Resistance of Normal Serum IgA and Secretory IgA to Bacterial IgA Proteases: Evidence for the Presence of Enzyme‐Neutralizing Antibodies in Both Serum and Secretory IgA, and Also in Serum IgG

Abstract

Normal serum IgA and secretory IgA (sIgA) of subclass IgA 1 were isolated from pooled human serum and milk, respectively. They were tested for their susceptibility to bacterial IgA proteases from Haemophilus influenzae, Streptococcus pneumoniae, Neisseria gonorrhoeae, and Neisseria meningitidis that cleave IgA of only the IgA 1 subclass. They were also tested for susceptibility to a novel IgA-protease from Clostridium ramosum that cleaves IgA of the IgA 1 as well as the IgA2 subclass of the A2m(1) allotype. Both normal serum IgA 1 and sIgA 1 exhibited resistance to most IgA proteases. The one exception was the IgA protease from C. ramosum which readily cleaved both the serum IgAl and sIgAl into Fab and Fc fragments. Secretory component (SC) had nothing to do with the resistance of these IgAs. The resistance of these IgAs to most of the IgA proteases was found to be due to their enzymeneutralizing antibody activity, since the Fab but not the Fc fragment of sIgA I showed enzyme-inhibitory activity against these IgA proteases. Similar enzyme-neutralizing antibody activity was found in the pepsin-digested normal serum IgG-(Fab')2 fragment. These results indicate that the induction of the enzyme-neutralizing antibodies against the bacterial IgA proteases took place not only in mucosal sIgA but also in serum IgA and IgG. No enzyme-neutralizing antibody activity against the novel IgA-protease of C. ramosum was detected in any immunoglobulin preparations used in the present study or in the serum of a patient who carries the IgA protease-producing strain of C. ramosum in his feces.

Obstructive pulmonary disease

“…Infection or colonization with IgAl protease-producing bacteria leaves protease-neutralizing antibodies in secretions (2,3,12,20). If the assumption that H. influenzae and certain other mucosal commensals and pathogens depend on an active IgAl protease in order to establish on human mucosal surfaces is correct, then such antibodies must restrict the subsequent colonization and infection to clones expressing an antigenically different IgAl protease.…”

Microbial Evasion of IgA Functions

“…The apparent lack of antibody response to the IgA protease of C. ramosum (Kobayashi et al, 1987) may be another example of a more subtle relationship between commensal bacteria and their host. High titers of neutralizing salivary antibodies against IgA1 proteases of S. mitis observed in occasional subjects may have been induced by pneumococci with antigenically related IgA1 proteases (Lomholt and Kilian, 1994;Bek-Thomsen et al, 2012).…”

“…Neutralizing antibodies are experimentally induced in rabbits or other animals that are injected with protease preparations and in sera and secretions of humans colonized or infected by IgA1 protease-producing bacteria (Gilbert et al, 1983;Kilian et al, 1983b;Brooks et al, 1992;Devenyi et al, 1993;Reinholdt and Kilian, 1995;Kirkeby et al, 2000;Janoff et al, 2014). In general, human milk contains neutralizing antibodies to bacterial IgA1 proteases, with the consequence that SIgA1 purified from human colostrum is resistant to most IgA1 proteases unless they are added in excessive amounts (Kobayashi et al, 1987).…”

Spondylodiscitis Due to Clostridium ramosum Infection in an Immunocompetent Elderly Patient

“…The origin of infection was probably the patient's own digestive tract. C. ramosum is able to produce immunoglobulin A1 and A2 proteases, which may facilitate mucosal penetration (17,24). Mucositis (oral ulceration, atrophy, or edema) is a common portal of entry, and the bacterium may invade the epithelium, reaching the vascular subcutaneous tissue.…”