Project 3: Monocyte derived lipid mediators and cytokines in regulating IgG2 production in early-onset periodontitis (EOP). Patients with EOP frequently have elevated levels of serum IgG2, and patients with high levels of IgG2 reactive with the EOP pathogen A. actinomycetemcomitans have less severe disease. The ability to produce elevated levels of IgG2 is reproducible in vitro using peripheral blood leukocytes (PBL). Further analysis supports the concept that high IgG2 responses in PBL from EOP patients are regulated by monocytes. Recent data indicates that soluble factors produced by monocytes have the IgG2 enhancing activity. These results prompt the hypothesis that the profile of monocyte-derived cytokines and/or lipid mediators from EOP patients are altered and that the adjusted levels of these soluble factors are responsible for increased production of serum IgG2 in EOP. These results prompt the hypothesis is that the profile of monocyte-derived cytokines and/or lipid mediators from EOP patients are altered and that the adjusted levels of these soluble factors are responsible for increased production of serum IgG2 in EOP. Preliminary data indicated that antibodies against the IL- 1beta, IL-6, IL-18 and IL-12 inhibit IgG2 production. Similarly, receptor inhibitors for platelet activating factor (PAF) or inhibitors of prostaglandin E2 (PGE2) synthesis dramatically reduced the production of IgG2. Furthermore, addition of PAF, of PG32 selectively increased IgG2 production in culture whereas addition of IL-1alpha inhibited IgG2 production. Interesting, recent data from our group indicates that genes involved in determining the type and among of IL-1 made appear to be associated with the risk of developing EOP. Moreover, we recently found a subpopulation of cells spontaneously emerging in 3 to 5 days cultures of monocytes from LIP with the morphological features of dendritic cells (DC) and DC promote IgG2 production. In short, the monocyte/macrophage/DC products: IL-1alpha, IL-1beta, IL-6, IL-12, PGE2, and PAF all appear to influence production of IgG2 and some appear to selectively regulate IgG2: We now propose to confirm and extend these results using both PWM and specific antigen to elicit IgG2 production in an effort to determine the factors involved in monocyte/macrophage DC-mediated regulation of IgG2 responses. A better understanding of IgG2 production in an effort to determine the factors involved in monocyte/macrophage/DC-mediated regulation of IgG2 responses. A better understanding of IgG2 responses may lead to better control of EOP and other diseases where IgG2 plays a critical role in host defense.