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 β2 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 uncover that local microbial communities (subgingival plaque) are the triggers for inflammatory periodontitis in LAD-I. We find that microbial products from LAD-associated communities may have a role in stimulating the local inflammatory response. Our studies demonstrate that bacterial LPS from local microbes translocates into the lesions of LAD-periodontitis potentially triggering immunopathology. In complementary in vitro assays with human macrophages and in vivo in animal models, we also demonstrate that microbial products from LAD-associated subgingival plaque trigger IL-23-related immune responses, which have been shown to dominate in patient lesions. Interestingly we also find that under the conditions of severe IL-17 dominated inflammation in LAD-periodontitis the composition of the subgingival microbiome becomes significantly altered. Our comprehensive characterization of the subgingival communities in LAD-I, using a 16S rRNA gene-based microarray, reveals that the LAD subgingival microbiome is distinct from that of health and Localized Aggressive Periodontitis. Select periodontitis-associated species in the LAD microbiome included Parvimonas micra, Porphyromonas endodontalis, Eubacterium brachy and Treponema species. Pseudomonas aeruginosa, a bacterium not typically found in subgingival plaque is detected in LAD-I. In conclusion, our current study characterizes the subgingival microbial communities in LAD-periodontitis and supports their role as triggers of disease pathogenesis.
| 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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