Evidence is provided that the High Molecular Weight Secretory Non- Immunoglobulin Agglutinins (NIA), isolated from parotid saliva, are some of the most potent C1 activating host substances known. NIA, like aggregated IgG, bind primarily to the C1q globular heads. While aggregated sIgA and aggregated Fab have limited effects on the alternative pathway, they are unable to activate the first complement component and the more potent classical complement pathway in the presence of physiological levels of C1 inhibitor. IgG and IgM enter the oral cavity via the minor salivary glands and via gingival crevicular fluid, but these immunoglobulins are rapidly cleaved, at their very susceptible hinge region, by oral bacterial proteases, causing release of their (C1-activating) Fc regions. Because NIA interact with aggregated Fab fragments of IgA, IgG and IgM and with sIgA, NIA are able to bind to the antibody which becomes coated on oral bacterial surfaces even after bacterial proteases remove the Fc fragment. This proposal will test the hypothesis that Secretory Non-Immunoglobulin Agglutinins have the potential, upon binding to secretory IgA and to Fab-alpha, Fab- gamma, or Fab-mu, to transfer a potent C1 binding potential, leading to effective activation of the classical complement pathway. It is hypothesized that the binding of the NIA to immobilized secretory IgA, Fab-alpha, Fab-gamma, or Fab-mu will generate an effective C1 activating potential, comparable to the C1 activating potential of aggregated IgG. Antigens on mucosal surfaces may become coated with sIgA (or Fab) and NIA prior to penetration into inflamed/disrupted mucosal tissues, where contact with a fully intact complement system would occur. Several mucosal diseases generate conditions for such interactions. Some of these include otitis media, bronchitis, sinusitis, celiac disease, aphthous stomatitis and gingivitis. The Specific Objectives of this proposal are:
Aim I. To study the C1 binding and C1 activating properties of salivary NIA, once the NIA have become bound to sIgA, Fab- alpha, Fab-gamma, or Fab-mu and to study the interactions of NIA and deglycosylated NIA with C1q (globular heads and collagen-like stems).
Aim II : - To examine the rate of C4b and C3b deposition mediated by activation of C1 [and the classical complement pathway] by NIA which have become bound to sIgA, Fab-alpha, Fab-gamma, or Fab-mu. To also determine the regulatory role of C1 inhibitor on C1 activation, C4 conversion and C4b and C3b deposition onto the immobilized NIA-sIgA, and NIA-Fab-alpha, NIA-Fab-gamma, or NIA-Fab-mu.
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| Boackle, R J; Dutton, S L; Robinson, W L et al. (1999) Effects of removing the negatively charged N-terminal region of the salivary acidic proline-rich proteins by human leucocyte elastase. Arch Oral Biol 44:575-85 |
| Chen, C H; Boackle, R J (1998) A newly discovered function for C1 inhibitor, removal of the entire C1qr2s2 complex from immobilized human IgG subclasses. Clin Immunol Immunopathol 87:68-74 |
| Chen, C H; Lam, C F; Boackle, R J (1998) C1 inhibitor removes the entire C1qr2s2 complex from anti-C1Q monoclonal antibodies with low binding affinities. Immunology 95:648-54 |
