To the Presence of Commensal Intestinal Bacteria

Although secretory IgA constitutes the bulk of our bodily antibody output, we have only limited information about its function. Selective IgA deficiency in either mouse or human has a relatively benign phenotype, but this is probably because IgM can substitute for IgA in both species. For either IgA or IgM to be transported through the surface epithelial cells into the intestinal lumen, they must be in polymeric form, containing J chain, and undergo transcytosis bound to the polymeric immunoglobulin receptor (Brandtzaeg 1973,1974). Mice deficient for this pIgR show a protein losing enteropathy, indicative of low-grade intestinal inflammation (Johansen et al. 1999).

To address the function of secretory immunoglobulin in protecting the mucosa against commensal bacteria we performed two different sorts of experiments (Macpherson and Uhr 2004). The first was to follow recolonisation of germ-free C57BL/6 (wild type) and Jh-/- (antibody deficient) animals in parallel as they acquired an SPF flora from a sentinel animal. In the first 48 h of the experiment there was overgrowth of both aerobic and anaerobic organisms, which then settled to steady-state levels with no significant differences between the strains. However, the penetration of culturable aerobes from the lumen to the MLN was greater in the JH-/- strain and persisted longer (from day 5 until day 42). Because the MLN do become sterile after a delay in the JH-/- strain, secreted antibodies are only part of the adaptation mechanism to commensal bacteria; they are not essential. In a different experimental setup we challenged SPF C57BL/6 wild-type mice and SPF JH-/- antibody-deficient animals (already containing an SPF flora) with graded doses of E. cloacae and compared the levels of live bacterial penetration to the MLN18 h later. This experiment also showed that the antibody-deficient strain had slightly higher levels of penetration at each dose compared with the wild-type control. In contrast, wild-type animals that had been conditioned with E. cloacae for a month and then rested for 7 days before challenge (resulting in a substantial increase in IgA levels as described in Sect. 3.3) had lower levels at every challenge dose compared with wild-type controls that had not been conditioned. Therefore, secreted antibodies appear to protect the mucosa overall from bacterial penetration beneath the epithelial surface.

Other experiments show that the function of IgA is probably not just immune exclusion. Studies of the activation-induced cytidine deaminase (AID) knockout strain, which is deficient in both isotype class switch recombination and affinity maturation, have shown that there is overgrowth of anaerobes and lymphonodular hyperplasia in the ileum (Fagarasan et al. 2002; Suzuki et al. 2004). This can be corrected by reconstituting IgA expression (Suzuki et al. 2004). A third possible functional consequence of IgA coating of intestinal bacteria may even be to increase the uptake via specialised IgA receptors on epithelial M cells overlying the Peyer's patches (Mantis et al. 2002; Roy and Varvayanis 1987; Weltzin et al. 1989), facilitating sampling of luminal bacteria.

The overall functional consequence of IgA expression is to limit penetration of bacteria beneath the intestinal epithelial surface. The IgA system therefore can work by negative feedback, whereby increased penetration of commensals into DC leads to IgA induction, which in turn limits bacterial translocation through the mucosa. Although secretory IgA is a protective mechanism against commensal bacteria, it is not essential—evolution has ensured that there are a number of protective responses against damage by the immunostimulatory molecules in the luxuriant intestinal commensal bacterial flora (Sansonetti 2004).

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