Delineation of the Role of Platelet-Activating Factor in the Immunoglobulin G2 Antibody Response

Abstract

Localized aggressive periodontitis (LAgP) is a chronic inflammatory disease characterized by severe destruction of periodontal tissues surrounding the first molars and incisors. LAgP subjects produce large amounts of immunoglobulin G2 (IgG2) antibody against oral pathogens, and this response is inversely correlated with the severity of disease. We previously demonstrated that platelet-activating factor (PAF) is required for optimal IgG2 responses. The present investigation was designed to determine the mechanism of IgG2 induction by PAF. Exogenous PAF acetylhydrolase suppressed approximately 80% of pokeweed mitogenstimulated IgG2 production, confirming that PAF is essential for optimal responses. PAF-activated leukocytes produced gamma interferon (IFN-␥), a Th1 cytokine that has been associated with IgG2 responses in previous studies. The monocyte-derived cytokines interleukin-12 (IL-12) and IL-18 are upstream of IFN-␥ production, and IgG2 production was suppressed by neutralizing antibodies against these proteins. In addition, PAF induced monocyte-derived dendritic cells (DC) but not macrophages (M⌽) to secrete IL-12 and IL-18. This observation was interesting because monocyte differentiation in LAgP subjects is skewed to the DC phenotype. Although other investigators have implicated IFN-␥ in IgG2 production, its precise role in this response is controversial. Our studies suggest that IFN-␥ induces isotype switching to IgG2 but only in concert with the Th2 cytokine IL-4. Thus, it appears that the unique PAF metabolism of LAgP monocytes or DC promotes Th1 responses that are essential for optimal IgG2 antibody production. As IgG2 antibodies opsonize oral bacteria and promote their clearance and destruction, these alterations in PAF metabolism may be essential for limiting disease severity in LAgP patients.

Boosting Adaptive Immunity: A New Role for PAFR Antagonists

“…This last assumption was supported by the augmented Tbet expression in PAFR-KO splenocytes: the Tbet transcription factor is related to Th1 cell differentiation, which controls the production of IFN-γ (the Th1 hallmark cytokine) in T cells, but its expression is also required for IgG2a IFN-γ-mediated class switch recombination in B cells2122. IFN-γ has also been shown to induce IgG2 class-switch in B cells when acting in synergy with the Th2 cytokine IL-4, and PAF was found to boost IFN-γ production by primary lymphocytes23. In this work, the authors suggest that the effect of PAF to promote IgG2 switch is not directly on B cells but rather on accessory cells, which would indirectly mediate this isotype production.…”

Oral mucosal dendritic cells and periodontitis: many sides of the same coin with new twists

“…Recent studies make a compelling case for the role of dendritic cell infiltration and response to the oral microbiota in periodontal disease pathogenesis (3,4,13,24,30 , 33 , 45 , 62 , 63 ,65,72,73, 90). Accordingly, this review will focus on how dendritic cells can mediate periodontal disease pathogenesis, including: (i) expression of mediators of recruitment and trafficking of dendritic cells and other inflammatory cells in and out of the tissues; (ii) pattern recognition by dendritic cells, leading to activation / maturation of dendritic cells and stimulation of an inflammatory T-cell response (or inhibition of dendritic cell maturation, leading to immune suppression); (iii) formation of semi-organized lymphoid aggregates, or oral lymphoid foci in the gingival lamina propria, first described in 2001 (65); and (iv) the potential ability of some dendritic cell subsets to directly develop into osteoclasts, thereby serving as osteoclast precursors.…”

Granulocytes as modulators of dendritic cell function

“…Moreover, TSLP-activated DCs were shown to increase OX40L expression, provide sustained proliferation and survival signals for naive CD4 + T cells, favor Th2-permissive microenvironments, and promote Th2 memory cell responses [117,132,133]. PAF receptor expression was shown on human moDCs, and its activation was associated with directional DC migration and IL-12 and IL-18 release [134,135]. As such, basophil-derived soluble factors may profoundly influence DC function, although ample evidence for direct DC-basophil crosstalk is still lacking.…”