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CRITICAL REVIEWS IN ORAL BIOLOGY & MEDICINE

Protective and Destructive Immunity in the Periodontium: Part 2—T-cell-mediated Immunity in the Periodontium

Y.-T.A. Teng

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


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 (I) T-CELL-MEDIATED IMMUNITY IN...
 (II) CONCLUSION
 REFERENCES
 
Based on the results of recent research in the field and Part 1 of this article (in this issue), the present paper will discuss the protective and destructive aspects of the T-cell-mediated adaptive immunity associated with the bacterial virulent factors or antigenic determinants during periodontal pathogenesis. Attention will be focused on: (i) osteoimmunology and periodontal disease; (ii) some molecular techniques developed and applied to identify critical microbial virulence factors or antigens associated with host immunity (with Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis as the model species); and (iii) summarizing the identified virulence factors/antigens associated with periodontal immunity. Thus, further understanding of the molecular mechanisms of the host’s T-cell-mediated immune responses and the critical microbial antigens related to disease pathogenesis will facilitate the development of novel therapeutics or protocols for future periodontal treatments. Abbreviations used in the paper are as follows: A. actinomycetemcomitans (Aa), Actinobacillus actinomycetemcomitans; Ab, antibody; DC, dendritic cells; mAb, monoclonal antibody; pAb, polyclonal antibody; OC, osteoclast; PAMP, pathogen-associated molecular patterns; P. gingivalis (Pg), Porphyromonas gingivalis; RANK, receptor activator of NF-{kappa}B; RANKL, receptor activator of NF-{kappa}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


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
(I) T-CELL-MEDIATED IMMUNITY IN...
 (II) CONCLUSION
 REFERENCES
 
The present paper continues from the previous discussion (see Teng, 2006) and briefly reviews some recent findings regarding T-cell-mediated immunity in the periodontium, including the osteoimmunology, RANKL, and cytokine network, and the microbial virulent factors or antigens identified and their association with periodontal immunity.


   (I) T-CELL-MEDIATED IMMUNITY IN THE PERIODONTIUM
TOP
 ABSTRACT
 INTRODUCTION
 (I) T-CELL-MEDIATED IMMUNITY IN...
(II) CONCLUSION
 REFERENCES
 
It is generally accepted that systemic immune status can affect local immune responses, including the periodontium, and that periodontal disease progression is critically determined by the nature of inflammatory responses generated in response to the challenges from the subgingival micro-organisms (or biofilm). The study of various genetic knockout and immunodeficient mouse strains and the use of advanced cellular and molecular biology techniques have brought us new understanding and insights into the nature of, and regulations associated with, inflammatory events in the periodontium. In addition to the protective and somewhat unclear inflammatory and anti-inflammatory activity of humoral Ig immunity in the periodontium, it is now clear that when the host’s T-cell-mediated immune system is absent or deficient during the course of periodontal infection, compared with that of the immunocompetent host, there is much less tissue inflammation and alveolar bone destruction (Baker et al., 1994, 1999, 2002; Baker, 2000; Teng et al., 2000; Taubman and Kawai, 2001; Teng, 2003). While CD8+ T-cells may be involved in killing and removing some bacteria-infected or -damaged host cells, they do not directly mediate the periodontal destruction in situ. Importantly, CD4+ T-cells and other phagocytic lineage or innate immune cells are critically involved in building effective defenses to eradicate the invading pathogens and directly participate in tissue inflammatory responses and alveolar bone destruction, in particular, through the cytokines they produce (Seymour and Gemmell, 2001; Gemmell et al., 2002; Kantarci et al., 2003; see also the TLR section of Part 1 in Teng, 2006).

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-{gamma}, 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. 1Go) 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.


Figure 1
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  		Figure 1. The RANKL and Cytokine Interactions Network (RACIN) proposed during periodontal pathogenesis (Teng et al., 2005). Local innate immune cells (i.e., dendritic cells, macrophages, or other antigen-presenting cells) encounter periodontal pathogens and pick up and present critical microbial antigens/peptides to prime naïve T-cells in the periodontal micro-environment, where RANKL-expressing Th1 vs. Th2 cells become activated by secreting IFN-{kappa} and TNF-{alpha} vs. IL-10 and TGF-β cytokines. There may exist cross-talk or feedback regulation between the interacting cytokines in the micro-environment that modulate or influence the resulting RANKL-mediated periodontal osteoclastogenesis and tissue inflammation or anti-inflammatory processes associated with tissue repair (i.e., via fibroblasts). Note that the overall contribution of periodontal/mucosal resident cells or mesenchymal tissues to RANKL/OPG-mediated osteoclastogenesis is not described here, due to the lack of in vivo data.

 
(A) Osteo-immunology and Periodontal Disease
Inflammatory bone diseases (i.e., rheumatoid arthritis, periodontitis, etc.) affect a large portion of the mucosal surface and the osteo-skeletal system in the human body, as a result of disturbed or dysregulated osteoclastic activity. A recently identified TNF family molecule, receptor activator of NF-{kappa}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. 1Go). Thus, note that the role of oral mucosal/residential cells is not described as part of the periodontal RACIN proposed in Fig. 1Go.

Despite some controversies, it has been shown that both TNF-{alpha} 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-{gamma} 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-{gamma} into Aa-infected HuPBL-NOD/SCID mice, followed by monitoring the co-expression of INF-{gamma} 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-{gamma} 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-{gamma} 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-{gamma} 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-{gamma}+ 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-{gamma} 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-{gamma} 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-{gamma}-treated or sham-treated A. actinomycetemcomitans-infected HuPBL-NOD/SCID mice (Teng et al., 2005; unpublished data). In addition, IFN-{gamma} 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-{gamma}). Moreover, it is known that IFN-{gamma} 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-{gamma} and RANKL-RANK/OPG under various inflammatory conditions (i.e., TNF-{alpha} 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. 1Go 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. 2Go). Furthermore, detection sensitivity can be enhanced via a single T-cell activation by means of a reporter construct (β-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).


Figure 2
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  		Figure 2. Diagram showing T-cell expression cloning strategy to identify critical virulence antigens associated with periodontal immunity in vivo. Genomic DNA of Aa was partially digested and size-fractionated (0.5–4.0 kb) before being ligated into the pTrcHis-C vector. Ligated plasmids were transformed into E. coli Top10 strain by electroporation and then distributed onto selective plates. The size of the genomic library was estimated at {approx} 106 clones/µg DNA insert. Periodontal CD4+ T-cells were purified from Aa-HuPBL-NOD/SCID mice (Teng et al., 2000) and then expanded by rhIL-2 in vitro. Later, the CD4+ T-cells were transfected with a linearized DNA vector of an IL-2-inducible reporter construct with a lacZ sequence (NF-AT-lacZ). Hygromycin-resistant T-cells were then selected and expanded in hrIL-2. Thus, T-cell activation can be measured and visualized as lacZ expression in single cells or in bulk cultures. Controls included the sham- and lacZ-only transfected CD4+ T-cells, which did not yield any positive clones from screening. To screen bacterial antigens recognized by CD4+ T-cells, we plated E. coli clones from the Aa genomic library and added IPTG in vitro to induce protein expression. In parallel, autologous HuPBL-derived monocytes/macrophages were prepared and cultured overnight with rhIFN-{gamma} to up-regulate HLA. CD4+ T-cells from Aa-HuPBL-NOD/SCID mice, after being transfected with NF-AT-lacZ, described above, were then added to the co-cultures for overnight incubation. The lacZ(+) cells were visualized by being stained with buffered X-gal. The positive wells giving blue signals were sequentially subjected to further screening for confirmation by the use of fewer clones (i.e., 5–10) per well, until a single positive clone was identified (for details, see Teng and Hu, 2003).

 
We have used genetically modified hCD4+ T-cells derived from A. actinomycetemcomitans-infected HuPBL-NOD/SCID mice as probes to screen an A. actinomycetemcomitans genomic library for critical antigens involved in periodontal immunity associated with active alveolar bone loss in vivo (see Fig. 2Go 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 1Go and 2Go 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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  		Table 1. Virulence Factors or Antigens of A. actinomycetemcomitans Studied that are Associated with Periodontal Disease Immunity
 

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  		Table 2. Virulence Factors or Antigens of P. gingivalis Studied that are Associated with Periodontal Immunity
 

   (II) CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 (I) T-CELL-MEDIATED IMMUNITY IN...
 (II) CONCLUSION
REFERENCES
 
The finite balance between local and systemic immune responses orchestrates the ultimate outcomes of microbial invasion and infection in the body, where the host’s innate immunity mounts a very rapid and non-specific defense directly or indirectly toxic to the invading pathogens via several key inflammatory molecules. In contrast, the defensive adaptive immunity is much slower and involves specific T-cells and effective Abs that target the pathogens with higher surgical precision.

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.


   ACKNOWLEDGMENTS
 
The author thank all of his lab colleagues for their help in the works associated with this manuscript. These works were supported by grants to Y.-T.A.T. from the Ministry of Health of Ontario, Canada, the Canadian Institute of Health Research (CIHR) (MOP-37960), the University of Rochester, and the US National Institutes of Health (DE12969, DE14473, DE015786).

Received for publication March 3, 2005. Accepted for publication September 6, 2005.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 (I) T-CELL-MEDIATED IMMUNITY IN...
 (II) CONCLUSION
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Journal of Dental Research, Vol. 85, No. 3, 209-219 (2006)
DOI: 10.1177/154405910608500302
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