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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) INNATE IMMUNITY AND...(II) HUMORAL IMMUNITY IN...REFERENCES |
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KEY WORDS: innate immunity • TLR • humoral Ig response • dendritic cells (DC) • pathogen-associated muscular patterns (PAMP)
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INTRODUCTION |
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TOPABSTRACTINTRODUCTION(I) INNATE IMMUNITY AND...(II) HUMORAL IMMUNITY IN...REFERENCES |
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(I) INNATE IMMUNITY AND THE PERIODONTIUM |
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TOPABSTRACTINTRODUCTION(I) INNATE IMMUNITY AND...(II) HUMORAL IMMUNITY IN...REFERENCES |
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TLR are specific recognition receptors that respond to ‘pathogen-associated molecular patterns (PAMP)’ whose signaling events can lead to the detection of microbial infections, activation of innate immune responses, subsequent activation and modulation of adaptive immunity, and, consequently, a triggering of the antibacterial host defense response (Janeway, 1989; Alvarez, 2005). Thus, the host can detect invading micro-organisms and, consequently, can elicit strong inflammatory responses to eliminate the infectious agents or source. In addition, TLR can modulate DC functions and initiate signals critically involved in activating adaptive immune responses located at distinct anatomical sites (for review, see Beutler et al., 2004; Foti et al., 2004; Iwasaki and Medzhitov, 2004; Netea et al., 2004). It is known that microbial pathogens can often inhibit TLR-mediated immune responses by either blocking TLR signals that stimulate further host defense mechanisms, or by down-regulating TLR expression levels (Netea et al., 2004; Portnoy, 2005). Some of the subverted-inhibitory mechanisms have been intensively studied in the bacterial system; however, the unique or specific features of periodontal infections have only recently begun to be thoroughly investigated (Cutler and Jotwani, 2004; Dixon et al., 2004). Presently, there is not sufficient evidence to ‘definitively’ demonstrate the cellular and molecular mechanisms behind the protective or destructive innate immune responses that come into play in response to microbial challenge in the periodontium. Further, it is clear that the innate immune response can directly modulate or activate subsequent adaptive immunity. The section below summarizes some recent findings in the general non-oral and periodontal microbial innate immune responses and attempts to bring some perspectives for further research.
(A) Toll-like Receptors (TLR): Signaling Legend?
To date, 11 different TLR have been identified in the mammalian system (for review, see Krutzik and Modlin, 2004; Quesniaux et al., 2004; Zhang et al., 2004), and their differential expression and distribution, and the specificities of TLR by host cells/tissues, determine the subsequent host immune interactions with microbes and their components. For example, gingival epithelial cells express TLR2 and 4, monocytes express CD14, TLR1, 2, 4, and 5, endothelial cells express mainly TLR4, gingival fibroblasts express TLR2 and 4 and CD14, and DC subsets express specific TLRs. In contrast to most Gram-negative LPS recognized by TLR4, P. gingivalis LPS has been shown to stimulate TLR2 by human and mouse macrophages (Hirschfeld et al., 2001; Martin et al., 2001) and suppress the activities of other TLR agonists (Yoshimura et al., 2002; Coats et al., 2003). Thus, identification of which TLR (2 or 4) is the key receptor for P. gingivalis-LPS stimulation in the periodontal tissues associated with disease pathogenesis will require further study.
TLR may trigger different cellular responses (i.e., Th1 or Th2 — Agrawal et al., 2003; Dillon et al., 2004; Krutzik and Modlin, 2004) through differential use of signaling adapter proteins (Cook et al., 2004; Iwasaki and Medzhitov, 2004; Portnoy, 2005). For example, via LPS engagement, TLR4 can signal MyD88 and TIRAP for the production of TNF-
and IL-12 and IL-6 cytokines, or signal via TRAM and TRIF in the absence of the MyD88 pathway before releasing IFN-/ß and IRF-3 (Cook et al., 2004; Sasai et al., 2005). It was originally discovered that LPS of Gram-negative microbes primarily use TLR4, and, more recently, that bacterial cell-wall lipoteichoic acid, peptidoglycans, and lipoproteins of Gram-positive bacteria, Mycobacteria, Borrelia, and yeast can stimulate TLR2 to initiate innate immune responses via the MyD88 pathway, which activates the downstream adapter MAPKs and the transcriptional factor NF-
B for activation of multiple (pro)-inflammatory genes. So far, at least 5 cytoplasmic adapter proteins—including MyD88, TRIF, TIRAP (or MAL), TRAM, and SARM—have been identified for TLR signaling cascades (Beutler et al., 2004). All TLRs, except TLR3, use MyD88 for downstream signaling. TLR2 uses MyD88 and TIRAF (likely the same for TLR1 and 6); TLR3 uses TRIF only; TLR4 uses MyD88, TIRAP, and TRIF; and TLR7 and 9 both use MyD88 only, without TIRAP or TRIF. Adapter TIRAP is required for coupling TLR4 to MyD88 in the cytosol before further downstream signaling (see Fig
.). Coupling different TLR and other cell-surface receptors has been shown to be critical in the activation of certain DC subsets at different anatomic sites (for review, see Foti et al., 2004; Iwasaki and Medzhitov, 2004; Sasai et al., 2005). Later, it was suggested that a common scheme including TRIF and MyD88 together promotes NF-B and MAPK activation, followed by pro-inflammatory cytokine gene transcription; whereas, TRIF activates IRF-3 for anti-viral IFN-ß synthesis (Beutler et al., 2004; Sasai et al., 2005). These findings explain why, in both MyD88-dificient and TIRAP (MAL)-deficient mice: (i) LPS signal transduction is only partially impaired, along with delayed phosphorylation of MAP kinases and NF-B activation; (ii) TLR2 signaling is completely lost; and (iii) TRIF and MyD88 ‘double’-mutant mice manifest no residual LPS signaling (Kawai et al., 2001; Yamamoto et al., 2002a,b; Hoebe et al., 2003). Importantly, the causes of adjuvanticity by the microbial LPS and by-products (i.e., dsRNA via TLR3) that are capable of stimulating the co-stimulatory molecules (i.e., CD80 and CD86, etc.) associated with triggering adaptive immune response are now known to require the TLR4-TRIF-IFNß-R axis, bypassing the need for MyD88 and NF-B signaling pathways (Hoebe et al., 2003; also see Fig.).
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.). Recent reports in the literature have shown that triggering TLR signal cascades or defective TLR signaling can result in different levels of antimicrobial immune responses, leading to bacterial clearance or chronic bacterial infection and the increase of host susceptibility and/or resistance (survival) to microbial infections. Some pathogenic species related to certain non-oral medical vs. periodontal infections are discussed below to highlight their different characteristics.
(B) Protective Role of TLR in Microbial Infections: To Be or Not To Be?
It has been suggested and shown that MyD88, a LTR signaling adapter, can confer protective immunity or resistance to Mycobacterium tuberculosis infection in mice (Hornef et al., 2002; Reiling et al., 2002; Branger et al., 2004; Cook et al., 2004; Portnoy, 2005), consistent with several other reports associated with Listeria monocytogenes, Staphylococcus aureus, Toxoplasma gondii, Borrelia burgdorferi, and Mycobacterium avium infections (Takeuchi et al., 2000; Scanga et al., 2002, 2004; Seki et al., 2002; Liu et al., 2004; Bellocchio et al., 2004; Way et al., 2004), where the host has markedly reduced IL-12, TNF-, IFN-
, and NOS-2 productions. However, in M. avium, the host manifests significantly impaired adaptive immunity and antigen-specific CD4+ T-cell activation, but, interestingly, this does not occur in MyD88(–/–) mice infected by M. tuberculosis in vivo (Feng et al., 2003; Shi et al., 2003; Sugawara et al., 2003b; Fremond et al., 2004). Further, TLR2, 4, and 6 knockout mice show no loss of protection to airborne M. tuberculosis infection (Abel et al., 2002; Reiling et al., 2002; Shim et al., 2003; Sugawara et al., 2003a), suggesting that MyD88 (largely for TLR signaling) is not always required, and/or that MyD88-independent signaling or alternative pathway(s) may exist for the effector function of the adaptive defense mechanisms in vivo. Similarly, the Gram-negative obligate intracellular bacterium Anaplasma phagocytophilum can elicit a protective adaptive immunity by controlling multiplication of the micro-organism, even in the presence of ‘cryptic’ TLR signaling via TLR2, TLR4, MyD88, TNF cytokine, and the NADPH oxidase complex, or NOS2 production (von Loewenich et al., 2004). These novel new findings pinpoint the redundancy of the innate immune response and the potential TLR-independent pathway for adaptive immunity. Equally important issues to be considered include, first, that there may be different ‘grades’ of handling vs. combatting the invading pathogen in the host. At times, the innate immunity may be somehow ‘delayed’ at the levels of monocytes/macrophages before the higher grades of T-cell-mediated immunity take place. Thus, it is possible that, even in the absence of MyD88 signaling and a 50% decrease in the pro-inflammatory cytokines and collateral innate responses, strong IFN- and adaptive T-cell-mediated immune responses can still sufficiently withhold specific microbial replication, survival, and bring about their eradication (Scanga et al., 2004). Second, the invading micro-organisms may develop control mechanisms beyond TLR for evasion (Hornef et al., 2002; Hertzog et al., 2003; and see below). Together, under some compromised conditions, in the absence of the innate immune system, the host can collaborate with other cellular signals or products from local resident and mucosal cells that sense the ‘danger’ by releasing endogenous factors such as membrane phospholipids, heat-shock proteins, or uric acids, etc., for further downstream activation and the ultimate adaptive defense mechanisms to deal with the invading or evading microbes in vivo (Netea et al., 2004; Underhill and Gantner 2004). Some of these mechanisms may include the known Fas-FasL killing, perforin-mediated target lysis, granzyme, granulysin, complements, and antibody effector functions.
In parallel, studies have also shown that MyD88-deficient mice display increased susceptibility to various microbial infections, such as Staphylococcus aureus, Listeria monocytogenes, Mycobacterium avium, Candida albicans, Toxoplasma gondii, Leishmania major, and Trichuris muris, and mice lacking functional TLR4 are also very prone to Gram-negative bacterial infections (i.e., Neisseria meningitides, E. coli, Haemophilus influenzae, Salmonella typhimurium, and Klebsiella pneumoniae) and C. albicans infection. In contrast, TLR2-deficient mice develop increased susceptibility to S. aureus or S. pneumoniae infections (Echchannaoui et al., 2002; Koedel et al., 2003), and patients with IRAK4 (IL-1R-associated kinase-4) deficiency suffer from recurrent pyrogenic bacteria infections (Picard et al., 2003; Medvedev et al., 2003). These results suggest that TLRs can not only mediate ‘early’ detection of invading pathogens for inflammatory cytokines, but also provide significant protection in vivo. In addition, NOD1 (i.e., nucleotide-binding oligomerization domain 1) and recently discovered NOD2 belong to the special cytosolic receptors involved in recognition of bacterial peptidoglycan fragments (Inohara and Nunez, 2003). NOD1 recognizes muramyl tri-peptides from Gram-positive and -negative microbes, which are characterized by the presence of meso-diaminopimelic acid (Chamaillard et al., 2003; Girardin et al., 2003). For some bacteria, like pathogenic L. monocytogenes, whose hydrolytic enzymes can activate NOD2 [recognizing the muramyl ‘di’-peptide common to peptidoglycans of all microbes (Girardin et al., 2003; Lenz et al., 2003)], the real picture of linking innate and adaptive immune responses in vivo can be even more complicated than what has been described above and elsewhere. For example, a recent study of CARD15-deficient mice with gene mutation resulted in significantly increased TLR2-mediated NF-B signaling and higher IL-12 production, a NOD2-encoded phenotype highly associated with Crohn’s disease in humans. Thus, CARD15 normally acts as a negative regulator for TLR2-driven Th1 response, where its mutation leads to an increased Th1 cytokine production, a characteristic of Crohn’s disease (Watanabe et al., 2004). In contrast, a recent clinical study suggests that two mutations in the CARD15 gene show no correlation with clinical adult periodontitis (Laine et al., 2004). Presently, their signaling pathways are unknown, but clearly include LTR2-, LTR4-, and MyD88-independent pathways, and require further investigation (see Fig.).
Some pathogens can evade immune recognition by secreting immuno-suppressive cytokines or avoiding interactions with TLR. For example, Yersinia enterocolitica and C. albicans induce TLR2-mediated IL-10 production (Sing et al., 2002; Netea et al., 2004). Mycobacteria-infected macrophages can release immunosuppressive IL-6, IL-10, and TGF-ß, all of which down-regulate inflammatory cytokine production and specific cell-mediated immunity (Toossi et al., 1995; Giacomini et al., 2001; Zuany-Amorim et al., 2002). Similarly, Bordetella pertussis (McGuirk et al., 2002) and Borrelia burgdorferi mediate their suppressive effects through TLR2-mediated IL-10 expression (Diterich et al., 2003). It is conceivable that, in the absence of certain TLRs (i.e., TLR2 and 4), severe inflammation in vivo may prevail during Pneumococcal meningitis and Bordetella pertussis infections (Echchannaoui et al., 2002; Koedel et al., 2003). Interestingly, TLRs can be stimulated to release IL-4, IL-5, IL-6, IL-10, and IL-13 (Re and Strominger, 2001; Agrawal et al., 2003), and G(-)-LPS and C. albicans have been shown to signal TLR2 and TLR4, whereby activation of T-regulatory cells, T-reg (Caramalho et al., 2003; Pasare and Medzhitov, 2003; Netea et al., 2004), down-regulates inflammatory immunity, favoring some Th2 response beneficial for chronic infection and long-term survival of the pathogens (Dillon et al., 2004). In addition, stimulation of TLR9 by unmethylated CpG can inhibit T-reg activation, further hindering the elimination of the long-term-persisting pathogens (Pasare and Medzhitov, 2003). It has been shown recently that Treponema phospholipids can inhibit TLR activation (i.e., 3, 4, and 9) by blocking LPS-binding protein and CD14 (Asai et al., 2003). P. gingivalis and Leptospira use different LPS structural moieties to avoid recognition by TLR4 or TLR5, respectively, and retain certain recognitions only by TLR2, thereby shifting the balance to a more anti-inflammatory Th2 response (Hirschfeld et al., 2001; Werts et al., 2001). In particular, P. gingivalis may use modified lipid-A in its LPS products to subvert a TLR4-dependent antagonistic response (Darveau et al., 2004). By the same token, Shigellae and Salmonellae apply different LPS moieties to promote and avoid (or decrease) host inflammation, respectively (Guo et al., 1997; D’Hauteville et al., 2002). Thus, from the host’s perspective, innate immunity is largely unable to control microbial infections as the microbes develop ‘stealth strategies’ for their own benefit. Together, these pathogens apply different escape mechanisms away from specific host immunity.
It has been found that Gram-negative LPS or the whole bacteria (i.e., S. typhimurium) can work with infiltrating leukocytes and available cytokines in the microenvironment (i.e., IL-12 p40) to block the differentiation of tissue-borne inflammatory monocytes into active DCs locally, and to trap the migratory DCs at the site of bacterial infection, thereby lowering or inhibiting the development of subsequent adaptive immune responses in vivo (Rotta et al., 2003). This finding suggests that bacteria-mediated signals, via TLR4 and other TLRs, can act as negative regulators of the host’s innate and adaptive immunity. Interestingly, a potentially dys-regulated differentiation of PBL-derived monocytes to the DC phenotype has been suggested to be a disease characteristic of A. actinomycetemcomitans-infected localized aggressive periodontitis in some patients (Barbour et al., 2002). P. gingivalis fimbriae can stimulate PBL monocytes to release IL-6, and MAP kinases and NF-B activation via TLR2, CD14, and CD11a/CD18 signaling (Ogawa et al., 2002), as opposed to IL-8 release from gingival epithelial cells via TLR2 (Asai et al., 2001). Bacterially unmethylated CpG motifs of periodontal pathogens have also been shown to exert potent effects on cytokine production via TLR9 stimulation (Nonnenmacher et al., 2003). Further, under inflamed conditions due to repeated stimulation by LPS or fimbriae of P. gingivalis or cytokine exposures (i.e., IFN-), attenuated production of certain inflammatory cytokines (i.e., IL-1, IL-6, TNF-, etc.), modulation of TLR expression levels (i.e., CD14, TLR2 and 4), altering signal intermediates (i.e., IRAK-1-mediated down-regulation) along the IB/NF-B pathways, and even down-regulation of the APC functions (i.e., inhibiting co-stimulatory CD80, CD86 expression) have been shown to contribute to the ‘de-sensitization’ of the host secondary innate immunity (i.e., LPS tolerance; see Martin et al., 2001; Uehara et al., 2002; Yoshimura et al., 2003; Cohen et al., 2004; Hajishengallis et al., 2004). In parallel, it has been proposed that some microbial products (i.e., P. gingivalis fimbriae) may recruit other cellular receptors (i.e., CD14 or CD11b/CD18) before engaging specific TLRs for further pro-inflammatory and chemokine signaling (Hajishengallis et al., 2004). In fact, both P. gingivalis and E. coli-LPS have been found to have similar but different effects, suggesting that host innate immune cells sense bacterial components differently and exhibit different response patterns (Zhou et al., 2005). Additional mechanisms include: (i) that P. gingivalis can release cysteine proteases, such as gingipains, to degrade host-derived pro-inflammatory cytokine [i.e., IL-6, IL-8, IL-12, and TNF- (Calkins et al., 1998; Banbula et al., 1999; Oido-Mori et al., 2001)] or down-regulate innate immune receptors (i.e., CD14; Duncan et al., 2004); (ii) that P. gingivalis- and A. actinomycetemcomitans-derived immunosuppressive factors can avoid local immunoregulatory or anti-inflammatory effects (Kurita-Ochiai and Ochiai 1996; Holt et al., 1999; Henderson et al., 2003); and (iii) that LPS can couple with the gingipain complex to evade immune-recognition by TLR4 and production of pro-inflammatory cytokines (Takii et al., 2005).
It has been suggested that TLRs can mediate protection against invading pathogens during periodontal infections; however, a recent epidemiological study involving TLR genotyping shows that polymorphic TLR2 (Arg677Trp and Arg753Gln) and TLR4 (Asp299Gly and Thr399Ile) alleles do not render the susceptible individuals at higher risk, or are not associated with higher incidence for chronic periodontal infections when compared with healthy control subjects (Folwaczny et al., 2004). A similar observation has been made in TLR4 single-nucleotide polymorphism, where no deficit in LPS sensitivity and inflammatory signaling was found (Imahara et al., 2005). This may mean that the host probably does not rely on the specific arms of innate immunity, like TLRs, to confer protection against subgingival micro-organisms in the periodontium. Furthermore, the results from studies of C3H/HeJ and C57BL/10ScCr mice with the non-functional TLR4 gene product have demonstrated a ‘reduced’ periapical bone loss or sepsis formation in vivo, suggesting that TLRs can function to increase pro-inflammatory responses and bone destruction in response to mixed anaerobic infections (Hou et al., 2000a).
Collectively, loss of TLR functions may either lead to increased susceptibility or confer resistance to different microbial infections (Sing et al., 2002; Hawn et al., 2003; Vazquez-Torres et al., 2004). Nevertheless, regardless of the levels of activation signals or inhibitions, the TLR innate immune network can ‘sense’ the presence and motions of the invading pathogens to alert and guide the adaptive immune response to combat and, ultimately, eliminate the dangerous pathogenic species. It is evident that the results of in vitro studies with cell lines or primary cells may neither mimic nor reflect the exact molecular mechanisms that have biological significance. This leaves us with an urgent need to explore and study how these complex host-immune parasite interactions are initiated, regulated, and/or controlled in vivo by using effective modeling systems and animal models.
(C) Commensal Flora: Periodontal Relevance?
It was long thought that commensal flora can affect and shape our body’s innate and adaptive immune system (Mowat, 2003; Jiang et al., 2004; MacPherson and Harris, 2004). Our understanding of the host immune-parasite interactions and relationship is changing. Today, it is believed that the human body maintains a critically and mutually beneficial relationship with the resident microbes. The discovery that experimental germ-free rats, lacking the gut flora, require a caloric intake 30% higher than that of their non-germ-free counterparts is in concordance with the above concept, that we can live compatibly with resident commensal micro-organisms (Wostmann et al., 1983).
Throughout post-natal development, there are transitions and changes in the composition of the gut commensal flora in our body. Research in oral biology based on recent advances in microbial culture and molecular biology techniques (i.e., 16S rRNA genes and genomics) has provided evidence that somewhat comparable transitions and qualitative changes in oral flora also occur in the supra-/subgingival periodontal tissues before and after the development of periodontal disease (Dzink et al., 1988; Socransky et al., 1998; Tanner et al., 1998; Nishihara and Koseki, 2004). It has been shown that different microbes can modulate or stimulate the expression of antimicrobial peptides in the mucosal surface (i.e., defensins; for review, see Mahida and Cunliffe, 2004) whose exact defense mechanisms are still unclear with respect to how the balance between the microbes and host interactions is maintained over a long period of time. The oral epithelium represents a physical barrier that may interact with periodontal micro-organisms and provide primary defense mechanisms via antimicrobial peptides (Chung et al., 2004; Shelburne et al., 2005). The invading pathogens (regardless of their nature—i.e., opportunistic, commensal, or pathogenic), after penetrating the epithelial layers, will be largely destroyed by resident phagocytes such as neutrophils and macrophages (Deas et al., 2003; Kantarci et al., 2003), and the resulting foreign microbial antigens are then processed and presented to local lymphocytes (i.e., intra-epithelial lymphocytes) to generate specific adaptive immune responses. It has been suggested that commensal microbes are non-pathogenic under normal circumstances; however, they may become harmful in response to local environment changes and/or breakdowns in host defense operations (van Winkelhoff, 1999). It is known that there is an ecological succession whereby virulent species become established in the subgingival micro-environment. It remains a mystery as to how the periodontal/oral mucosal tissue and the immune system deal with the vast population of oral/periodontal flora existing in the human gut, how they tolerate the daily microbial stimuli and antigens, and how their endogenous regulation or imbalance affects the establishment of other virulent species in the periodontium.
Other than the bulk of data and studies described above, additional lines of evidence suggest that there are in fact well-controlled anti-inflammatory systems [i.e., peroxisome proliferator-activated receptor- (PPAR-); Su et al., 1999; Kelly et al., 2004] and tolerance mechanisms [i.e., tolerogenic DCs and T-reg cells (Groux et al., 2004; O’Garra and Vieira 2004)], which are involved in maintaining the active anti-inflammatory or suppressive state, aside from immuno-surveillance, for the microbes ‘trespassing’ in the local mucosal tissues (Khoo et al., 1997). For example, non-pathogenic Gram-positive bacteria can induce the expression and activation of PPAR- to down-regulate the inflammatory response locally. Further, it has recently been suggested that P. gingivalis-LPS may act as an APC inactivator, rather than a stimulator, regarding immune co-stimulation (Cohen et al., 2004), and, as a result, the key effector function of the subsequent TLR-mediated activation of the T-cell response is to block T-reg-mediated suppression (Pasare and Medzhitov, 2004), thus helping them ‘escape’ from the immune system associated with the microbially infected lesions/sites. Although these phenomena may explain that TLR-induced cytokines produced by DCs render antigen-specific T-cells unresponsive to T-reg-mediated suppression (Pasare and Medzhitov, 2003), other mechanisms may exist, such as: (i) non-specific T-cell stimulation by various bacterial lipoproteins; and (ii) both types I and II IFN cytokines, produced via the STAT-4 signaling pathway during T-cell activation, without the involvement of T-reg in vivo (Nguyen et al., 2002; Sobek et al., 2004).
All PAMP (i.e., TLRs) are not equal in their signaling ability. Potential cross-talks with different TLRs or other cell receptors may act to modify the primary innate and subsequent adaptive immune responses generated (Agrawal et al., 2003; Re and Strominger, 2004; Underhill and Gantner, 2004). Thus, depending on the nature of the infection and its microbial components, different cell types in various locations/niches (i.e., more supragingival tissue associated with ‘gingivitis’ and more subgingival tissue associated with ‘periodontitis’) will likely have different impacts on the activation of signaling cascades via different adapters (or co-factors) and consequently affect not only the course but also the outcome/balance of host-parasite interactions in the periodontium. Furthermore, molecular analyses with valid and representative in vivo models would be required to clarify the relationship of ‘critical’ microbial components to ‘specific arms’ of the innate vs. adaptive host defenses, which may explain the existing differences or conflicts in the immune responses to different microbial strains, including differences due to host genetic backgrounds, various cell types involved, different routes of infection, the developing repertoire of innate and adaptive immunity, and the key signaling transducers and adapters for effector functions. Based on the preliminary data from a recent study by Dixon et al.(2004), it was recently shown, in a comparison of germ-free vs. conventionally reared mice, that ‘commensal flora’ colonized in the oral cavity can indeed influence host innate cytokine IL-1ß expression at both mRNA and protein levels in the ‘healthy’ periodontal tissues. Furthermore, do commensal and/or opportunistic species remain avirulent and non-hostile, and then become virulent and pathogenic in the periodontal-oral tissues under different steady-state or stress conditions? These questions await answers and continue to challenge oral biologists to explore and understand host-microbial interactions in the periodontium.
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(II) HUMORAL IMMUNITY IN THE PERIODONTIUM |
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The established effect of immune protection mediated by humoral immunity in periodontal infection came from the studies of B-cell-deficient mice, where higher amounts of periodontal bone loss or abscess formation were detected in vivo post-inoculation with either A. viscosus and P. gingivalis or mixed anaerobic micro-organisms (Klausen et al., 1989; Hou et al., 2000b). Later, two separate, independent, studies of the immunodeficient SCID and NOD/SCID mice showed the same results, i.e., that B-cell-mediated humoral immunity did not play a significant role in pathogen-induced alveolar bone destruction in vivo (Baker et al., 1994, 1999b; Teng et al., 2000; Teng, 2003). Many studies have clearly shown that Abs can effectively inhibit bacterial colonization in gingival crevices (see Table for examples of Ig-mediated immune protection), and that B-cell deficiency is strongly associated with higher susceptibility to bacterial infections following both primary and secondary immune responses (Teitelbaum et al., 1998; Hou et al., 2000b; Mittrucker et al., 2000). However, most of the human clinical and animal studies have shown that serum Abs titers do not correlate well with the clinical stages of periodontal infection and alveolar bone loss (Ebersole and Taubman, 1994; Genco et al., 1994; Baker et al., 1999a; Albandar et al., 2001; Ebersole et al., 2001; Ebersole, 2003). As a result, this ‘crippled or degenerated’ protection may tip the balance to a more destructive process during disease pathogenesis. Thus, humoral B-cell immunity and Abs can contribute to the initial control of periodontal infections in the mucosa, but, in most situations, are unable to complete the task without the help of T-cell-mediated immunity (for review, see Teng, 2003).
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, and iNOS or other Th cytokines, but not in mice deficient in CD8+ T-cells (Yuan et al., 1997; Beenhouwer et al., 2001; Rivera et al., 2002). It has been shown recently that coupling a mAb to Streptococcus mutans for mucosal immunization results in alteration of the Ab isotype distribution, the amount of expression, and the specificity detected when compared with those in mice immunized with the bacterium alone, suggesting that antigen-Ab complexes may be able to regulate their own Ab immunity and host inflammatory response (Rhodin et al., 2004). This has also been found to be the case when, in vivo, a mAb against P. gingivalis HagA was coupled to a bacterial vaccine-induced mucosal immunization strategy for studying immune protection (van Tilburg et al., 2001). Thus, the protective Ig response against microbial infections may be dependent upon T-cell-mediated immunity; yet, in this regard, currently there are no obvious rules to determine any immune vs. pathogenic characteristics among all microbes. A separate study by Maitta et al.(2004) suggests that human-VH gene usage may influence the development of the antigen-Ab specificity and efficacy associated with the susceptibility and resistance to cryptococcal infection in vivo. Interestingly, it was also shown that co-administration of non-protective Abs can reduce the efficacy of the protective ones, probably due to the competition or biological avidity encountered (Nussbaum et al., 1996). This phenomenon may explain why, for certain micro-organisms, such as P. gingivalis or A. actinomycetemcomitans, it has been difficult to seek or acquire totally effective Ig treatment, since the microbes stimulate both ‘protective’ and ‘non-protective’ Ig immune responses in vivo (Ebersole et al., 2001). Nevertheless, analysis of the data in the periodontal literature suggests, as a general mechanism, that effective Ig protection depends on intact T-cell-mediated immune responses. Humoral Ig response is known to be able to modulate the tissue inflammation associated with cell-mediated immunity, including the complement-mediated pro-inflammatory response, FcR-mediated phagocytosis, which alters the release of cytokines and chemokines and antigen presentation functions (for review, see Casadevall and Pirofski, 2003). Further, it has been recently suggested that some Abs (i.e., both IgM and IgG) can induce an anti-inflammatory effect (Bayry et al., 2003), probably through a differential modulation of FcR stimulation or inhibition by different Ab isotypes or (antigen-Ab)/complexes (Samuelsson et al., 2001; Underhill and Gantner, 2004; van Mirre et al., 2004). This has been suggested to occur in some anti-viral, -fungal, and -bacterial LPS Ab immune responses (Wright et al., 1991; Sutterwala et al., 1998; Kang et al., 1999; Su et al., 2001). A special bi-phasic mAb specific to P. gingivalis hemagglutinin domain and human FcR1 was shown to enhance PMN clearance of the periodontal pathogen in vitro, but whether this is mediated via in vivo anti-inflammatory and protective effects is not clear (Kobayashi et al., 2004). Currently, there are very few data to describe or support the effects and mechanisms of humoral Ig immunity regarding its dependent or independent anti-inflammatory and/or pro-inflammatory properties during periodontal infection in vivo. Understanding how Ig immunity and the in vivo net effects of the antigen-Ab complex induce or modulate the local tissue’s inflammatory state during the course of periodontal pathogenesis will greatly enhance our capability of developing better protective Ig therapeutics and vaccine designs for treating human inflammatory periodontal disease.
(B) A Future Perspective for Periodontal Humoral Immunity
There have been considerable interest and efforts in generating protective or effective mAbs as potential vaccines in treating P. gingivalis infection (i.e., Booth et al., 1996; Katoh et al., 2000; Hosogi et al., 2001; Ross et al., 2001; Yonezawa et al., 2001; DeCarlo et al., 2003; Kaizuka et al., 2003; Tsurumi et al., 2003; Gibson et al., 2004; Kobayashi et al., 2004) than with any other periodontal pathogens (see Table). However, there is presently no mAb or Igs available to study the potential effects or therapeutic efficacy associated with A. actinomycetemcomitans infection in the periodontium, although a few potential targets have been suggested (Cao et al., 2004). (Note that peptide-based immunogens and protein immunizations are not discussed in the present review.)
There have been debates about the identification of the ‘immunodominant epitopes/antigens’ (i.e., small numbers of B- or T-cell epitopes expressing efficient or regulatory activity to that particular antigen for the primary immune response) for any given periodontal pathogen (Podmore et al., 2001), and the search for the right ‘protective’ mAbs against virulence factors or antigens as potential vaccine candidates continues. Yet the power of neutralizing mAbs to treat infectious diseases, including periodontal infection, cannot be overlooked, since the recent development and construction of human single-chain variable fragments (scFv) and human-type mAbs capable of neutralizing virulence factors/antigens have shown promise for future applications (e.g., Abiko, 2000). Therefore, with more advances in engineering the protein display for Ab screening, DNA plasmid and vaccine technologies, effective control of humoral Ig-induced T-cell-mediated immunity and associated anti-inflammatory effects in vivo, there will be some new applications developing from the older scheme of ‘passive’ immunotherapy, where passive may not be as passive in the near future.
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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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