Our studies have particularly focused on 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). In LAD1, CD18 mutations compromise neutrophil adhesion and extravasation to sites of infection or inflammation. Affected individuals suffer from recurrent infections at mucosal or skin surfaces, and experience severe generalized aggressive periodontitis often losing their entire dentition by early adulthood. The severity of LAD1-associated periodontal disease provides one of the clearest pieces of evidence that neutrophils within oral tissues are required for the maintenance of periodontal health. However, our recent findings revealed that absence of tissue neutrophils does not lead to an invasive infection and challenged a long-standing assumption in the field (see above Microbiome in LAD1 project). In fact, we have now shown that LAD1-periodontitis is a lesion of severe immunopathology resulting from the lack of tissue neutrophils which play a critical immunoregulatory role in the periodontium.
The aim of our study was to define regulatory roles of tissue neutrophils in periodontitis and identify therapeutic targets for LAD1 periodontitis, a disease recalcitrant to standard-of-care periodontal treatment and antibiotics. Research Accomplished: Our detailed evaluation of lesional tissues in LAD1 patients and relevant animal models (LFAKO, CD11a-/-) revealed an IL-23/IL-17-dominated molecular signature in diseased tissues. These findings were consistent with disruption of the neutrostat homeostatic mechanism. The neutrostat theory refers to neutrophil recruitment and clearance in tissues (efferocytosis; uptake of apoptotic neutrophils by phagocytes), which regulates neutrophil production (granulopoiesis) through a negative feedback loop involving the cascade of cytokines IL-23IL-17G-CSF axis. When neutrophils cannot transmigrate to peripheral tissues, as in LAD1, the neutrostat regulatory circuit is disrupted, leading to unrestrained expression of IL-23 and downstream cytokines, including IL-17 and G-CSF. In LAD1 increased granulopoiesis and blood neutrophilia were previously recognized, but overproduction of IL-17 had not been linked to this disease in animal models or in humans. Our combined mouse and human studies showed that in LAD1, the local microbiome triggers an IL-23/IL-17 inflammatory response (as shown above), which is unrestrained in the absence of tissue neutrophils. Importantly, antibody-mediated neutralization of IL-23 or IL-17 in a mouse model of LAD1 (LFAKO, CD11a-/-) reversed inflammatory bone loss, clarifying that the IL-23/IL-17 axis is the driving force for tissue destruction and immunopathology in LAD1-periodontitis. This in turn suggested that the inhibition of IL-23/IL-17 would be a therapeutic target in human LAD1 periodontal disease.Based on our data and preclinical studies, we treated one patient with moderate LAD1 and associated periodontitis and a significant non-healing sacral wound with ustekinumab, an antibody inhibitor for p40, the shared chain of IL-23 and IL-12. Ustekinumab has shown efficacy to date in the treatment of IL-17 mediated diseases such as psoriasis and psoriatic arthritis. After more than two years of therapy, the patient has had no serious infections and has dramatic resolution of his sacral wound and reduced oral inflammation. Importantly, based on this work, an intervential trial for the treatment of LAD1-associated immunopathologies has been initiated at the NIH CC in collaboration with NIAID investigators (NCT03366142). In this past period, and based on our findings of Th17 cells and immunity playing a role in periodontal homeostasis, our group has also been characterizing the clinical phenotype, immune response and oral microbiome in patients with defects affecting the Th17 pathway. Our studies have focused on patients with loss of function (LOF; Autosomal Dominant Hyper IgE Syndrome; (AD-HIES) mutations in STAT3. In this population defects in STAT3 lead to defects in Th17 differentiation with patients having drastically reduced Th17 cells and defective Th17 immunity. Our current studies evaluate consequences of defective Th17 immunity on the oral immune response and establishment of the oral commensal microbiome.
| 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 |
| 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 |
| 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 |
| 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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