The adaptive immune system has evolved distinct responses against different pathogens, but the mechanism(s) by which a particular response is initiated is poorly understood. In this study, we investigated the type of Ag-specific CD4+ Th and CD8+ T cell responses elicited in vivo, in response to soluble OVA, coinjected with LPS from two different pathogens. We used Escherichia coli LPS, which signals through Toll-like receptor 4 (TLR4) and LPS from the oral pathogen Porphyromonas gingivalis, which does not appear to require TLR4 for signaling. Coinjections of E. coli LPS + OVA or P. gingivalis LPS + OVA induced similar clonal expansions of OVA-specific CD4+ and CD8+ T cells, but strikingly different cytokine profiles. E. coli LPS induced a Th1-like response with abundant IFN-γ, but little or no IL-4, IL-13, and IL-5. In contrast, P. gingivalis LPS induced Th and T cell responses characterized by significant levels of IL-13, IL-5, and IL-10, but lower levels of IFN-γ. Consistent with these results, E. coli LPS induced IL-12(p70) in the CD8α+ dendritic cell (DC) subset, while P. gingivalis LPS did not. Both LPS, however, activated the two DC subsets to up-regulate costimulatory molecules and produce IL-6 and TNF-α. Interestingly, these LPS appeared to have differences in their ability to signal through TLR4; proliferation of splenocytes and cytokine secretion by splenocytes or DCs from TLR4-deficient C3H/HeJ mice were greatly impaired in response to E. coli LPS, but not P. gingivalis LPS. Therefore, LPS from different bacteria activate DC subsets to produce different cytokines, and induce distinct types of adaptive immunity in vivo.

Previous studies have analyzed the lymphoid and myeloid foci within the gingival mucosa in health and chronic periodontitis (CP); however, the principal APCs responsible for the formation and organizational structure of these foci in CP have not been defined. We show that in human CP tissues, CD1a+ immature Langerhans cells predominantly infiltrate the gingival epithelium, whereas CD83+ mature dendritic cells (DCs) specifically infiltrate the CD4+ lymphoid-rich lamina propria. In vivo evidence shows that exacerbation of CP results in increased levels of proinflammatory cytokines that mediate DC activation/maturation, but also of counterregulatory cytokines that may prevent a Th-polarized response. Consistently, in vitro-generated monocyte-derived DCs pulsed with Porphyromonas gingivalis strain 381 or its LPS undergo maturation, up-regulate accessory molecules, and release proinflammatory (IL-1β, PGE2) and Th (IL-10, IL-12) cytokines. Interestingly, the IL-10:IL-12 ratio elicited from P. gingivalis-pulsed DCs was 3-fold higher than that from Escherichia coli-pulsed DCs. This may account for the significantly (p < 0.05) lower proliferation of autologous CD4+ T cells and reduced release of IFN-γ elicited by P. gingivalis-pulsed DCs. Taken together, these findings suggest a previously unreported mechanism for the pathophysiology of CP, involving the activation and in situ maturation of DCs by the oral pathogen P. gingivalis, leading to release of counterregulatory cytokines and the formation of T cell-DC foci.

The results of this study indicate the presence of a significant relationship between periodontitis, hyperlipidemia, and serum antibodies against P. gingivalis LPS that warrants further examination in a larger patient population. Furthermore, these studies indicate that elevated triglycerides are able to modulate IL-1beta production by PMNs stimulated with P. gingivalis LPS.

Periodontitis has been traditionally regarded as a chronic inflammatory oral infection. However, recent studies indicate that this oral disease may have profound effects on systemic health. The search for cellular/molecular mechanisms linking periodontitis to changes in systemic health and systemic physiology has resulted in the evolution of a new area of lipid research establishing linkages between existing multidisciplinary biomedical literature, recent observations concerning the effects of serum lipids on immune cell phenotype/function, and a heightened interest in systemic responses to chronic localized infections. There appears to be more than a casual relationship between serum lipid levels and systemic health (particularly cardiovascular disease, diabetes, tissue repair capacity, and immune cell function), susceptibility to periodontitis, and serum levels of pro-inflammatory cytokines. In terms of the potential relationship between periodontitis and systemic disease, it is possible that periodontitis-induced changes in immune cell function cause metabolic dysregulation of lipid metabolism through mechanisms involving proinflammatory cytokines. Sustained elevations of serum lipids and/or pro-inflammatory cytokines may have a serious negative impact on systemic health. The purpose of this paper is to present the background, supporting data, and hypotheses related to this concept. As active participants in this emerging and exciting area of investigation, we hope to stimulate interest and awareness among biomedical scientists and practitioners.

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