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We investigated the variable Valpha and Vbeta gene usage of Actinobacillus actinomycetemcomitans-reactive periodontal CD4+ T cell receptors (TCR) from: (i) four A. actinomycetemcomitans-infected localized juvenile periodontitis (LJP)... more
We investigated the variable Valpha and Vbeta gene usage of Actinobacillus actinomycetemcomitans-reactive periodontal CD4+ T cell receptors (TCR) from: (i) four A. actinomycetemcomitans-infected localized juvenile periodontitis (LJP) patients, (ii) four groups of A. actinomycetemcomitans-inoculated NOD/SCID mice engrafted with individual LJP-derived HuPBL and (iii) HuPBL samples of four LJP patients and two healthy control subjects, by quantitative PCR analyses. The results show that: (i) the majority of the TCR genes (82.5% of Valpha and 91.1% of Vbeta) used by periodontal CD4+ T cells in A. actinomycetemcomitans-inoculated HuPBL-engrafted NOD/SCID mice overlap with those used by local periodontal T cells in LJP patients, (ii) although A. actinomycetemcomitans-reactive periodontal CD4+ TCR repertoire is relatively widespread, there are a few dominant genes shared by the LJP patients, suggesting a limited number of antigens or epitopes commonly recognized and (iii) A. actinomycetemcomitans likely lacks superantigenic characteristics. These results suggest A. actinomycetemcomitans-associated human CD4+ T cell repertoire established in HuPBL-NOD/SCID mice provides a useful approach to study specific aspects of immune-parasite interactions in the periodontium.
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Research Interests: Engineering, Immunology, Biology, Inflammation, Medicine, and 14 moreOsteoimmunology, Dendritic Cells, Biological Sciences, Cell Differentiation, Humans, Animals, Osteoclasts, Dendritic cell, Immune system, Bone Mineral Density, Bone Loss, Bone Resorption, Bone Diseases, and Medical and Health Sciences
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Research Interests: Immunology, Biology, Medicine, Humans, Mice, and 15 moreFemale, Animals, Clinical, Male, Expression, Glycoproteins, Adult, Dental Disease, Coronary heart disease, Clinical Investigation, Bone Resorption, Adoptive Transfer, Aggregatibacter actinomycetemcomitans, Alveolar bone loss, and Medical and Health Sciences
A potent virulence factor, cagE homologue of Actinobacillus actinomycetemcomitans, was identified via an expression cloning strategy and periodontitis-associated CD4(+)T-cells of a humanized mouse model. Through the immuno-gold labeling... more
A potent virulence factor, cagE homologue of Actinobacillus actinomycetemcomitans, was identified via an expression cloning strategy and periodontitis-associated CD4(+)T-cells of a humanized mouse model. Through the immuno-gold labeling with transmission electron microscopy, immunofluorescent staining, in vitro co-cultures and Western blot studies, the resulting data clearly demonstrate that: (i) in CagE-homologue treated human epithelia in vitro, there are ultra-structural features of plasma membrane blebbing, sub-cellular disorganization with condensed and marginalized chromatins along the nuclear membrane, consistent with the pro-apoptotic characteristics, (ii) the disturbed membrane integrity detected above is associated with localization of the CagE proteins on target cell surface, and (iii) CagE-homologue is located in the cytoplasm of A. actinomycetemcomitans and associated with a bacterial type-IV secretion system (T4SS), suggesting that its translocation is required for secretion. Thus, CagE-homologue may be critically involved in A. actinomycetemcomitans-induced tissue destruction, inflammation and subsequent adverse immunity in periodontal pathogenesis.
Research Interests: Microbiology, Immunology, Medical Microbiology, Biology, Cell Biology, and 15 moreApoptosis, Medicine, Humans, Mice, Animals, Microbial Pathogenesis, Mouse Model, Epithelial cells, KB cells, Membrane Integrity, Cytoplasm, Plasma Membrane, Aggregatibacter actinomycetemcomitans, Cell Membrane, and coculture techniques
Research Interests: Microbiology, Biology, Helicobacter pylori, Apoptosis, Medicine, and 15 moreGene expression, Humans, Sequence alignment, Mutation, Epithelial cells, Adult, Western blot, Periodontitis, Genomic Library, Amino Acid Sequence, Biochemistry and cell biology, Aggregatibacter actinomycetemcomitans, Molecular Sequence Data, Medical biochemistry and metabolomics, and Agrobacterium tumefaciens
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ABSTRACTRecent studies have shown the biological and clinical significance of signaling pathways of osteogenic cytokines RANKL-RANK/OPG in controlling osteoclastogenesis associated with bone pathologies, including rheumatoid arthritis,... more
ABSTRACTRecent studies have shown the biological and clinical significance of signaling pathways of osteogenic cytokines RANKL-RANK/OPG in controlling osteoclastogenesis associated with bone pathologies, including rheumatoid arthritis, osteoporosis, and other osteolytic disorders. In contrast to the inhibitory effect of gamma interferon (IFN-γ) on RANKL-mediated osteoclastogenesis reported recently, alternative new evidence is demonstrated via studies of experimental periodontitis using humanized NOD/SCID and diabetic NOD mice and clinical human T-cell isolates from diseased periodontal tissues, where the presence of increasing IFN-γ is clearly associated with (i) enhancedActinobacillus actinomycetemcomitans-specific RANKL-expressing CD4+Th cell-mediated alveolar bone loss during the progression of periodontal disease and (ii) a concomitant and significantly increased coexpression of IFN-γ in RANKL(+) CD4+Th cells. Therefore, there are more complex networks in regulating RANKL-RANK/...
Research Interests: Immunology, Biology, Medicine, Biological Sciences, Humans, and 15 moreMice, Female, Animals, Complex network, Male, Connective tissue, Adult, Brain Abscess, Interferon gamma, Aggregatibacter actinomycetemcomitans, Inflammatory response, Alveolar bone loss, Hip Joint, Medical and Health Sciences, and B cell
To study anti-inflammatory cytokine effects on RANKL + -T-cell-mediated osteoclastogenesis in vivo, we injected human interleukin-10 (hIL-10) into pathogen-infected HuPBL-NOD/SCID mice. The results show significantly decreased RANKL +... more
To study anti-inflammatory cytokine effects on RANKL + -T-cell-mediated osteoclastogenesis in vivo, we injected human interleukin-10 (hIL-10) into pathogen-infected HuPBL-NOD/SCID mice. The results show significantly decreased RANKL + Th1-associated alveolar bone loss and coexpression of human gamma interferon (hIFN-γ) and human macrophage colony-stimulating factor, but not hIL-4, in RANKL + Th cells compatible with those from successfully treated aggressive periodontitis subjects. Thus, there are critical cytokine interactions linking hIFN-γ + Th1 cells to RANKL-RANK/OPG signaling for periodontal osteoclastogenesis in vivo.
Research Interests: Microbiology, Immunology, Immune response, Biology, Adolescent, and 15 moreMedicine, Biological Sciences, Humans, Mice, Animals, Cytokine, In Vivo, Adult, Periodontitis, Bone remodeling, Interleukin, Interferon gamma, Aggregatibacter actinomycetemcomitans, Alveolar bone loss, and Medical and Health Sciences
Diabetic patients experience a higher risk for severe periodontitis; however, the underlying mechanism remains unclear. We investigated the contribution of antibacterial T-cell–mediated immunity to enhanced alveolar bone loss during... more
Diabetic patients experience a higher risk for severe periodontitis; however, the underlying mechanism remains unclear. We investigated the contribution of antibacterial T-cell–mediated immunity to enhanced alveolar bone loss during periodontal infection in nonobese diabetic (NOD) mice by oral inoculation with Actinobacillus actinomycetemcomitans, a G(−) anaerobe responsible for juvenile and severe periodontitis. The results show that 1) inoculation with A. actinomycetemcomitans in pre-diabetic NOD mice does not alter the onset, incidence, and severity of diabetes; 2) after A. actinomycetemcomitans inoculation, diabetic NOD mice (blood glucose >200 mg/dl and with severe insulitis) exhibit significantly higher alveolar bone loss compared with pre-diabetic and nondiabetic NOD mice; and 3) A. actinomycetemcomitans–reactive CD4+ T-cells in diabetic mice exhibit significantly higher proliferation and receptor activator of nuclear factor κB ligand (RANKL) expression. When diabetic mice...
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Dendritic cells (DC) are innate immune effectors and are critically involved in regulating T cell immunity. Osteoclasts (OC) are bone-resorbing cells derived from the monocyte/macrophage lineage in response to receptor activator of NF-κB... more
Dendritic cells (DC) are innate immune effectors and are critically involved in regulating T cell immunity. Osteoclasts (OC) are bone-resorbing cells derived from the monocyte/macrophage lineage in response to receptor activator of NF-κB ligand (RANKL). DC and T cells form aggregates in the inflammatory infiltrates at active disease sites in human and in experimental rheumatoid arthritis and periodontitis. We investigated whether DC interactions with T cells in the bone environment can support the development of functional OC. In the present study, we demonstrate that upon proper activation by microbial or protein Ags (namely Actinobacillus actinomycetemcomitans, bovine insulin, and outer membrane protein-1) and during immune interactions with CD4+ T cells in vitro, murine BM-derived and splenic CD11c+ DC (CD11b−F4/80−Ly-6C−CD31−) develop into TRAP+CT-R+cathepsin-k+ functional OC in a RANKL/RANK-dependent manner. Rescue and blocking experiments using CD11c+ DC derived from Csf-1−/−o...
Research Interests: Immunology, Biology, Cell Biology, Medicine, Dendritic Cells, and 15 moreCell Differentiation, Mice, Female, Animals, Osteoclasts, Bone marrow, Phenotype, RANKL, Immune system, Isoenzymes, Cell Survival, Bone Resorption, Aggregatibacter actinomycetemcomitans, Acid Phosphatase, and coculture techniques
Our understanding of the pathogenesis in human periodontal diseases is limited by the lack of specific and sensitive tools or models to study the complex microbial challenges and their interactions with the host’s immune system. Recent... more
Our understanding of the pathogenesis in human periodontal diseases is limited by the lack of specific and sensitive tools or models to study the complex microbial challenges and their interactions with the host’s immune system. Recent advances in cellular and molecular biology research have demonstrated the importance of the acquired immune system not only in fighting the virulent periodontal pathogens but also in protecting the host from developing further devastating conditions in periodontal infections. The use of genetic knockout and immunodeficient mouse strains has shown that the acquired immune response—in particular, CD4+ T-cells—plays a pivotal role in controlling the ongoing infection, the immune/inflammatory responses, and the subsequent host’s tissue destruction. In particular, studies of the pathogen-specific CD4+ T-cell-mediated immunity have clarified the roles of: (i) the relative diverse immune repertoire involved in periodontal pathogenesis, (ii) the contribution ...
Research Interests: Genetics, Dentistry, Immunology, Immune response, Biology, and 15 moreMedicine, Lipopolysaccharide, Humans, Mice, Immunity, Animals, Dendritic cell, Immune system, Disease Progression, Fc Receptor, Immunoglobulin, Aggregatibacter actinomycetemcomitans, Inflammatory response, Alveolar bone loss, and B cell
To investigate the role of suppressor of cytokine signaling (SOCS) molecules in periodontal immunity and RANKL-mediated dendritic cell (DC)-associated osteoclastogenesis, we analyzed SOCS expression profiles in CD4 + T cells and the... more
To investigate the role of suppressor of cytokine signaling (SOCS) molecules in periodontal immunity and RANKL-mediated dendritic cell (DC)-associated osteoclastogenesis, we analyzed SOCS expression profiles in CD4 + T cells and the effect of SOCS3 expression in CD11c + DCs during periodontal inflammation-induced osteoclastogenesis and bone loss in nonobese diabetic (NOD) versus humanized NOD/SCID mice. Our results of ex vivo and in vitro analyses showed that (i) there is significantly higher SOCS3 expression associated with RANKL + T-cell-mediated bone loss in correlation with increased CD11c + DC-mediated osteoclastogenesis; (ii) the transfection of CD11c + DC using an adenoviral vector carrying a dominant negative SOCS3 gene significantly abrogates TRAP and bone-resorptive activity; and (iii) inflammation-induced TRAP expression, bone resorption, and SOCS3 activity are not associated with any detectable change in the expression levels of TRAF6 and mitogen-activated protein kinase...