The gastrointestinal immune system

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3.1. Gut-associated lymphoid tissue (GALT) (Brandtzaeg et al. 1989)

The first, and in normal individuals only, contact that ingested bacteria, including probiotics, have with the immune system is with the GALT. The human intestine represents the largest mass of lymphoid tissue in the body, containing over 106 lymphocytes/g tissue. In addition, about 60% of the total immunoglobulin (Ig; several grams) produced daily is secreted into the gastrointestinal tract. GALT is part of the mucosal immune system (i.e. gastrointestinal tract, respiratory tract, oral cavity, urogenital tract and mammary glands) and has unique cell types and mechanisms of immunity. The special nature of intestinal immunity has evolved under constant exposure to environmental antigens, whilst requiring an effective response to an invading pathogen despite the presence of dietary antigens. The difference between immune responses to dietary proteins and antigens of colonizing bacteria may play a role in the prevention of hypersensitivity reactions to food proteins.

3.2. The structure of GALT and cell distribution

Intestinal immune cells are organized in different compartments: aggregated in follicles and the Peyer's patches; distributed within the mucosa as diffuse lymphocyte populations; and in the epithelium (reviewed by McKay & Perdue, 1993). The GALT T-lymphocytes are not homogeneous. These are classified as CD4+ helper/inducer cells and CD8+ suppressor/cytotoxic cells, generating different cytokine profiles with distinct yet unproven functions (reviewed by Brandtzaeg et al. 1989; Brandtzaeg, 1995). The majority of the intra-epithelial T-cells have a suppressor/cytotoxic phenotype, contrasting with the lamina propria cells, which show mainly a helper/inducer phenotype. The lamina propria is also endowed with lymphocytes belonging to the B-cell lineage. These are mainly memory cells and plasmocytes, where 70-90 % of them are IgA-producing cells.

The epithelial layer of the small-intestinal mucosa is arranged in folds, consisting of villi and crypts, which increase the absorptive surface area. The epithelium consists of a single layer of absorptive columnar epithelial cells, goblet cells and intra-epithelial lymphocytes. The intraepithelial lymphocytes are a heterogeneous population of cells. In the mouse, the primary intra-epithelial lymphocytes are CD3+, CD8+, T-cells with a 7/ô-T-cell receptor (T-cell receptor 1) and in man CD8 T-cells expressing an a//3-cell receptor (T-cell receptor 2). The proportion of T-cell receptor 1 cells in the epithelium is greater than in peripheral blood. The 7/ô-T-cell receptor cells are thought to mature in the epithelium rather than in the thymus, thus their development might be more susceptible to environmental exposures. Intra-epithelial lymphocytes are known to mediate both non-major-histocompatibility-complex-restricted and major-histocompatibility-complex-restricted cytotoxicity, and regulate neighbouring immune and epithelial cells by secreting cytokines.

The epithelium is surrounded by the lamina propria, which comprises lymphoid organs such as reticular tissue and which contains plasma cells, T-helper cells, granulocytes and mast cells. The lamina propria is surrounded by smooth-muscle tissue. Along the small intestine are Peyer's patches, which are organized lymphoid follicle aggregates. The Peyer's patches are more accessible to micro-organisms than other epithelial surfaces of the gut, because they have reduced numbers of the mucus-secreting goblet cells. In addition, the epithelial layer of the Peyer's patches contains specialized transport cells called M-cells, which lack microvilli and are able to phagocytose both soluble antigens and micro-organisms.

3.3. Immunophysiological regulation (Brandtzaeg, 1995)

Different components of the mucosal immune system act to focus a specific response against offending antigens. The first line in this defence, immune exclusion involving IgA antibodies, is non-inflammatory (Brandtzaeg, 1995). The best-characterized component of the mucosal immune defence is the secretory IgA system (Brandtzaeg, 1995). IgA antibody production is abundant at mucosal surfaces. IgG-, IgM- and IgE-secreting cells function also, but at a significantly lower frequency in GALT. In contrast to IgA in serum, secretory IgA is present in dimeric or polymeric form in the gut. The predominance of IgA in the mucosal immune system results from IgA-selective T-cell regulation in GALT, particularly in the Peyer's patches, where specific immune responses are generated (Biewenga et al. 1993). After being synthesized by IgA precursor cells, polymeric IgA is transported to the mucosal surface by epithelial transcytosis mediated by the polymeric immunoglobulin receptor, the secretory component. Secretory IgA is resistant to intraluminal proteolysis, and does not activate complement or inflammatory responses, which makes IgA ideal for protecting the mucosal surfaces. Hence, the main function of secretory antibodies is, in cooperation with non-immunological defence mechanisms (Sanderson & Walker, 1993), to mediate immune exclusion of foreign antigens by preventing epithelial adherence and penetration of invasive pathogenic micro-organisms, neutralizing toxins and viral multiplication.

Although GALT is mainly involved in specific immune protection of the gut, there is evidence for a 'common mucosal immune system': an immune response initiated in GALT can affect immune responses at other mucosal surfaces (Brandtzaeg, 1995). The lymphocytes activated within Peyer's patches disseminate via mesenteric lymph nodes, thoracic duct and the bloodstream back to the lamina propria, and traffic between other secretory tissues, including the respiratory tract and the lachrymal, salivary and mammary glands.

There are differences between the upper and lower parts of the human GALT in isotype distribution of immuno-globulin-producing cells. Two IgA subclasses are available (IgA] and IgA2). IgA! immunocytes predominate in the small-intestinal mucosa, while IgA2 are most frequent in normal colonic mucosa. IgA2 in the colon is resistant to most bacterial proteases that cleave IgA[ (Brandtzaeg, 1995).

Immune elimination is directed towards removal of foreign antigens that have penetrated the mucosa. This second line of defence involves antibodies such as IgG and a large number of mediators such as inflammatory cytokines, which are considered to be responsible for the pathophysiology associated with local inflammation (Brandtzaeg, 1995). Immune regulation pertains to the state of specific hyporesponsiveness induced by prior oral administration of antigens, inducing oral tolerance. Consequently, hyporesponsiveness to ubiquitous antigens such as dietary antigens is a hallmark of the intestinal immune system (Weiner et al. 1994). This has been taken to be a combined effect of immune exclusion and suppression of the systemic immune response, but it is still a matter of debate.

3.4. Regulation of antigen transfer (Isolauri et al. 1993a, b)

Antigens are proteins foreign to the host. Factors that influence antigenicity include molecular complexity, solubility and concentration. Most antigens are macromolecules in the molecular mass range 10 000-70 000 Da.

Apart from the barrier function, the intestinal mucosa is efficient in assimilating antigens. For this purpose, there are specialized antigen transport mechanisms in the villous epithelium and particularly in the Peyer's patches (Heyman et al. 1982). The manner in which an antigen is transported across the mucosa determines the subsequent immune response (Heyman et al. 1982; Heyman & Desjeux, 1992; Isolauri et al. 1993a, b\ Sanderson & Walker, 1993).

Most antigens are excluded by a well-functioning mucosal barrier but an immunologically important fraction of antigen does bypass it (Heyman et al. 1982; Isolauri et al. 1993a, b). Antigens are absorbed across the epithelial layer by transcytosis, and the main degradative pathway entails lysosomal processing of the antigen. A minor pathway allows the transport of unprocessed antigens. The Peyer's patches are covered by a unique epithelium and antigen transport across this is characterized by rapid uptake and reduced degradation of antigens. In health, paracellular leakage of macromolecules is prevented because intact intercellular tight junctions maintain the barrier to macromolecules. Consequently, in healthy subjects antigen transfer is well controlled and aberrant antigen absorption does not occur.

There is evidence that during the process of absorption across the intestinal mucosa, dietary antigens are altered into a tolerogenic form (Weiner et al. 1994). By interfering with this process intestinal inflammation is an important risk factor for the development of hypersensitive disorders (Fargeas et al. 1995).

3.5. Interactions between the intestinal microflora and the GALT (Moreau & Coste, 1993)

After birth, the intestine is rapidly colonized by bacteria, which probably act as a source of antigens and non-specific immunomodulators. The dual role of the digestive flora on the immune system should be emphasized. Bacteria can be considered as antigens able to elicit specific systemic and local immune responses. Furthermore, they exert a considerable influence on the number and distribution of the GALT cell populations and play an important role in the regulation of immune responses. These data have emerged mainly from animal studies using germ-free and gnotobiotic animal models (see section 6.5). As direct evidence from human subjects is scarce, we can only extrapolate from experimental results obtained in mice. Such studies are important to determine the exact role played by different bacteria present in the digestive flora, with the aim of improving the bacterial equilibrium and allowing the best immune modulation by functional foods. The cellular and molecular events by which the digestive flora modulates the immune system are still poorly understood.

The digestive flora is the major antigenic stimulus responsible for the migratory pathway and maturation of precursor lymphoid cells present in the Peyer's patches. Consequently, it acts on the development and maturation of the IgA plasmocytes. In germ-free mice, IgA-plasmocyte number is decreased tenfold as compared with controls. It has been shown that the sequential establishment of the digestive flora from birth to weaning is responsible for the progressive increase in IgA plasmocyte numbers in the lamina propria of the small intestine in the growing normal mouse. In addition, Gram-negative bacteria such as Escherichia coli and Bacteroides play an important role in this immunologically non-specific effect.

The digestive flora also modulates the specific immune responses at local and systemic levels. It allows the persistence of the systemic unresponsiveness to an antigen, induced by a previous feeding with the same antigen (oral tolerance) (Moreau & Gaboriau-Routhiau, 1996) and shortens the abrogation of oral tolerance mediated by cholera toxin or E. coli toxin (Gaboriau-Routhiau & Moreau, 1996), which seems to be a property of Gramnegative bacteria (M. C. Moreau and V. Gaboriau, unpublished results). In another study the presence of the gut flora modulated the intestinal antibody IgA response to rotavirus. Recently, the development of an experimental model of adult germ-free mice infected with a heterologous strain of rotavirus allowed investigation of the immunomodulating properties of a strain of Bifidobacterium on the enhancement of the intestinal anti-rotavirus IgA antibody response at cellular and faecal levels (Moreau et al. 1998). At the systemic level, in gnotobiotic mice harbouring a human strain of Bifidobacterium in the intestine or two bacterial strains from yoghurt, Lactobacillus bulgaricus and Streptococcus thermophilus, increases of the specific antibody response in serum and in the phagocytic activity of peritoneal phagocytes were observed respectively (Moreau et al. 1994).

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