Autoimmunity and Sjogrens syndrome (65%) An important objective of our studies is to define the underlying mechanisms by which inflammatory and immune responses go awry, resulting in autoimmune pathogenesis, as exemplified by Sjogrens syndrome. The autoimmune hallmarks of SS include focal lymphoid cell infiltration of the exocrine glands (focus score) and the production of autoantibodies. The etiology of SS remains largely unknown and a conundrum is presented by the failure of many drugs that are effective in other autoimmune disorders, particularly TNF antagonists, such as etanercept. A potential clue to the lack of efficacy of TNF inhibitors is the elevated IL-17 in SS patients peripheral circulation, which is also unmodulated by anti-TNF therapy. In salivary gland biopsies, we performed gene profiling to correlate specific gene expression with T cell subsets and/or their products within the inflamed tissues. At the cellular level, we have shown that expression of IL-17 and also TGFbeta progressively increases with higher biopsy focus scores. Thus, we have connected IL-17 to SS tissue pathology, along with several cytokines that have been shown to be supporting molecules for development of this lineage (TGFbeta, IL-23 and IL-6) without a corresponding increase in Treg with severe disease. This imbalance between pro- and anti-inflammatory forces may perpetuate the autoimmune lesions. Among the locally involved innate immune defense populations are macrophages, which have been linked to IL-12 and IL-23 that moderate T lymphocyte lineage commitment. In our microarray analysis of target tissues from SS patients with mild to severe histopathologic lesions compared to those with sicca symptomatology but negative minor salivary gland biopsy, we focused on disease related overexpressed genes. Among the most highly expressed genes were members of the mammalian chitinase family, not previously associated with exocrinopathies. Both chitinase-3-like-1 (CHI3L1/YKL-40) and chitinase 1 (CHIT1), highly conserved members of the mammalian chitinase-like glycoprotein family, one with and one lacking enzymatic activity, were evident at the transcriptome levels, as well as detected as glycoproteins within inflamed salivary glands. Monocyte to macrophage differentiation is accompanied by an increase in chitinase expression, which can be augmented by cytokine exposure, including IFN. Since the elevated expression of these and other macrophage-derived molecules corresponded with more severe disease in SS patients, these observations suggested a potential immunopathologic macrophage involvement and furthermore, that the MSG macrophage transcriptional profile represents a bellwether for an IFN influence. SLPI regulation of proteolytic cascade in inflammation and cancer (35%) Enhanced inflammation, delayed healing and susceptibility to infection in the absence of SLPI have suggested a link between SLPI and regulation of inflammatory responses. Based on a series of experiments, we demonstrated that a SLPI-annexin II interaction interrupts the proteolytic cascade responsible for plasmin generation. Moreover, we have shown that in SLPI null mice, macrophages process unregulated levels of plasmin, which contributes to excess tissue degradation, increased inflammation and failed healing following tissue injury. By inhibiting plasmin, which has a myriad of downstream consequences relative to complement activation, fibrinolysis, cytokine regulation, TGF-beta activation and other inflammatory sequelae, SLPI can exert control over proteolytic and inflammatory activation networks. Because fibrinolytic processes are fundamental not only to inflammation, coagulation and tissue repair, but growing evidence highlights their dysregulation in the pathogenesis of multiple chronic inflammatory disorders, cardiovascular disease and malignancy, further defining and regulating these pathways is of major significance. Relevant to these findings, we have explored the role of SLPI in metastatic head and neck squamous cell carcinoma (HNSCC), which remains one of the 10 most frequently occurring cancers worldwide with a very poor prognosis, in collaboration with investigators at UMD. SLPI expression was higher in noninvolved than in malignant tissue, and levels significantly inversely correlated with oral squamous cancer stage, pattern of invasion and NFkB activation. Tumor adjacent tissue areas with higher SLPI exhibited reduced elastase and plasmin. Thus, our data imply that SLPI may have anti-tumor activities, which may include interference with requisite proteolytic steps underlying tumor cell invasion and affecting the cell-associated plasminogen activation system, suggesting a strategy to predict/biomarker and/or prevent tumor invasive potential in oral cancer. Our continuing studies include investigation of potential SLPI regulation in carcinogenesis and more explicitly defining these pathways in a model of squamous cell carcinoma in SLPI null and WT C57BL/6 mice. Our evidence in this mouse model confirms that the absence of SLPI is associated with more rapid and extensive development of tumors, enabling characterization of the cellular and molecular pathways involved. Utilizing the DMBA-induced murine skin squamous cell carcinoma (SCC) model, evidence supported a role for SLPI in the kinetics and incidence of skin papilloma, and in significantly inhibiting lung metastasis (81% of SLPI null mice developed lung metastatic tumors compared to 56% in wildtype mice (p=0.035). However, SLPI did not appear to influence the conversion of papilloma to cancer, thereby focusing our efforts on its role in invasion, migration and metastasis.
| Moutsopoulos, Niki M; Kling, Heather M; Angelov, Nikola et al. (2012) Porphyromonas gingivalis promotes Th17 inducing pathways in chronic periodontitis. J Autoimmun 39:294-303 |
| Ashcroft, Gillian S; Jeong, Moon-Jin; Ashworth, Jason J et al. (2012) Tumor necrosis factor-alpha (TNF-?) is a therapeutic target for impaired cutaneous wound healing. Wound Repair Regen 20:38-49 |
| Hubbard, Jonathan J; Greenwell-Wild, Teresa; Barrett, Lisa et al. (2012) Host gene expression changes correlating with anti-HIV-1 effects in human subjects after treatment with peginterferon Alfa-2a. J Infect Dis 205:1443-7 |
| Smith, P D; Smythies, L E; Shen, R et al. (2011) Intestinal macrophages and response to microbial encroachment. Mucosal Immunol 4:31-42 |
| Greenwell-Wild, Teresa; Moutsopoulos, Niki M; Gliozzi, Maria et al. (2011) Chitinases in the salivary glands and circulation of patients with Sjögren's syndrome: macrophage harbingers of disease severity. Arthritis Rheum 63:3103-15 |
| Vázquez, Nancy; Schmeisser, Hana; Dolan, Michael A et al. (2011) Structural variants of IFN? preferentially promote antiviral functions. Blood 118:2567-77 |
| Wahl, Sharon M; Redford, Maryann; Christensen, Shawna et al. (2011) Systemic and mucosal differences in HIV burden, immune, and therapeutic responses. J Acquir Immune Defic Syndr 56:401-11 |
| Wen, Jie; Nikitakis, Nikolaos G; Chaisuparat, Risa et al. (2011) Secretory leukocyte protease inhibitor (SLPI) expression and tumor invasion in oral squamous cell carcinoma. Am J Pathol 178:2866-78 |
| Challacombe, S J; Fidel Jr, P L; Tugizov, S et al. (2011) HIV infection and specific mucosal immunity: workshop 4B. Adv Dent Res 23:142-51 |
| Malamud, Daniel; Wahl, Sharon M (2010) The mouth: a gateway or a trap for HIV? AIDS 24:5-16 |
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