Bacteria have evolved several mechanisms for evading immune responses in the gut. These approaches include interfering with passive and active immunity by specifically cleaving secretory IgA1, preventing FcaRI activation by sterically occluding the receptor-binding site on IgA, and even hijacking the transcytotic pathway via interaction with pIgR to invade the mucosal epithelium. The first two avenues for immune evasion have not yet been fully elucidated through high-resolution crystal structures, although we can gather some insight from knowledge of the solution structure of intact IgA1 and the crystal structure of IgA1-Fc. IgA1 proteases are secreted by a number of bacterial genera, including Neisseria, Streptococcus, and Haemophilus species (Plaut et al. 1975; Male 1979). These proteases share a common feature of specificity for Pro-Thr or Pro-Ser dipeptides in the hinge region of IgA1 (Kilian et al. 1980), although the IgA1-Fc region has also been implicated in substrate recognition (Chintalacharuvu et al. 2003). As described above, IgA1
has an elongated hinge region that is found in an extended conformation, due to both its amino acid sequence and its high levels of O-linked glycosylation (Fig. 1a). These characteristics render the IgA1 hinge a suitable substrate for the IgA1 proteases. Given that IgA2 has a 13-residue truncation in the hinge region, this subclass is not susceptible to proteolysis. Cleavage of the hinge region of IgA1 would leave only the Fab regions specifically bound to the bacterial surface, thus significantly minimizing steric occlusion arising from an intact secretory IgA1 (Reinholdt and Kilian 1987). Furthermore, in Streptococcus pneumoniae, anticapsular Fab fragments remaining after cleavage of IgA1 facilitate adhesion to epithelial cells, apparently by minimizing the negative charge of the bacterial capsule (Weiser et al. 2003).
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