rissoan et al., 1999). Interestingly, we have been unable to detect P-DCs in the intestinal lamina propria, even in IBD and coeliac disease (Jahnsen et al., 2000). Therefore, the apparent inability of this DC subset to home to intestinal effector sites might contribute to the Th1 dominance of immune responses in the human gut as a result of little cross-regulation from local Th2 responses. The paucity of human intestinal Th2 responsiveness (MacDonald and Monteleone, 2001) is emphasized by the fact that there is usually no detectable IgE production at this mucosal effector site, even in adult food-allergic individuals with overt atopy (Bengtsson et al., 1991). Hence, there may be several mechanisms other than a local mucosal Th2 response to explain gastrointestinal allergy against dietary antigens (Bruijnzeel-Koomen et al., 1995; Bischoff et al., 2000), including recruitment of mast cells armed with IgE from mesenteric lymph nodes, type III (immune complex)-mediated reactions and type IV (delayed type) hypersensitivity (Brandtzaeg, 1997b).

The feeding and treatment regimen (e.g. antibiotics) to which the newborn is subjected and its nutritional state have a significant impact on the composition of its indigenous microbiota, as well as on its gut integrity, and may hence disturb the balance of its developing mucosal immune system (Zeiger, 2000;

Hoppu et al., 2001; Isolauri et al., 2001). The role of commensal bacteria for mucosal tolerance induction in humans was highlighted in a recent clinical trial with postnatal colonization (for 6 months) of a probiotic lactobacillus strain (Kalliomaki et al., 2001a); after 2 years, a 50% reduction of atopic eczema was observed in these children, compared with placebo controls. Intestinal colonization of lactobacilli and bifidobacteria is promoted by breast milk, because of its large amounts of oligosaccharides, which have prebiotic properties (Hoppu et al., 2001); these microorganisms may directly enhance the Th1 profile in the gut by inducing IL-12, IL-18 and IFN-7 (Miettinen et al., 1998; Hessle et al., 1999). Also notably, E. coli is a strong inducer of IL-10 secretion, apparently derived from APCs (Hessle et al., 2000a, b). This has been suggested to be an important suppressive cytokine in the gut (Steidler et al., 2000). Thus, the indigenous microbiota may have an impact on mucosal homoeostasis beyond that of enhancing the SIgA system or promoting a Th1-cytokine profile that counterbalances Th2-cell responsiveness (Holt, 2000).

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