Monocyte Modulation in LAgP

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DESCRIPTION (provided by applicant): Localized Aggressive Periodontitis (LAgP) is an inflammatory disorder of the periodontal tissues that primarily affects molars and incisors. LAgP is an infectious disease and has been linked to several oral pathogens, most notably Actinobacillus actinomycetemcomitans (Aa) and Porphyromonas gingivatis (Pg). However, the host response contributes to disease progression and may dictate the pattern and severity of the disease. Several lines of evidence suggest that LAgP monocytes exhibit a unique phenotype. For example, these cells exhibit exaggerated responses to gram negative LPS, reduced catabolism of the bioactive lipid platelet-activating factor (PAF), and produce soluble mediators that enhance the lgG2 antibody response, while non-periodontitis (NP) subjects monocytes do not have these effects. Although both LAgP and NP monocytes differentiate into monocyte-derived dendritic cells (DC), a higher percentage of LAgP monocytes undergo this process, suggesting that monocyte differentiation in LAgP is skewed to the DC phenotype. Based on these observations, we hypothesized that the gene expression profiles of LAgP and NP monocytes would differ and used microarray analyses to address this question. Our preliminary studies indicate that >600 genes are differentially expressed in the two groups of monocytes. Many of these are associated with innate and adaptive immunity, including genes involved in Th1/Th2 responses, chemotaxis, antigen presentation, and interferon signaling. Thus, these initial microarray experiments have provided us with several "leads" that will help in the further characterization of LAgP monocytes, their roles in the immune response against oral pathogens, and how their biology might both promote immunity and permit these chronic infections to persist. We now propose to use more quantitative methods to accurately compare gene expression in LAgP and NP monocytes. In addition, biological assays will be performed to assess the functional consequences of the changes in gene expression. It is possible that the LAgP monocyte phenotype is strictly related to the genotype of LAgP subjects. However, oral bacteria can modulate monocyle biology, suggesting that interactions between LAgP monocyles and Aa or Pg could generate the changes in gene expression. To address this issue. NP monocytes will be cultured together Aa or Pg and the microarray approach will be used Io compare gene expression profiles in these cells to NP monocytes that have not been exposed to bacteria. Together; these studies should provide us with a clearer understanding of host-pathogen interactions in LAgP and potentially with mechanisms for modifying these interactions and thereby controlling this chronic infectious disease.