Defining the role of mSMGP/mPIP as an immunoregulatory molecule in host defense

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Defining a role for mSMGP as an immunoregulatory molecule in host defense HYPOTHESIS: The mouse submaxillary (submandibular) gland protein, mSMGP, is an important immunoregulatory molecule that plays a role in both innate and adaptive immune host defense. PROPOSAL: To examine mSMGP’s influence on the adaptive immune system and to delineate the mechanisms of its innate antimicrobial activities. My laboratory is interested in the biology and physiology of the submandibular gland. The submandibular gland in the mouse, as in most other mammals, exhibits both endocrine and exocrine functions, and is the site of synthesis of several biologically active polypeptides, including hormones, growth factors, and digestive enzymes. Many of these proteins are well studied and characterized, however, the function of several others remain elusive. I have identified a gene that is highly expressed in this gland and whose protein we termed the mouse submaxillary gland protein (mSMGP). The function of mSMGP has not been delineated. Following this initial discovery, we subsequently found that not only was mSMGP expressed in salivary glands, but was also expressed at immunologically important ports of entry for pathogens, such as skin, eyes and ears and the secreted protein found in the bodily fluids produced by these tissues such as saliva, tears and sweat. We further demonstrated that mSMGP binds to and aggregates bacteria including several human and mouse oral strains, prohibiting their multiplication and spread. These observations led us to hypothesize that mSMGP plays a role in innate host defense. However, clues that mSMGP may have a broader role in immunity have come from other studies carried out on a human homologue which was shown, like mSMGP, not only to possess the ability to bind to bacterial strains but was capable of binding to the CD4 molecule and inhibit T lymphocyte apoptosis. Furthermore, using a mSMGP knockout model which we generated as a tool to address protein function, we demonstrated that knockout mice had abnormal lymphocytes that exhibited abnormal proliferation rates, had impaired Th1 and possibly, Th2 immune responses and had increased susceptibility to Leishmania major infection. We demonstrated for the first time that mSMGP was involved in cell mediated immunity. We also showed that KO mice saliva was less effective in aggregating oral bacteria and that the composition of the oral flora was different from its wild type counterpart, with a preponderance of representation from the genus Streptococcus. Additionally we showed that loss of mSMGP function resulted in the up regulation of a class of salivary proteins recently identified as putative markers of disease. Our current objectives are to investigate the role of the mSMGP in cell mediated immunity and to delineate the mechanism of mSMGP antimicrobial activities. Protection against invading organisms or infection, particularly via oral contamination is to date, poorly understood. The proposed studies are among the very few that approach the infection phenomenon from an oral perspective. I anticipate this study will yield critical insights into the function and biology of the mSMGP, and will further contribute to increasing our understanding of submandibular gland biology and immunity.