The initial focus of our studies has been patient populations with severe neutrophil defects. Patients with severe neutropenia or defective neutrophil recruitment into tissues are known to develop severe-aggressive periodontitis at a young age. However, the mechanisms by which tissue neutrophils alter microbial colonization and regulation of mucosal immunity had not been investigated until recently. One such rare patient cohort is that of Leukocyte Deficiency I (LAD-I). Leukocyte Adhesion Deficiency I (LAD-I) is a primary immunodeficiency caused by single gene mutations in the CD18 subunit of 2 integrins which result in defective transmigration of neutrophils into the tissues. Affected patients suffer from recurrent life threatening infections and severe oral disease (periodontitis), which historically has been attributed to the lack of neutrophil surveillance of the periodontal infection. Our ongoing studies provide an alternative mechanism by showing that the cytokine interleukin-17 (IL-17) plays a major role in the oral pathology of LAD-I. Defective neutrophil recruitment in LAD-I patients or in LFA-1 (CD11a/CD18)deficient mice-which exhibit the LAD-I periodontal phenotype-was associated with excessive production of predominantly T cellderived IL-17 in the periodontal tissue, although innate lymphoid cells also contributed to pathological IL-17 elevation in the LFA-1deficient mice. Local treatment with antibodies to IL-17 or IL-23 in LFA-1deficient mice not only blocked inflammatory periodontal bone loss but also caused a reduction in the total bacterial burden, suggesting that the IL-17driven pathogenesis of LAD-I periodontitis leads to dysbiosis. Therefore, our findings support an IL-17targeted therapy for periodontitis in LAD-I patients. Our studies also evaluate the role of the microbiome in LAD periodontitis. Specifically, we aimed to determine whether LAD1 periodontitis is an invasive infection, characterize the subgingival microbiome in LAD1, and study the role of the subgingival microbiome in LAD1 periodontitis pathogenesis. Our studies in patient tissues revealed that LAD1 periodontitis is not an invasive infection but rather a lesion of immunopathology, suggesting that host factors may be the principal drivers of disease pathogenesis. However, our characterization of the LAD1 subgingival microbiome demonstrated the presence of dysbiotic microbial communities. We found that the subgingival microbiome in LAD1 patients is distinct from that of health and from that observed in patients with aggressive and chronic periodontitis. Key characteristics in LAD1 were an increased biomass but with reduced numbers of species detected, primarily due to the depletion of health-associated commensals. Interestingly, microbial products from LAD1-associated communities (such as bacterial LPS) were found to translocate into the lesions of LAD1-periodontitis potentially triggering immunopathology. We further investigated the potential role of the LAD1 microbiome in triggering inflammation by exposing human macrophages in vitro and animals in vivo to microbial plaque from LAD patients. We found that LAD1-associated subgingival plaque triggers an IL-23/IL-17-related immune response. Our study characterizes the subgingival microbial communities in LAD1-periodontitis and supports their role as triggers of local IL-23/IL-17-related inflammation.
| 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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