Several of the features described for the Established Lesion will persist at this stage. Plasma Cells continue to be the predominant cell type within the inflammatory infiltrate. Further destruction of collagen subjacent to the junctional epithelium is seen, with fibrosis at distant sites. A prime characteristic of the Advanced Lesion is the extension of the lesion into the periodontal ligament and supporting bone. The resulting outcome is bone loss that is exhibited as clinical attachment loss and pocket formation. The mediators of inflammation that have been identified as playing a significant role in alveolar bone resorption include interleukin-1β, interleukin-6, Tumor Necrosis Factor-α (TNFα), and Prostaglandin E2. Every cell involved in the immune response is capable of secreting these molecules. In addition, each of these mediators has been shown to increase in periodontitis sites compared to sites displaying gingivitis or health. The newest area of investigation involves the Receptor Activator of Nuclear Factor κB Ligand, (RANKL) and its decoy receptor, osteoprotegerin. The role of RANKL will be discussed in the following section on Osteoimmunology.