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Lab. of Molecular Microbial Immunity, Eastman Department of Dentistry, Eastman Dental Center, Box-683, 625 Elmwood Ave., and Centre for Oral Biology, Dept. of Microbiology and Immunology, School of Medicine and Dentistry, The University of Rochester Medical Center, Rochester, NY 14620, USA; andy_teng{at}urmc.rochester.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTION(I) T-CELL-MEDIATED IMMUNITY IN...(II) CONCLUSIONREFERENCES |
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B; RANKL, receptor activator of NF-B ligand; OPG, osteoprotegerin; TCR, T-cell-receptors; TLR, Toll-like receptors.
KEY WORDS: Actinobacillus actinomycetemcomitans (Aa) • T-cell-mediated immunity • RANKL and cytokine interactions network (RACIN) • osteoclastogenesis • osteoimmunology
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INTRODUCTION |
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TOPABSTRACTINTRODUCTION(I) T-CELL-MEDIATED IMMUNITY IN...(II) CONCLUSIONREFERENCES |
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(I) T-CELL-MEDIATED IMMUNITY IN THE PERIODONTIUM |
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TOPABSTRACTINTRODUCTION(I) T-CELL-MEDIATED IMMUNITY IN...(II) CONCLUSIONREFERENCES |
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There is no doubt that the cytokines expressed locally in the periodontal tissues and by the inflammatory cells contribute to the state of protective vs. destructive phases of the disease progression (for review, see Baker, 2000; Seymour and Gemmell, 2001; Taubman and Kawai, 2001; Gemmell et al., 2002). Experimental evidence has clearly shown that, based on cytokine expression profiles, (i) both Th1 and Th2 cells and cytokines are often present simultaneously in the infected periodontal tissues (Baker et al., 1999; Ukai et al., 2001; Teng 2002, 2003; Garlet et al., 2003), and (ii) pathogen-reactive Th1 cells and the cytokines they produce (i.e., IFN-
, etc.) can mediate the active inflammatory response associated with tissue and alveolar bone destruction (Kawai et al., 2000; Taubman and Kawai, 2001). This paper: (i) briefly discusses some of the recent findings regarding the proposed RANKL-and-cytokine interactions network (called RACIN; see Fig. 1
) during periodontal disease progression, (ii) highlights some modern and new technologies used to identify potentially critical microbial antigens or factors associated with periodontal immunity, and, last, (iii) summarizes some of those virulence factors for their reported immune characteristics.
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B ligand (RANKL; or TRANCE, OPGL, ODF), its receptor (RANK) and natural antagonist, osteoprotegerin (OPG), have been shown to be the key regulators of bone remodeling and are directly involved in the differentiation, activation, and survival of osteoclasts (OC) and OC precursors (Simonet et al., 1997; Wong et al., 1997; Lacey et al., 1998; Yasuda et al., 1998). In addition, RANKL-RANK signaling is also critical for DC survival, lymph node formation, and organogenesis and is involved in DC/T-cell interactions (Anderson et al., 1997; Kong et al., 1999). Genetic mutations of RANKL and RANK demonstrate similar phenotypes in OC development in severe osteopetrosis, suggesting that they are essential for osteoclastogenesis during bone remodeling (Kong et al., 1999; Li et al., 2000; Theill et al., 2002). OPG transgenic mice are osteopetrotic with defective OC activity, and OPG-deficient mice are severely osteoporotic (Simonet et al., 1997; Mizuno et al., 1998; Theill et al., 2002). Thus, RANKL, RANK, and OPG are essential for controlling OC development and functions in bone remodeling. These studies have supported the new paradigm of linking adaptive immunity and bone remodeling (termed ‘osteo-immunology’) associated with various inflammatory bone disorders.
By using experimental mouse models, we and others have shown that CD4+ T-cells are critically involved in regulating alveolar bone loss in vivo (Baker et al., 1999; Baker, 2000; Kawai et al., 2000; Taubman and Kawai, 2001; Valverde et al., 2004), and activated CD4+ T-cells express RANKL, which can directly trigger osteoclastogenesis and alveolar bone loss associated with periodontitis in vivo (Teng et al., 2000; Teng, 2002, 2003). Interestingly, blocking RANKL activity via OPG injections has been shown to result in significantly reduced bone loss in arthritis (Kong et al., 1999), periodontitis (Teng et al., 2000; Theill et al., 2002), osteoporosis (Mizuno et al., 1998; Hofbauer and Schoppet, 2004), cancer-related bone metastasis (Honore et al., 2000; Brown et al., 2004), and the enhanced alveolar bone loss associated with type-1 diabetes in vivo (Mahamed et al., 2005). In particular, OPG injections into both HuPBL-NOD/SCID and diabetic NOD mice with live micro-organisms, to induce experimental periodontitis, consistently yield significant inhibition of alveolar bone loss, by 80% vs. 90%, respectively, suggesting that the RANKL-RANK/OPG axis is the key pathway controlling osteoclastogenesis in the periodontium (Teng et al., 2000; Mahamed et al., 2005). More recently, studies have shown that periodontal resident cells (i.e., PDL fibroblasts or mesenchymal tissues) can also be induced to express RANKL/OPG under microbial- or microbial-product-induced inflammatory conditions in vivo or in vitro (Rani and MacDougall, 2000; Hasegawa et al., 2002; Nagasawa et al., 2002; Nukaga et al., 2004), suggesting the broad range and contributions of the cytokine RANKL-RANK/OPG signaling network in periodontal disease. It is evident that the key sources of RANKL that mediates alveolar bone loss in vivo in periodontitis are lymphocytes (i.e., T-cells) and macrophages (Kong et al., 1999; Teng et al., 2000; Theill et al., 2002; Crotti et al., 2003; Mahamed et al., 2005). Yet there are no available in vivo data for assessment of the overall contributions of gingival fibroblasts or resident/mesenchymal cells to RANKL/OPG-mediated periodontal osteoclastogenesis (see Fig. 1
). Thus, note that the role of oral mucosal/residential cells is not described as part of the periodontal RACIN proposed in Fig. 1.
Despite some controversies, it has been shown that both TNF-
and/or IL-1 can work synergistically or independently with RANKL to modulate bone resorption in arthritis and osteoporotic disorders (Azuma et al., 2000; Romas et al., 2002; Teng, 2003; O’Gradaigh et al., 2004; Wei et al., 2005). Further, Gram-negative anaerobic microbe-specific periodontal RANKL+CD4+ T-cells manifest a mixed Th1-Th2 cytokine profile in active periodontal lesions, in which specific cytokines, such as IFN- and IL-4, are significantly co-expressed with RANKL during osteoclastogenesis in vivo (Teng, 2002; Mahamed et al., 2005; Teng et al. 2005). To understand further the underlying cytokine interactions and regulatory mechanisms associated with RANKL-mediated osteoclastogenesis during the progression of periodontal disease in the inflammatory lesions ‘in vivo’, we applied different approaches to: (i) detect early cytokine expression profiles and their interactions by injecting hIFN- into Aa-infected HuPBL-NOD/SCID mice, followed by monitoring the co-expression of INF- and RANKL and alveolar bone loss over time in vivo; (ii) analyze human clinical T-cells purified from the diseased periodontal tissues of aggressive periodontitis (AgP) subjects infected by A. actinomycetemcomitans; and (iii) assess cytokine expression profiles in diabetic NOD mice exhibiting significantly enhanced alveolar bone loss after oral challenge with live A. actinomycetemcomitans in vivo. Despite the fact that some recent studies have suggested an inhibitory effect of IFN- on RANKL-associated osteoclastogenesis in vitro and in vivo, possibly via a STAT1-dependent promotion of TRAF6 degradation in the OC precursor pool (Fox and Chambers, 2000; Takayanagi et al., 2000; De Klerck et al., 2004), the results of our above analyses showed that IFN- can indeed positively modulate its co-expression with RANKL in periodontal micro-organism-specific periodontal CD4+Th1 cells, which can further mediate osteoclastogenesis associated with alveolar bone loss in vivo. This phenomenon is also evident (i) in a separate mouse model, where auto-immune ‘diabetic’ NOD mice manifest significantly exacerbated alveolar bone loss when orally challenged with live A. actinomycetemcomitans; and (ii) in A. actinomycetemcomitans-associated alveolar bone loss mediated by a virulence antigen (i.e., CagE-homologue; Teng and Hu, 2003; Teng and Zhang, 2005), both of which are associated with higher expression of IFN- in micro-organism-specific RANKL+ Th1-cells in vivo (Mahamed et al., 2005; Teng et al., 2005). Interestingly, Th2 cytokine IL-10 in our models exerts an anti-inflammatory effect by down-regulating RANKL-mediated osteoclastogenesis, both in vivo and in vitro (unpublished findings), consistent with the finding of a mixed endodontic infection in the mouse model (Sasaki et al., 2004). Collectively, these results suggest that there is a network of regulatory interactions between RANKL and immune cytokines in the periodontium in vivo (see below).
It has also been shown that IFN-+ Th1 cells are strongly associated with enhanced alveolar bone loss during periodontal infections (Baker et al., 1999; Kawai et al., 2000; Taubman and Kawai, 2001; Valverde et al., 2004), and RANKL is often highly co-expressed in Th1 cells (Josien et al., 1999; Chen et al., 2001). Further, there is strong evidence suggesting that this RANKL and IFN- co-expression exists in active arthritic lesions in vivo (Canete et al., 2000; Ortmann and Shevach, 2001; Park et al., 2001; Ronaghy et al., 2002), and that deficient IFN- expression significantly reduces the severity of periodontal bone loss in mice after a microbial challenge (Baker et al., 1999). At present, the in vivo molecular mechanism(s) of this phenomenon described above remain unclear; however, it may not be attributed solely to the proteosome degradation pathway(s) or signaling, since there are no significant differences regarding the TRAF6 transcripts and proteins in the periodontal tissues between IFN--treated or sham-treated A. actinomycetemcomitans-infected HuPBL-NOD/SCID mice (Teng et al., 2005; unpublished data). In addition, IFN- might mediate its downstream signaling effects dependent or independent of RANKL-induced osteoclastogenesis pathways under various inflammatory conditions in vivo (i.e., in the presence of TNF-). Moreover, it is known that IFN- can up-regulate the expressions of MHC-class II and other accessory molecules on the antigen-presenting cells, leukocytes, and mesenchymal cells, which may further recruit other signaling molecules and/or immune effectors associated with bone remodeling (Ellis and Beaman, 2004; Herold, 2004; Mochizuki et al., 2004).
Based on these reports and findings, the fine balance between IFN- and RANKL-RANK/OPG under various inflammatory conditions (i.e., TNF- or IL-1) may directly or indirectly contribute to the outcome of their co-expression on Th1 cells for osteoclastogenesis associated with bone remodeling in vivo. Therefore, there are more complex cytokine networks in regulating RANKL-RANK/OPG signaling pathways for osteoclastogenesis in vivo than have been suggested to date (see Fig. 1 for the proposed ‘Interactions Network’ called ‘RACIN’). Further research is required to decipher the molecular interactions and mechanisms for the development of future therapeutics in modulating the host immune responses in human periodontal infection.
(B) Identify Critical Microbial Virulence Factors/Antigens Associated with Periodontal Immunity
Over the last few years, several advanced molecular biology techniques have been applied in attempts to identify and study potentially critical microbial virulent antigens or host factors associated with host immunity (i.e., IgG or CD4+ T-cells) in experimental animal models and clinical subjects (i.e., with the use of serum samples) or primarily based on bio-informatics and available databases for specific gene structure or functions and nucleotide sequences. All of these screening techniques provide some specific advantages over the traditional biochemical analyses based on a single virulence gene or gene product, but they also have some intrinsic disadvantages. Meanwhile, these different screening approaches offer opportunities for the identification of potential genes and gene products related to microbial pathogenesis, critical immune responses or immunity, diagnostic tools, or future vaccine candidates. They are summarized below.
(i) Bio-informatics
During the search for potential vaccine candidates for adult periodontitis, Ross et al. developed a bio-informatics search strategy based on the assumption that these potential vaccine targets are likely accessible on bacterial surfaces (i.e., outer membrane proteins: OMPs) whose encoded sequences and/or motif homologies in the available database (www.angis.org.au at the University of Sydney, Australia) are predictive of surface localization (Ross et al., 2001, 2004). Through a signal sequence analysis with homology comparison algorithms, and the shotgun sequencing of the P. gingivalis genome, about 15,000 open reading frames (ORFs) were generated, from which 74 proteins were identified, 46 of which had significant similarity with OMPs of other bacteria. The resulting selected genes were then cloned for expression in E. coli and further screened by P. gingivalis anti-sera before purification and testing. Recently, two of these recombinant proteins (PG32 and PG33) yielded significant protection in a murine abscess model (Ross et al., 2004). Due to the selection assumptions and the lack of functions assigned to the genes of interest before the search and screening, further analysis with gain-of-functionality is often required in the above approach (i.e., the use of gene knockout, anti-sera, or T-cell responses).
(ii) In vivo-induced Antigen Technology (IVIAT)
This is a modified immunologic screening technique primarily based on the use of sera from infected patients to probe a protein expression library to identify antigens expressed specifically in vivo during human infections (see Etz et al., 2002). The key steps rely on the modification of the convalescent-pooled sera adsorption, which allows for the removal of antibodies that bind antigens expressed during a standard in vitro cultivation period, while retaining antibodies that recognize antigens specifically expressed during in vivo growth (Cao et al., 2004; Rollins et al., 2005). Careful selection of convalescent sera for IVIAT can provide identification of antigens at different stages of microbial infection and potentially unveil individual immune characteristics from the study subjects. This technique has been applied to the study of A. actinomycetemcomitans and several other micro-organisms (Rollins et al., 2005), with resulting isogenic mutations for in vitro functional analysis (Cao et al., 2004). It is generally thought that IVIAT is a relatively easy and feasible approach to the identification of potent virulent antigens during the course of microbial infection; however, the antigens identified may not reflect the immunological nature of the host’s protective vs. destructive immunity, nor the cell-mediated immune responses that are now considered to be critically involved in the development and progression of periodontal disease (Taubman and Kawai, 2001; Baker et al., 2002; Gemmell et al., 2002).
(iii) Genomic Micro-array with Quantitative-PCR Screening
Micro-array platforms (i.e., gene-chips) allow for the simultaneous analysis of large numbers of genes of interest for their expression, and quantitative-PCR (Q-PCR) is a highly sensitive and reproducible technique, with the key advantage of requiring limited valuable tissue/cell samples for study. A recent study by Hart et al.(2004) has successfully combined both techniques in a high-throughput system using a customized ImmunoQuantArray (Akilesh et al., 2003) to cleverly compare the potential differential gene profiling of a 48-gene set from the gingiva and spleen samples of the alveolar-bone-susceptible and -resistant mouse strains (Balb/cByJ and A/J, respectively), following post-oral infection with P. gingivalis in vivo. Since there were functional criteria assigned before molecular screening, the resulting genes that were expressed and uncovered are therefore discretely associated with the genetic determinant traits or phenotypes for alveolar bone loss during the inflammatory processes of periodontal infection. Further research will be needed to validate the significance of gene products identified during periodontal pathogenesis in vivo.
(iv) Expression Cloning by Functionally Defined T-cells Carrying Inducible NFAT-LacZ Sequences for Screening
T-cell receptors (TCR) recognize processed antigenic peptides in the context of self-MHC (mouse) or HLA (human) molecules. Cytotoxic CD8+ T (Tc)-cells recognize antigenic peptides bound to MHC class I molecules, while helper T (Th)-cells recognize antigenic peptides bound to MHC class II molecules. Antigens processed by antigen-presenting cells (APC) are presented as oligopeptides (class I, 8–9 a.a.; class II, 13–21 a.a.). These peptides bind in the binding groove of MHC class-I or -II and are presented to TCR by APC. Thus, TCR recognition of the MHC-peptide complex occurs through protein-protein interactions, and TCR/peptide-MHC interactions have been intensely characterized. Peptides destined for MHC-I are usually generated from protein synthesized in or introduced into the cytoplasm (e.g., virus-infected cells), whereas peptides destined for MHC-II are normally produced in the endosome-lysosomal compartments (e.g., phagocytosed bacteria and endocytosed proteins). Further, peptides for both MHC-I and -II can be generated from transfected genes via endogenous pathways (Mougneau et al., 1995; Sanderson et al., 1995a). Macrophages can be induced to generate peptide/MHC-II complexes by Fc-R interaction with recombinant proteins or phagocytosis of transformed bacteria (Pfeifer et al., 1992). Thus, gene transfer and antigen-processing in APC can produce T-cells stimulating MHC-I or -II peptide complexes from genomic or cDNA libraries (called expression cloning; see Fig. 2). Furthermore, detection sensitivity can be enhanced via a single T-cell activation by means of a reporter construct (ß-gal with IL-2 enhancer NFAT) induced by TCR engagement (Sanderson et al., 1994). This assay can identify rare APC ligands (~ 1 per 103 cells) and measure peptide/MHC-I or -II-specific T-cell activation in a simple, fast, and sensitive manner for identifying unknown T-cell antigens/peptides (Sanderson et al., 1995a, b). The combination of TCR activation and expression cloning has been used to identify various MHC-I or -II-associated tumor antigens, infectious agents, allo- and self-antigens, and cross-reactive antigens of known or unknown specificities (Mandelboim et al., 1994; Scott et al., 1995; Fujii et al., 2001; Probst et al., 2001).
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for protocol diagram: Teng and Hu, 2003; Teng and Zhang, 2005). In these mice, A. actinomycetemcomitans-reactive CD4+ T-cells present in the HuPBL-engrafted NOD/SCID mice were functionally active (Teng et al., 1999, 2000; Teng, 2002), and their TCR repertoire overlapped significantly (
83–91%) with that of clinical T-cell isolates in aggressive periodontitis patients (Gao and Teng, 2002). Based on the functional characteristics analyzed, the results of such screening uncovered several novel genes of A. actinomycetemcomitans associated with destructive periodontal immunity characterized by alveolar bone loss. One of the first genes identified was shown to be homologous to the cagE gene of the bacterial type IV secretion system (T4SS: a special transporter) in Helicobacter pylori (Tummuru et al., 1995; Censini et al., 1996), hereafter designated as cagE-homologue (in short, cagE; Teng and Hu, 2003; Teng and Zhang, 2005: GenBank Accession number AF319456). The second one is an outer membrane protein of 28 kDa (called OPM-1; Accession number AF321231). Interestingly, while being recognized by serum IgG of A. actinomycetemcomitans-infected aggressive periodontitis patients and by periodontal CD4+T, respectively, CagE is involved in inducing apoptosis of several human cell types, including epithelia, endothelia, osteoblasts, and T-lymphocytes via its N-terminus, which has a lytic transglycosylase (SLT) domain (Teng and Zhang, 2005). Further biochemical analyses show that CagE is localized in the bacterial cytoplasm and acts as a soluble virulence antigen associated with bacteria-induced tissue inflammation, subsequent adverse adaptive immunity, and alveolar bone destruction in vivo (Teng and Zhang, 2005). In parallel, A. actinomycetemcomitans-associated OMP-1 is shown to be capable of inducing a strong T-cell-mediated immune response in an experimental mouse model exhibiting significant alveolar bone loss (Teng et al., unpublished data). While the other established Aa bacterial clones are being analyzed, these findings suggest that T-cell expression cloning is effective in identifying pathogen-mediated virulence antigens (i.e., CagE and OMP-1) associated with host immune responses; however, its application in developing therapeutic endeavors awaits further study.
(C) A Summary of Microbial Virulence Factors or Antigens Studied and Associated with Periodontal Immunity
Tables 1 and 2 outline summary lists of microbial virulence factors or antigens of A. actinomycetemcomitans and P. gingivalis, as the model species associated with periodontal pathogenesis, along with their immune properties characterized to date. The key purposes of these lists are: (i) to provide a brief overview of what has been initiated or established regarding these two etiologically important periodontal pathogens, and (ii) to highlight and emphasize some key features related to the host innate and/or adaptive immune responses associated with these virulence factors or antigens. Most of these virulence factors/antigens came from traditional biochemical and cell-culture analyses; very few were derived or cloned by use of the whole species or by the systematic molecular or genetic screening techniques described in the above sections. Thus, it is our hope that some of these virulence factors or antigens will be applied to serve as useful diagnostic or therapeutic agents, including the targets for vaccination, in the future.
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(II) CONCLUSION |
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TOPABSTRACTINTRODUCTION(I) T-CELL-MEDIATED IMMUNITY IN...(II) CONCLUSIONREFERENCES |
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It is clear that a host deficient in MyD88 is compromised in some ‘TLR-mediated’ Th1 development and not Th2 response, suggesting the critical role of innate defense for adaptive immunity. However, conflicting data also exist regarding the protective role of activating TLR signaling cascades, revealing the complexity of these immune interactions, as discussed above. Therefore, distinct involvement of various TLR pathways in mucosal tissues, DCs, and professional phagocytes (or APCs), and their subsequent interactions with T-cells and B-cells, will likely influence the development of acute vs. chronic inflammation seen in human periodontal disease. The complexity of microbial and host gene expression profiles during human periodontal infection cannot be measured by in vitro experiments alone. Further, potential differences based on the findings in animal compared with human studies can be exploited to analyze the genetic basis of the periodontal infection. Recent advances in micro-array technology (for a review, see Actis et al., 2003; Kuramitsu, 2003), the genomics and proteomics, and immunology tools will be the next steps toward dissecting the in vivo-induced gene analysis and regulations in the newly developed mouse models for the study of periodontal infection and disease pathogenesis (i.e., Hart et al., 2004).
Some recent studies have shed light on the potential underlying interactions between the innate and adaptive immunity of periodontal infection and certain system conditions or disorders (i.e., implications associated with atherosclerosis and cardiovascular disease; Gibson et al. 2004b; Pussinen et al. 2004, 2005). There will be twists and turns to be revealed and resolved in the paths along the interactions between innate and adaptive immunity before any new therapies and treatment modalities become further available. An equally important matter is the need for further understanding of the key and critical virulence factors or antigenic determinants that are of immunological importance (i.e., innate immune regulators, immunogenic B- or Th-cell epitopes for protection) among the periodontal pathogens regarding the mechanism(s) that trigger the innate vs. adaptive immune interactions for protection or destruction in the host tissues and body. This remains the key challenge in the coming decades. A successful periodontal immunotherapy and/or vaccine strategy (or vaccination) could potentially benefit not only periodontal health but also its systemic linkages in the human population.
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ACKNOWLEDGMENTS |
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Received March 3, 2005; Accepted September 6, 2005
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REFERENCES |
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TOPABSTRACTINTRODUCTION(I) T-CELL-MEDIATED IMMUNITY IN...(II) CONCLUSIONREFERENCES |
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Akifusa S, Poole S, Lewthwaite J, Henderson B, Nair SP (2001). Recombinant Actinobacillus actinomycetemcomitans cytolethal distending toxin proteins are required to interact to inhibit human cell cycle progression and to stimulate human leukocyte cytokine synthesis. Infect Immun 69:5925–5930.
Akilesh S, Shaffer DJ, Roopenian DC (2003). Customized molecular phenotyping by quantitative gene expression and pattern recognition analysis. Genome Res 13:1719–1727.
Al-Darmaki S, Knightshead K, Ishihara Y, Best A, Schenkein HA, Tew JG, et al. (2004). Delineation of the role of platelet-activating factor in the immunoglobulin G2 antibody response. Clin Diagn Lab Immunol 11:720–728.
Amano A, Nakagawa I, Okahashi N, Hamada N (2004). Variations of Porphyromonas gingivalis fimbriae in relation to microbial pathogenesis. J Periodontal Res 39:136–142.[ISI][Medline]
Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, et al. (1997). A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 390:175–179.[Medline]
Asai Y, Ohyama Y, Gen K, Ogawa T (2001). Bacterial fimbriae and their peptides activate human gingival epithelial cells through Toll-like receptor 2. Infect Immun 69:7387–7395.
Asakawa R, Komatsuzawa H, Kawai T, Yamada S, Goncalves RB, Izumi S, et al. (2003). Outer membrane protein 100, a versatile virulence factor of Actinobacillus actinomycetemcomitans. Mol Microbiol 50:1125–1139.[ISI][Medline]
Azuma Y, Kaji K, Katogi R, Takeshita S, Kudo A (2000). Tumor necrosis factor-alpha induces differentiation of and bone resorption by osteoclasts. J Biol Chem 275:4858–4864.
Baker PJ (2000). The role of immune responses in bone loss during periodontal disease. Microbes Infect 2:1181–1192.[ISI][Medline]
Baker PJ, Evans RT, Roopenian DC (1994). Oral infection with Porphyromonas gingivalis and induced alveolar bone loss in immunocompetent and severe combined immunodeficient mice. Arch Oral Biol 39:1035–1040.[ISI][Medline]
Baker PJ, Dixon M, Evans RT, Dufour L, Johnson E, Roopenian DC (1999). CD4(+) T cells and the proinflammatory cytokines gamma interferon and interleukin-6 contribute to alveolar bone loss in mice. Infect Immun 67:2804–2809.
Baker PJ, Howe L, Garneau J, Roopenian DC (2002). T cell knockout mice have diminished alveolar bone loss after oral infection with Porphyromonas gingivalis. FEMS Immunol Med Microbiol 34:45–50.[ISI][Medline]
Belibasakis GN, Johansson A, Wang Y, Chen C, Kalfas S, Lerner UH (2005). The cytolethal distending toxin induces receptor activator of NF-kappaB ligand expression in human gingival fibroblasts and periodontal ligament cells. Infect Immun 73:342–351.
Booth V, Lehner T (1997). Characterization of the Porphyromonas gingivalis antigen recognized by a monoclonal antibody which prevents colonization by the organism. J Periodontal Res 32:54–60.[ISI][Medline]
Booth V, Ashley FP, Lehner T (1996). Passive immunization with monoclonal antibodies against Porphyromonas gingivalis in patients with periodontitis. Infect Immun 64:422–427.[Abstract]
Brown JM, Zhang J, Keller ET (2004). OPG, RANKL and RANK in cancer metastasis: expression and regulation. Cancer Treat Res 118:149–172.[Medline]
Calkins CC, Platt K, Potempa J, Travis J. I (1998). Inactivation of tumor necrosis factor-alpha by proteinases (gingipains) from the periodontal pathogen, Porphyromonas gingivalis. Implications of immune evasion. J Biol Chem 273:6611–6614.
Canete JD, Martinez SE, Farres J, Sanmarti R, Blay M, Gomez A, et al. (2000). Differential Th1/Th2 cytokine patterns in chronic arthritis: interferon gamma is highly expressed in synovium of rheumatoid arthritis compared with seronegative spondyloarthropathies. Ann Rheum Dis 59:263–268.
Cao SL, Progulske-Fox A, Hillman JD, Handfield M (2004). In vivo induced antigenic determinants of Actinobacillus actinomycetemcomitans. FEMS Microbiol Lett 237:97–103.[ISI][Medline]
Censini S, Lange C, Xiang Z, Crabtree JE, Ghiara P, Borodovsky M, et al. (1996). cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors. Proc Natl Acad Sci USA 93:14648–14653.
Chen NJ, Huang MW, Hsieh SL (2001). Enhanced secretion of IFN-gamma by activated Th1 cells occurs via reverse signaling through TNF-related activation-induced cytokine. J Immunol 166:270–276.
Cohen N, Morisset J, Emilie D (2004). Induction of tolerance by Porphyromonas gingivalis on APCS: a mechanism implicated in periodontal infection. J Dent Res 83:429–433.
Crotti T, Smith MD, Hirsch R, Soukoulis S, Weedon H, Capone M, et al. (2003). Receptor activator NF kappaB ligand (RANKL) and osteoprotegerin (OPG) protein expression in periodontitis. J Periodontal Res 38:380–387.[ISI][Medline]
DeCarlo AA, Huang Y, Collyer CA, Langley DB, Katz J (2003). Feasibility of an HA2 domain-based periodontitis vaccine. Infect Immun 71:562–566.
De Klerck B, Carpentier I, Lories RJ, Habraken Y, Piette J, Carmeliet G, et al. (2004). Enhanced osteoclast development in collagen-induced arthritis in interferon-gamma receptor knock-out mice as related to increased splenic CD11b+ myelopoiesis. Arthritis Res Ther 6:R220–R231.[ISI][Medline]
Deslauriers M, Haque S, Flood PM (1996). Identification of murine protective epitopes on the Porphyromonas gingivalis fimbrillin molecule. Infect Immun 64:434–440.[Abstract]
Dobrovolskaia MA, Medvedev AE, Thomas KE, Cuesta N, Toshchakov V, Ren T, et al. (2003). Induction of in vitro reprogramming by Toll-like receptor (TLR)2 and TLR4 agonists in murine macrophages: effects of TLR "homotolerance" versus "heterotolerance" on NF-kappa B signaling pathway components. J Immunol 170:508–519.
Duncan L, Yoshioka M, Chandad F, Grenier D (2004). Loss of lipopolysaccharide receptor CD14 from the surface of human macrophage-like cells mediated by Porphyromonas gingivalis outer membrane vesicles. Microb Pathog 36:319–325.[ISI][Medline]
Dusek DM, Progulske-Fox A, Brown TA (1994). Systemic and mucosal immune responses in mice orally immunized with avirulent Salmonella typhimurium expressing a cloned Porphyromonas gingivalis hemagglutinin. Infect Immun 62:1652–1657.
Ellis TN, Beaman BL (2004). Interferon-gamma activation of polymorphonuclear neutrophil function. Immunology 112:2–12.[ISI][Medline]
Etz H, Minh DB, Henics T, Dryla A, Winkler B, Triska C, et al. (2002). Identification of in vivo expressed vaccine candidate antigens from Staphylococcus aureus. Proc Natl Acad Sci USA 99:6573–6578.
Fox SW, Chambers TJ (2000). Interferon-gamma directly inhibits TRANCE-induced osteoclastogenesis. Biochem Biophy Res Commun 276:868–872.[ISI][Medline]
Fujii S, Uemura Y, Iwai LK, Ando M, Senju S, Nishimura Y (2001). Establishment of an expression cloning system for CD4+ T cell epitopes. Biochem Biophys Res Commun 284:1140–1147.[ISI][Medline]
Gao X, Teng YT (2002). T-cell-receptor gene usage of Actinobacillus actinomycetemcomitans-reactive periodontal CD4+ T cells from localized juvenile periodontitis patients and human peripheral blood leukocyte-reconstituted NOD/SCID mice. J Periodontal Res 37:399–404.[ISI][Medline]
Garlet GP, Martins W Jr, Ferreira BR, Milanezi CM, Silva JS (2003). Patterns of chemokines and chemokine receptors expression in different forms of human periodontal disease. J Periodontal Res 38:210–217.[ISI][Medline]
Gemmell E, Yamazaki K, Seymour GJ (2002). Destructive periodontitis lesions are determined by the nature of the lymphocytic response. Crit Rev Oral Biol Med 13:17–34.
Gibson FC 3rd, Genco CA (2001). Prevention of Porphyromonas gingivalis-induced oral bone loss following immunization with gingipain R1. Infect Immun 69:7959–7963.
Gibson FC 3rd, Gonzalez DA, Wong J, Genco CA (2004a). Porphyromonas gingivalis-specific immunoglobulin G prevents P. gingivalis-elicited oral bone loss in a murine model. Infect Immun 72:2408–2411.
Gibson FC 3rd, Hong C, Chou HH, Yumoto H, Chen J, Lien E, et al. (2004b). Innate immune recognition of invasive bacteria accelerates atherosclerosis in apolipoprotein E-deficient mice. Circulation 109:2801–2806.[ISI][Medline]
Gonzalez D, Tzianabos AO, Genco CA, Gibson FC 3rd (2003). Immunization with Porphyromonas gingivalis capsular polysaccharide prevents P. gingivalis-elicited oral bone loss in a murine model. Infect Immun 71:2283–2287.
Hajishengallis G, Sojar H, Genco RJ, DeNardin E (2004). Intracellular signaling and cytokine induction upon interactions of Porphyromonas gingivalis fimbriae with pattern-recognition receptors. Immunol Invest 33:157–172.[ISI][Medline]
Hart GT, Shaffer DJ, Akilesh S, Brown AC, Moran L, Roopenian DC, et al. (2004). Quantitative gene expression profiling implicates genes for susceptibility and resistance to alveolar bone loss. Infect Immun 72:4471–4479.
Hasegawa T, Yoshimura Y, Kikuiri T, Yawaka Y, Takeyama S, Matsumoto A, et al. (2002). Expression of receptor activator of NF-kappa B ligand and osteoprotegerin in culture of human periodontal ligament cells. J Periodontal Res 37:405–411.[ISI][Medline]
Herminajeng E, Asmara W, Yuswanto A, Barid I, Sosroseno W (2001). Protective humoral immunity induced by surface-associated material from Actinobacillus actinomycetemcomitans in mice. Microbes Infect 3:997–1003.[ISI][Medline]
Herold KC (2004). Achieving antigen-specific immune regulation. J Clin Invest 113:346–349.[ISI][Medline]
Hofbauer LC, Schoppet M (2004). Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases. J Am Med Assoc 28:490–495.
Honore P, Luger NM, Sabino MA, Schwei MJ, Rogers SD, Mach DB, et al. (2000). Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord. Nat Med 6:521–528.[ISI][Medline]
Ito HO, Shuto T, Takada H, Koga T, Aida Y, Hirata M, et al. (1996). Lipopolysaccharides from Porphyromonas gingivalis, Prevotella intermedia and Actinobacillus actinomycetemcomitans promote osteoclastic differentiation in vitro. Arch Oral Biol 41:439–444.[ISI][Medline]
Iwase M, Korchak HM, Lally ET, Berthold P, Taichman NS (1992). Lytic effects of Actinobacillus actinomycetemcomitans leukotoxin on human neutrophil cytoplasts. J Leukoc Biol 52:224–227.[Abstract]
Jagels MA, Ember JA, Travis J, Potempa J, Pike R, Hugli TE (1996). Cleavage of the human C5A receptor by proteinases derived from Porphyromonas gingivalis: cleavage of leukocyte C5a receptor. Adv Exp Med Biol 389:155–164.[Medline]
Josien R, Wong BR, Li HL, Steinman RM, Choi Y (1999). TRANCE, a TNF family member, is differentially expressed on T cell subsets and induces cytokine production in dendritic cells. J Immunol 162:2562–2568.
Jotwani R, Cutler CW (2004). Fimbriated Porphyromonas gingivalis is more efficient than fimbria-deficient P. gingivalis in entering human dendritic cells in vitro and induces an inflammatory Th1 effector response. Infect Immun 72:1725–1732.
Kachlany SC, Planet PJ, Desalle R, Fine DH, Figurski DH, Kaplan JB (2001). flp-1, the first representative of a new pilin gene subfamily, is required for non-specific adherence of Actinobacillus actinomycetemcomitans. Mol Microbiol 40:542–554.[ISI][Medline]
Kadowaki T, Nakayama K, Yoshimura F, Okamoto K, Abe N, Yamamoto K (1998). Arg-gingipain acts as a major processing enzyme for various cell surface proteins in Porphyromonas gingivalis. J Biol Chem 273:29072–29076.
Kantarci A, Oyaizu K, Van Dyke TE (2003). Neutrophil-mediated tissue injury in periodontal disease pathogenesis: findings from localized aggressive periodontitis. J Periodontol 74:66–75.[ISI][Medline]
Kato T, Okuda K (2001). Actinobacillus actinomycetemcomitans possesses an antigen binding to anti-human IL-10 antibody. FEMS Microbiol Lett 204:293–297.[ISI][Medline]
Katz J, Black KP, Michalek SM (1999). Host responses to recombinant hemagglutinin B of Porphyromonas gingivalis in an experimental rat model. Infect Immun 67:4352–4359.
Kawai T, Eisen-Lev R, Seki M, Eastcott JW, Wilson ME, Taubman MA (2000). Requirement of B7 costimulation for Th1-mediated inflammatory bone resorption in experimental periodontal disease. J Immunol 164:2102–2109.
Kawai T, Takeuchi O, Fujita T, Inoue J, Muhlradt PF, Sato S, et al. (2001). Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J Immunol 167:5887–5894.
Kirby AC, Meghji S, Nair SP, White P, Reddi K, Nishihara T, et al. (1995). The potent bone-resorbing mediator of Actinobacillus actinomycetemcomitans is homologous to the molecular chaperone GroEL. J Clin Invest 96:1185–1194.[ISI][Medline]
Kohler JJ, Pathangey LB, Brown TA (1998). Oral immunization with recombinant Salmonella typhimurium expressing a cloned Porphyromonas gingivalis hemagglutinin: effect of boosting on mucosal, systemic and immunoglobulin G subclass response. Oral Microbiol Immunol 13:81–88.[ISI][Medline]
Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, et al. (1999). OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397:315–323.[Medline]
Kozarov E, Miyashita N, Burks J, Cerveny K, Brown TA, McArthur WP, et al. (2000). Expression and immunogenicity of hemagglutinin A from Porphyromonas gingivalis in an avirulent Salmonella enterica serovar typhimurium vaccine strain. Infect Immun 68:732–739.
Kuboniwa M, Amano A, Shizukuishi S, Nakagawa I, Hamada S (2001). Specific antibodies to Porphyromonas gingivalis Lys-gingipain by DNA vaccination inhibit bacterial binding to hemoglobin and protect mice from infection. Infect Immun 69:2972–2979.
Kumagai Y, Konishi K, Gomi T, Yagishita H, Yajima A, Yoshikawa M (2000). Enzymatic properties of dipeptidyl aminopeptidase IV produced by the periodontal pathogen Porphyromonas gingivalis and its participation in virulence. Infect Immun 68:716–724.
Kuramitsu HK (2003). Molecular genetic analysis of the virulence of oral bacterial pathogens: an historical perspective. Crit Rev Oral Biol Med 14:331–344.
Kurita-Ochiai T, Ochiai K (1996). Immunosuppressive factor from Actinobacillus actinomycetemcomitans down regulates cytokine production. Infect Immun 64:50–54.[Abstract]
Lacey DL, Timms E, Tan HL, Kelley MJ, Dunstan CR, Burgess T, et al. (1998). Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93:165–176.[ISI][Medline]
Lally ET, Golub EE, Kieba IR, Taichman NS, Rosenbloom J, Rosenbloom JC, et al. (1989). Analysis of the Actinobacillus actinomycetemcomitans leukotoxin gene. Delineation of unique features and comparison to homologous toxins. J Biol Chem 264:15451–15456.
Lally ET, Kieba IR, Sato A, Green CL, Rosenbloom J, Korostoff J, et al. (1997). RTX toxins recognize a beta2 integrin on the surface of human target cells. J Biol Chem 272:30463–30469.
Li J, Sarosi I, Yan XQ, Morony S, Capparelli C, Tan HL, et al. (2000). RANK is the intrinsic hematopoietic cell surface receptor that controls osteoclastogenesis and regulation of bone mass and calcium metabolism. Proc Natl Acad Sci USA 97:1566–1571.
Lourbakos A, Potempa J, Travis J, D’Andrea MR, Andrade-Gordon P, Santulli R, et al. (2001). Arginine-specific protease from Porphyromonas gingivalis activates protease-activated receptors on human oral epithelial cells and induces interleukin-6 secretion. Infect Immun 69:5121–5130.
Mahamed DA, Marleau A, Alnaeeli M, Singh B, Zhang X, Penninger JM, et al. (2005). G(-) anaerobes-reactive CD4+T cells trigger RANKL-mediated enhanced alveolar bone loss in diabetic NOD mice. Diabetes 54:1477–1486.
Mandelboim O, Berke G, Fridkin M, Feldman M, Eisenstein M, Eisenbach L (1994). CTL induction by a tumour-associated antigen octapeptide derived from a murine lung carcinoma. Nature 369:67–71.[Medline]
Mangan DF, Taichman NS, Lally ET, Wahl SM (1991). Lethal effects of Actinobacillus actinomycetemcomitans leukotoxin on human T lymphocytes. Infect Immun 59:3267–3272.
Martin M, Katz J, Vogel SN, Michalek SM (2001). Differential induction of endotoxin tolerance by lipopolysaccharides derived from Porphyromonas gingivalis and Escherichia coli. J Immunol 167:5278–5285.
Mizuno A, Amizuka N, Irie K, Murakami A, Fujise N, Kanno T, et al. (1998). Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin. Biochem Biophys Res Commun 247:610–615.[ISI][Medline]
Mochizuki S, Kobayashi M, Suzuki T, Oikawa A, Koseki T, Nishihara T, et al. (2004). Gamma-interferon enhances expression of CD14/MyD88 and subsequent responsiveness to lipopolysaccharide from Actinobacillus actinomycetemcomitans in human gingival fibroblasts. J Periodontal Res 39:333–343.[ISI][Medline]
Mougneau E, Altare F, Wakil AE, Zheng S, Coppola T, Wang ZE (1995). Expression cloning of a protective Leishmania antigen. Science 268:563–566.
Nagasawa T, Kobayashi H, Kiji M, Aramaki M, Mahanonda R, Kojima T, et al. (2002). LPS-stimulated human gingival fibroblasts inhibit the differentiation of monocytes into osteoclasts through the production of osteoprotegerin. Clin Exp Immunol 130:338–344.[ISI][Medline]
Nakagawa T, Saito A, Hosaka Y, Ishihara K (2003). Gingipains as candidate antigens for Porphyromonas gingivalis vaccine. Keio J Med 52:158–162.[Medline]
Nakayama K (2003). Molecular genetics of Porphyromonas gingivalis: gingipains and other virulence factors. Curr Protein Pept Sci 4:389–395.[ISI][Medline]
Nishikubo S, Ohara M, Ueno Y, Ikura M, Kurihara H, Komatsuzawa H, et al. (2003). An N-terminal segment of the active component of the bacterial genotoxin cytolethal distending toxin B (CDTB) directs CDTB into the nucleus. J Biol Chem 278:50671–50681.
Nukaga J, Kobayashi M, Shinki T, Song H, Takada T, Takiguchi T, et al. (2004). Regulatory effects of interleukin-1beta and prostaglandin E2 on expression of receptor activator of nuclear factor-kappaB ligand in human periodontal ligament cells. J Periodontol 75:249–259.[ISI][Medline]
O’Brien-Simpson NM, Black CL, Bhogal PS, Cleal SM, Slakeski N, Higgins TJ, et al. (2000a). Serum immunoglobulin G (IgG) and IgG subclass responses to the RgpA-Kgp proteinase-adhesin complex of Porphyromonas gingivalis in adult periodontitis. Infect Immun 68:2704–2712.
O’Brien-Simpson NM, Paolini RA, Reynolds EC (2000b). RgpA-Kgp peptide-based immunogens provide protection against Porphyromonas gingivalis challenge in a murine lesion model. Infect Immun 68:4055–4063.
O’Gradaigh D, Ireland D, Bord S, Compston JE (2004). Joint erosion in rheumatoid arthritis: interactions between tumor necrosis factor alpha, interleukin 1, and receptor activator of nuclear factor kappa B ligand (RANKL) regulate osteoclasts. Ann Rheum Dis 63:354–359.
Oda T, Yoshie H, Yamazaki K (2003). Porphyromonas gingivalis antigen preferentially stimulates T cells to express IL-17 but not receptor activator of NF-kappaB ligand in vitro. Oral Microbiol Immunol 18:30–36.[ISI][Medline]
Ogawa T, Kono Y, McGhee ML, McGhee JR, Roberts JE, Hamada S, et al. (1991). Porphyromonas gingivalis-specific serum IgG and IgA antibodies originate from immunoglobulin-secreting cells in inflamed gingiva. Clin Exp Immunol 83:237–244.[ISI][Medline]
Ogawa T, Asai Y, Yamamoto H, Taiji Y, Jinno T, Kodama T, et al. (2000). Immunobiological activities of a chemically synthesized lipid A of Porphyromonas gingivalis. FEMS Immunol Med Microbiol 28:273–281.[ISI][Medline]
Ogawa T, Asai Y, Hashimoto M, Uchida H (2002). Bacterial fimbriae activate human peripheral blood monocytes utilizing TLR2, CD14 and CD11a/CD18 as cellular receptors. Eur J Immunol 32:2543–2550.[ISI][Medline]
Ohyama H, Matsushita S, Kato N, Nishimura F, Oyaizu K, Kokeguchi S, et al. (1998). T cell responses to 53-kDa outer membrane protein of Porphyromonas gingivalis in humans with early-onset periodontitis. Hum Immunol 59:635–643.[ISI][Medline]
Oido-Mori M, Rezzonico R, Wang PL, Kowashi Y, Dayer JM, Baehni PC, et al. (2001). Porphyromonas gingivalis gingipain-R enhances interleukin-8 but decreases gamma interferon-inducible protein 10 production by human gingival fibroblasts in response to T-cell contact. Infect Immun 69:4493–4501.
Okahashi N, Inaba H, Nakagawa I, Yamamura T, Kuboniwa M, Nakayama K, et al. (2004). Porphyromonas gingivalis induces receptor activator of NF-kappaB ligand expression in osteoblasts through the activator protein 1 pathway. Infect Immun 72:1706–1714.
Ortmann RA, Shevach EM (2001). Susceptibility to collagen-induced arthritis: cytokine-mediated regulation. Clin Immunol 98:109–118.[ISI][Medline]
Oyaizu K, Ohyama H, Nishimura F, Kurihara H, Matsushita S, Maeda H, et al. (2001). Identification and characterization of B-cell epitopes of a 53-kDa outer membrane protein from Porphyromonas gingivalis. Oral Microbiol Immunol 16:73–78.[ISI][Medline]
Park SH, Min DJ, Cho ML, Kim WU, Youn J, Park W, et al. (2001). Shift toward T helper 1 cytokines by type II collagen-reactive T cells in patients with rheumatoid arthritis. Arthritis Rheum 44:561–569.[ISI][Medline]
Pfeifer JD, Wick MJ, Russell DG, Normark SJ, Harding CV (1992). Recombinant Escherichia coli express a defined, cytoplasmic epitope that is efficiently processed in macrophage phagolysosomes for class II MHC presentation to T lymphocytes. J Immunol 149:2576–2584.[Abstract]
Probst P, Stromberg E, Ghalib HW, Mozel M, Badaro R, Reed SG, et al. (2001). Identification and characterization of T cell-stimulating antigens from Leishmania by CD4 T cell expression cloning. J Immunol 166:498–505.
Pussinen PJ, Alfthan G, Tuomilehto J, Asikainen S, Jousilahti P (2004). High serum antibody levels to Porphyromonas gingivalis predict myocardial infarction. Eur J Cardiovasc Prev Rehabil 11:408–411.[ISI][Medline]
Pussinen PJ, Nyyssonen K, Alfthan G, Salonen R, Laukkanen JA, Salonen JT (2005). Serum antibody levels to Actinobacillus actinomycetemcomitans predict the risk for coronary heart disease. Arterioscler Thromb Vasc Biol 25:833–838.
Rajapakse PS, O’Brien-Simpson NM, Slakeski N, Hoffmann B, Reynolds EC (2002). Immunization with the RgpA-Kgp proteinase-adhesin complexes of Porphyromonas gingivalis protects against periodontal bone loss in the rat periodontitis model. Infect Immun 70:2480–2486.
Rani CS, MacDougall M (2000). Dental cells express factors that regulate bone resorption. Mol Cell Biol Res Commun 3:145–152.[Medline]
Reddi K, Meghji S, Nair SP, Arnett TR, Miller AD, Preuss M, et al. (1998). The Escherichia coli chaperonin 60 (groEL) is a potent stimulator of osteoclast formation. J Bone Miner Res 13:1260–1266.[ISI][Medline]
Rollins SM, Peppercorn A, Hang L, Hillman JD, Calderwood SB, Handfield M, et al. (2005). In vivo induced antigen technology (IVIAT). Cell Microbiol 7:1–9.[ISI][Medline]
Romas E, Gillespie MT, Martin TJ (2002). Involvement of receptor activator of NFkappaB ligand and tumor necrosis factor-alpha in bone destruction in rheumatoid arthritis. Bone 30:340–346.[Medline]
Ronaghy A, Prakken BJ, Takabayashi T, Firestein GS, Boyle D, Zvailfler NJ, et al. (2002). Immunostimulatory DNA sequences influence the course of adjuvant arthritis. J Immunol 168:51–56.
Ross BC, Czajkowski L, Hocking D, Margetts M, Webb E, Rothel L, et al. (2001). Identification of vaccine candidate antigens from a genomic analysis of Porphyromonas gingivalis. Vaccine 19:4135–4142.[ISI][Medline]
Ross BC, Czajkowski L, Vandenberg KL, Camuglia S, Woods J, Agius C, et al. (2004). Characterization of two outer membrane protein antigens of Porphyromonas gingivalis that are protective in a murine lesion model. Oral Microbiol Immunol 19:6–15.[ISI][Medline]
Sanderson S, Shastri N (1994). LacZ inducible antigen/MHC specific T cell hybrids. Int Immunol 6:369–376.
Sanderson S, Frauwirth K, Shastri N (1995a). Expression of endogenous peptide-major histocompatibility complex class II complexes derived from invariant chain-antigen fusion proteins. Proc Natl Acad Sci USA 92:7217–7221.
Sanderson S, Campbell DJ, Shastri N (1995b). Identification of a CD4+T cell-stimulating antigen of pathogenic bacteria by expression cloning. J Exp Med 182:1751–1757.
Sasaki H, Okamatsu Y, Kawai T, Kent R, Taubman M, Stashenko P (2004). The interleukin-10 knockout mouse is highly susceptible to Porphyromonas gingivalis-induced alveolar bone loss. J Periodontal Res 39:432–441.[ISI][Medline]
Schreiner HC, Sinatra K, Kaplan JB, Furgang D, Kachlany SC, Planet PJ, et al. (2003). Tight-adherence genes of Actinobacillus actinomycetemcomitans are required for virulence in a rat model. Proc Natl Acad Sci USA 100:7295–7300.
Scott DM, Ehrmann IE, Ellis PS, Bishop CE, Agulnik AI, Simpson E (1995). Identification of a mouse male-specific transplantation antigen H-Y. Nature 376:695–698.[Medline]
106 clones/µg DNA insert. Periodontal CD4+ T-cells were purified from Aa-HuPBL-NOD/SCID mice (