The degree of antigenic and mitogenic exposure is decisive not only for the post-natal development of IELs, but also for the secretory immune system. Antigenic constituents of food clearly exert a stimulatory effect on the intestinal B-cell system, as suggested by the occurrence of fewer lamina propria IgA immunocytes both in mice fed on hydrolysed milk proteins (Sagie et al., 1974) and in parenterally fed babies (Knox, 1986). Likewise, mice given total parenteral (intravenous) nutrition have reduced numbers of B- and T-cells in the gut, as well as decreased SIgA levels (Li et al., 1995a, b; Janu et al., 1997), and they show impaired SIgA-dependent influenza-specific immunity (Renegar et al., 2001). The effect of food in the gut lumen could be direct immune stimulation or mediated via release of gastrointestinal neuropeptides. The indigenous microbial flora is also extremely important for secretory immunity, as shown by the fact that the intestinal IgA system of germ-free or specific pathogen-free mice is normalized after about 4 weeks of conventionalization (Crabbe et al., 1970; Horsfall et al., 1978). Bacteroides and Escherichia coli strains seem to be particularly stimulatory for the development of intestinal IgA immunocytes (Lodinova et al., 1973; Moreau et al., 1978). The large dietary and bacterial antigen load in the gut lumen therefore explains why the greatest density of IgA immunocytes is seen in the intestinal lamina propria, amounting to some 1010 cells m-1 of adult gut (Brandtzaeg et al., 1999a).
In human lactating mammary glands the immunocyte density is much less, one gland showing an IgA-producing capacity similar to that of only 1 m of intestine (Brandtzaeg, 1983). Thus, the daily output of IgA kg-1 wet weight of tissue (minus fat) is no more for lactating mammary glands than for salivary glands. In fact, it remains an enigma how any terminal plasma cell differentiation at all is accomplished in these secretory effector organs, which are at considerable distances from antigen-exposed mucosal surfaces (Brandtzaeg et al., 1999a). Anyhow, the large capacity for storage of pIgA/SIgA in the mammary-gland epithelium and duct system, rather than a high immunocyte density, explains the remarkable output of SIgA during breast-feeding (Brandtzaeg, 1983).
In keeping with an important stimulatory effect of antigens on local B-cell differentiation, defunctioning colostomies in children showed a 50% numerical reduction of mucosal IgA and IgM immunocytes after 2-11 months (Wijesinha and Steer, 1982). Prolonged studies of defunctioned ileal segments in lambs revealed an even more striking scarcity of mucosal immunocytes. This was caused by decreased local proliferation and differentiation of B-cell blasts and perhaps reduced homing from GALT (Reynolds and Morris, 1984). Accordingly, the post-natal establishment of the mucosal IgA system is usually much faster in developing countries than in the industrialized part of the world, a difference that seems to hold true even in undernourished children (Nagao et al., 1993). However, severe vitamin A deficiency has been reported to have an adverse effect on mucosal IgA antibody responses in rodents (Wiedermann et al., 1993), but with no consistent down-regulation of epithelial IgA transport (Stephensen et al., 1996).
It has been reported that undernourished children respond to bacterial overgrowth in the gut with enhanced synthesis, as well as up-regulated external transport, of IgA (Beatty et al., 1983). It is of great clinical importance that detrimental effects of severe malnutrition exerted on the SIgA system can apparently be reversed with nutritional rehabilitation (Watson et al., 1985). In a recent study based on whole gut lavage obtained from healthy adult volunteers in Dhaka, Bangladesh, the intestinal concentration of IgA was found to be almost 50% higher than that of comparable samples collected in Edinburgh, UK; the intestinal IgA antibody titre against lipopolysaccharide (LPS) core types of E. coli was almost seven times higher in the former group of subjects, in contrast to the lower levels of ovalbumin antibodies (Hoque et al., 2000).
In view of the above information, the possibility exists that sub-optimal stimulatory reinforcement of the SIgA-dependent mucosal barrier function might contribute to the increased frequency of certain diseases in industrialized countries, particularly allergies and other inflammatory mucosal disorders. This 'hygiene hypothesis' has been tested in several experimental and clinical studies by evaluating the beneficial effect of probiotic bacterial preparations. In particular, viable strains of the commensal intestinal microflora, such as lactobacilli and bifidobacteria, have been reported to enhance IgA responses, in both humans and experimental animals, apparently in a T-cell-dependent manner (Kaila et al., 1992, 1995; Isolauri et al., 1995; Yasui et al., 1995; Malin et al., 1996; Prokesovâ et al., 1999). Interestingly, early colonization of infants with a non-enteropathogenic strain of E. coli has been reported to have a long-term beneficial effect by reducing both infections and allergies (Lodinovâ-Zâdnikovâ and Cukrowskâ, 1999). Likewise, a recent double-blind study of infants with a family history of atopic (IgE-mediated) allergy reported the prevalence of atopic eczema to be reduced by 50% at the age of 2 years in those receiving the probiotic Lactobacillus GG strain daily for 6 months, compared with those receiving placebo (Kalliomâki et al., 2001a). It remains to be shown whether this striking beneficial effect was mediated via SIgA enhancement or by promotion of oral tolerance, as discussed later.
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