Browsing School, Graduate by Title "Th17 Cells in Gingival Immunity and Their Key Role in Periodontitis Pathogenesis"
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Th17 Cells in Gingival Immunity and Their Key Role in Periodontitis PathogenesisPeriodontitis is a very common human disease characterized by inflammatory bone destruction in the oral cavity. It affects more than 64 million adults in the United States and is often linked to systemic or distant co-morbidities. T helper (Th) cells and specifically Th17 have been identified as important constituents of the inflammatory lesion in periodontitis. However, the specific role of Th17 cells in periodontitis and whether they drive inflammatory pathology is not fully understood. We performed a detailed characterization of gingival tissues and found that Th17 are amplified in the lesions of human periodontitis. In fact, Th17 cells represent the major source of IL-17A in humans and in animal models of periodontitis and we show that their accumulation in gingival tissues is IL-6 dependent. Th17 differentiation and IL-17A expression are tightly regulated by signal transducer and activator of transcription-3 (STAT3). To analyze the role of Th17/STAT3 in humans with periodontitis we have evaluated a large cohort of patients with autosomal dominant mutations in STAT3. Autosomal Dominant Hyper IgE Syndrome (AD-HIES) patients have a defect in Th17 differentiation and lack Th17 cells in the circulation. We clinically characterized patients with AD-HIES and evaluated Th17 responses in their oral tissues. We find that AD-HIES patients have reduced susceptibility to periodontitis and present minimal oral inflammation, consistent with blunted Th17 tissue responses. To mechanistically dissect the role of Th17 cells and STAT3 in periodontitis, we performed periodontitis induction in mouse models specifically lacking Th17 cells. Cd4creStat3floxed mice lacked Th17 cells but other sources of IL-17 producing cells were unaffected in gingival tissues and importantly, were resistant to inflammatory bone loss. These results demonstrate the key role of Th17 in periodontitis and suggest inhibition of Th17 through Stat3 in the treatment/prevention of disease. Indeed, we performed preclinical studies of Stat3 inhibition (using C188-9 inhibitor, a small-molecule compound designed to prevent Stat3 activation) and demonstrated that pharmacologic inhibition of Stat3 prevented inflammatory bone loss in periodontitis models. Our work uncovers the pathogenic potential of Th17 cells in periodontal inflammatory bone loss and suggests pharmacologic inhibition through STAT3 in the prevention of this common inflammatory disease.