Killing of Streptococcus pneumoniae by capsular polysaccharide–specific polymeric IgA, complement, and phagocytes

Abstract

The role of IgA in the control of invasive mucosal pathogens such as Streptococcus pneumoniae is poorly understood. We demonstrate that human pneumococcal capsular polysaccharide-specific IgA initiated dose-dependent killing of S. pneumoniae with complement and phagocytes. The majority of specific IgA in serum was of the polymeric form (pIgA), and the efficiency of pIgA-initiated killing exceeded that of monomeric IgA-initiated killing. In the absence of complement, specific IgA induced minimal bacterial adherence, uptake, and killing. Killing of S. pneumoniae by resting phagocytes with immune IgA required complement, predominantly via the C2-independent alternative pathway, which requires factor B, but not calcium. Both S. pneumoniae-bound IgA and complement were involved, as demonstrated by a 50% decrease in killing with blocking of Fcα receptor (CD89) and CR1/CR3 (CD35/CD11b). However, IgA-mediated killing by phagocytes could be reproduced in the absence of opsonic complement by pre-activating phagocytes with the inflammatory products C5a and TNF-α. Thus, S. pneumoniae capsule-specific IgA may show distinct roles in effecting clearance of S. pneumoniae in the presence or absence of inflammation. These data suggest mechanisms whereby pIgA may serve to control pneumococcal infections locally and upon the pathogen's entry into the bloodstream.

Human IgA Activates the Complement System Via the Mannan-Binding Lectin Pathway

“…It is generally agreed that IgA cannot activate the classical complement pathway (14). Activation of the alternative complement pathway by IgA is supported by both in vitro (27)(28)(29) and in vivo observations (30), as well as by the present study. It has been argued that complement activation by IgA has to rely on studies using artificially modified or presented IgA (14).…”

“…Differences between mutant and wild-type sera were evaluated by a t test. ‫,ء‬ p ϭ 0.015; ‫,ءء‬ p ϭ 0.001. differences have been previously reported for activation of the alternative pathway by rat and human IgA (16,26,29). In addition, polymeric IgA shows enhanced binding to the phagocytic IgA FcR CD89 (33) and to human mesangial cells (34).…”

“…In addition, polymeric IgA shows enhanced binding to the phagocytic IgA FcR CD89 (33) and to human mesangial cells (34). The stronger effector functions of polymeric IgA have a beneficial role for the defense functions of IgA (29,35,36). In accordance, circulating Ag-specific IgA produced upon primary pathogen contact predominantly consists of polymers (29).…”

“…For example, xenoreactive human IgA Abs can induce complement-mediated lysis of pig endothelial cells in a calcium-independent way (28). Furthermore, binding of human serum IgA to Streptococcus pneumonia induces neutrophil-mediated bacterial killing that was complement dependent and proceeded in the presence of MgEGTA (29).…”

The IgA system: a comparison of structure and function in different species

“…On the contrary, earlier data suggested a noninflammatory function of IgA. This is accentuated by the fact that IgA is a poor activator of complement although IgA can trigger, under certain conditions, the alternative complement pathway [40], it cannot bind C1q, therefore it cannot activate the classical pathway [47]. However, the ability of IgA to induce phagocytosis has now been confirmed by several laboratories [74].…”