Defense mechanisms involving Fc-dependent functions of immunoglobulin A and their subversion by bacterial immunoglobulin A proteases

The majority of immunoglobulin A (IgA) produced in the human body is secreted onto the vast area of mucosal surfaces, becoming the principal mediator of humoral immunity at these sites. The serum and mucosal IgA systems differ with regard to ontogeny, regulation, cellular origin, and molecular configuration of the respective immunoglobulin molecules. The functional properties of IgA from both systems depend on the Fc portion of the IgA molecule. Unlike IgG and IgM, which activate the complement and phagocytic systems, both serum and secretory IgA are relatively ineffective in interacting with these inflammatory effector systems. However, the polymeric configuration, ability to bind to a secretory component, hydrophilicity, and charge, conferred by the Fc part of secretory IgA, give this immunoglobulin isotype special mucosal defense properties. Serum IgA may have a unique function in regulating immune effector mechanisms mediated by the delivery of null or negative signals by its Fc region. Several microbial pathogens that colonize or invade through mucosal surfaces can interfere with such Fc-mediated functions of IgA by releasing proteases that specifically cleave the hinge region of human IgA subclass 1 (IgA1). These IgA1 proteases are virulence factors that enable mucosal pathogens to counteract secretory IgA-mediated defense mechanisms; they probably also affect the complex microbial ecology of mucosal surfaces, and they may cause temporary or local deficiencies in mucosal immunity. Furthermore, IgA1 proteases are hypothesized to provide a unique mechanism by which the three principal agents of bacterial meningitis can evade immune defense mechanisms and cause invasive disease.