In this period our studies have particularly focused on patients with defects in the development of Th17 cells. Among the recognized immune defeciencies with Th17 defects are patients with autosomal dominant hyper-IgE syndrome (AD-HIES or Jobs syndrome) which harbor loss of function (LOF) mutations in the signal transducer and activator of transcription (STAT) 3 gene. AD-HIES patients have been classically characterized by the triad of eczema, skin and lung infections, and extremely elevated serum IgE . They also present with recurrent oral Candida infections, indicating a critical role for STAT3 mediated oral immunity. STAT3 is a key transcription factor downstream of cytokine signaling from IL-6, IL-21, IL-10, and IL-23 among other immune mediators. STAT3 is also defined as a key transcription factor in the differentiation of Th17 (28, 29). However, although IL-17/Th17 related defects have a dominant oral phenotype, it is not well understood whether defects in STAT3 and related Th17/IL-17 in humans affect commensal microbial communities and predispose to mucosal microbial dysbiosis. Therefore, our current study, aimed to further our understanding of the consequences of LOF STAT3 and related Th17 defects on establishment and dynamics of the mucosal mycobiome and bacteriome We specifically, aimed to understand consequences of Th17 deficiency in human oral immunity and in establishment of the oral mucosal mycobiome and bacteriome. Our clinical evaluation confirmed previous reports of increased rates of oral candidiasis, but also revealed previously undocumented oral phenotypes. Thus, apart from oral candidiasis, patients with STAT3/Th17 deficiency presented with barrier defects, as evidenced by recurrent oral ulcers and also displayed severe dental caries susceptibility. Molecular characterization of fungal and bacterial communities in AD-HIES showed specific susceptibility to the commensal C. albicans and overgrowth of oral streptococci within candidiasis lesions. Our work supports a model in which STAT3/Th17 is critical in oral antifungal immunity specifically against C. albicans, with overgrowth of C. albicans leading to shifts in bacterial communities and consequent secondary dental infections. Our studies reveal novel clinical phenotypes in patients with STAT3/Th17 deficiency and highlight a critical role for STAT3/Th17 in surveillance of oral fungal and bacterial commensal communities. Despite (fungal) infection susceptibility in patients with Th17 defects, we document reduced prevalence and severity of periodontitis. In fact, patients with HIES presented with reduced gingival inflammation and bone loss compared to age/gender matched healthy volunteers. However, while we do document that patients with AD-HIES present with reduced periodontitis susceptibility, it is not possible to formally prove resistance to periodontitis in this setting. Yet, these clinical findings do suggest a potential role for Th17 cells in periodontal disease pathogenesis.

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National Institute of Dental & Craniofacial Research
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Abusleme, Loreto; Diaz, Patricia I; Freeman, Alexandra F et al. (2018) Human defects in STAT3 promote oral mucosal fungal and bacterial dysbiosis. JCI Insight 3:
Abusleme, L; Moutsopoulos, N M (2017) IL-17: overview and role in oral immunity and microbiome. Oral Dis 23:854-865
Moutsopoulos, Niki M; Zerbe, Christa S; Wild, Teresa et al. (2017) Interleukin-12 and Interleukin-23 Blockade in Leukocyte Adhesion Deficiency Type 1. N Engl J Med 376:1141-1146
Shah, Nirali N; Freeman, Alexandra F; Su, Helen et al. (2017) Haploidentical Related Donor Hematopoietic Stem Cell Transplantation for Dedicator-of-Cytokinesis 8 Deficiency Using Post-Transplantation Cyclophosphamide. Biol Blood Marrow Transplant 23:980-990
Dutzan, Nicolas; Konkel, Joanne E; Greenwell-Wild, Teresa et al. (2016) Characterization of the human immune cell network at the gingival barrier. Mucosal Immunol 9:1163-1172
Hajishengallis, George; Moutsopoulos, Niki M (2016) Role of bacteria in leukocyte adhesion deficiency-associated periodontitis. Microb Pathog 94:21-6
Falcone, E Liana; Abusleme, Loreto; Swamydas, Muthulekha et al. (2016) Colitis susceptibility in p47(phox-/-) mice is mediated by the microbiome. Microbiome 4:13
Cuellar-Rodriguez, Jennifer; Freeman, Alexandra F; Grossman, Jennifer et al. (2015) Matched related and unrelated donor hematopoietic stem cell transplantation for DOCK8 deficiency. Biol Blood Marrow Transplant 21:1037-45
Moutsopoulos, N M; Lionakis, M S; Hajishengallis, G (2015) Inborn errors in immunity: unique natural models to dissect oral immunity. J Dent Res 94:753-8
Moutsopoulos, Niki M; Chalmers, Natalia I; Barb, Jennifer J et al. (2015) Subgingival microbial communities in Leukocyte Adhesion Deficiency and their relationship with local immunopathology. PLoS Pathog 11:e1004698

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