Handling of absorbed food antigens

Intact antigens have in several studies been shown to cross the normal gut barrier and enter the bloodstream even in adults, particularly after food intake (Brandtzaeg et al., 1987), although the actual amount reaching the intestinal lamina propria remains uncertain. Work performed in experimental animals with mucosal application of 125I-labelled albumin has been difficult to interpret, due to marker instability; both degradation of the carrier molecule and release of the label can result in considerable overestimation of protein penetrability as determined by scintillation counting, compared with data based on immuno-logical quantification (Brandtzaeg and Tolo, 1977). Intact dietary antigens appear in the circulation of healthy adults 2-5 h after a meal, being partly present in immune complexes. Thus, intake of 1.2 l of bovine milk resulted in some 3 ng ml-1 of p-lactoglobulin in peripheral blood (Paganelli and Levinsky, 1980). Ovalbumin up to 10 ng ml-1 has likewise been found, corresponding to approximately 10-5 of the amount consumed (Husby et al., 1985). Furthermore, both p-lactoglobulin and ovalbumin have been detected in the breast milk of lactating women, but with unexplained large intra- and interindividual variations, the levels ranging from 0.9 to 150 ^g l-1 (Kilshaw and Cant, 1984; H0st et al., 1990).

Several routes may be visualized for the penetration of intact soluble antigens through the normal intestinal epithelium: paracellular diffusion bypassing the tight junctions; via epithelial discontinuities, such as the cell extrusion zones of the villus tips; translocation through enterocytes by endocytosis and subsequent exocytosis; or transport by M cells in GALT. As discussed elsewhere (Brandtzaeg et al., 1987; Brandtzaeg, 1996a), the relative importance of these mechanisms remains unknown, and the consequences in terms of sensitization or induction of oral tolerance probably depend on the route of uptake, as well as on the nature of the antigen - that is, soluble, lectin-like or particulate (Fig. 14.8). There is likewise no definite knowledge about the effects transmission of food antigens to breast milk might have on the suckling's immune system (Zeiger, 2000; Hoppu et al., 2001), although animal experiments have suggested the possibility of tolerance induction (Johansen et al., 2001).

External transport of pIgA-containing immune complexes by the pIgR has been suggested as an efficient, non-inflammatory antigen clearance mechanism

Rapid antigen uptake

  1. Pathogens 3. Lack of
  2. Binding epithelial (lectins) integrity

Ordinary uptake of soluble proteins

Slow uptake with degradation of antigen

  1. Pathogens 3. Lack of
  2. Binding epithelial (lectins) integrity

Sensitization and usually no induction of oral tolerance

Gut processing with tolerogen formation, suppression or anergy

Non-immunogenic peptides (tolerated)

Fig. 14.8. Various theoretical routes of antigen uptake in the gut and putative immunological consequences. Pathogenic microorganisms and dead particulate antigens (1), as well as proteins with special lectin-like properties (2), are rapidly transported through M cells (M) of follicle-associated epithelium covering gut-associated lymphoid tissue (to the left). Breaching of the gut epithelium (3) also allows rapid antigen uptake. Soluble proteins may be taken up by the paracellular route through the villus epithelium and then endocytosed by subepithelial antigen-presenting cells (APCs), or they are transported and presented by enterocytes to intraepithelial (CD8) or subepithelial T-cells (T). The transcellular route through the enterocyte is presumably speeded up by the lectin-like properties of the antigen (2). lf the antigen is aggregated, luminal endogenous or bacterial enzymes may degrade it extensively to become non-immunogenic (to the right).

Sensitization and usually no induction of oral tolerance

Gut processing with tolerogen formation, suppression or anergy

Non-immunogenic peptides (tolerated)

Fig. 14.8. Various theoretical routes of antigen uptake in the gut and putative immunological consequences. Pathogenic microorganisms and dead particulate antigens (1), as well as proteins with special lectin-like properties (2), are rapidly transported through M cells (M) of follicle-associated epithelium covering gut-associated lymphoid tissue (to the left). Breaching of the gut epithelium (3) also allows rapid antigen uptake. Soluble proteins may be taken up by the paracellular route through the villus epithelium and then endocytosed by subepithelial antigen-presenting cells (APCs), or they are transported and presented by enterocytes to intraepithelial (CD8) or subepithelial T-cells (T). The transcellular route through the enterocyte is presumably speeded up by the lectin-like properties of the antigen (2). lf the antigen is aggregated, luminal endogenous or bacterial enzymes may degrade it extensively to become non-immunogenic (to the right).

from the gut lamina propria (Fig. 14.7). This notion has recently been supported by experiments performed in vivo (Robinson et al., 2001). Pentameric IgM (in contrast to hexameric IgM without J chain) also appears to have little or no complement-activating properties and therefore could probably support the non-inflammatory functions of pIgA in competition with corresponding proinflammatory IgG antibodies (Brandtzaeg et al., 1999a, b). Interestingly, monomeric IgA or IgG antibodies, when cross-linked via antigen to pIgA of the same specificity, might contribute to such pIgR-mediated epithelial transcystosis of foreign material (Mazanec et al., 1993). Conversely, complement-activating IgG antibodies against infectious agents and dietary proteins could on its own adversely affect mucosal penetrability for a variety of exogenous proteins while contributing to local protection. This possibility has been suggested by experiments ex vivo (Brandtzaeg and Tolo, 1977) and in vivo (Lim and Rowley, 1982); IgG antibodies against one antigen were shown to enhance mucosal penetration of bystander molecules. Mucosal integrity was apparently damaged by lysosomal enzymes released from polymorphonuclear granulocytes, which are attracted when immune complexes form locally. Perhaps antigen interaction with maternal IgG antibodies could explain why abrupt introduction of native cow's milk proteins in infants often causes gastrointestinal bleeding (Ziegler et al., 1990).

The pro-inflammatory potential of maternally-derived or locally-produced IgG antibodies is probably less important in the gut of infants who are breastfed, because milk SIgA antibodies will exert a non-inflammatory blocking effect. Moreover, breast milk contains large amounts of the soluble complement inhibitor protectin, CD59 (Bj0rge et al., 1993). Also, this factor and other complement regulatory proteins are expressed by the gastrointestinal epithelium (Berstad and Brandtzaeg, 1998), and these probably counteract immune complex-mediated (type III hypersensitivity) damage of the epithelial barrier.

There is further experimental evidence to suggest that IgA may influence mucosal homoeostasis in various ways through its binding to the Fca receptor (CD89) when present on lamina propria leucocytes, although in the normal state CD89 expression is extremely low on human intestinal macrophages (Smith et al., 2001). Interestingly, IgA can down-regulate the secretion of the pro-inflammatory cytokine TNF-a from activated monocytes and inhibit activation-dependent generation of reactive oxygen intermediates in neutrophils and monocytes (Wolf et al., 1994a, b). On the other hand, pIgA or aggregated monomeric IgA can trigger monocytes to show increased activity, such as TNF-a secretion (Deviere et al., 1991), and also up-regulate B7 on APCs (Geissmann et al., 2001) and induce eosinophil degranulation (Abu-Ghazaleh et al., 1989). This pro-inflammatory potential of IgA probably reflects the need for reinforcement of mucosal antigen elimination mechanisms when immune exclusion fails, such as in intestinal parasitic infestations.

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