**4. Conclusion**

*Periodontal Disease - Diagnostic and Adjunctive Non-surgical Considerations*

When the inflammatory response becomes chronic, the lymphocytes of the adaptive immune system invade the periodontal tissues releasing inflammatory and immune molecular mediators, which alter the balance of bone metabolism, marking the transition from gingivitis to periodontitis [29]. The activation of lymphocytes requires two types of signals: a signal induced by the antigen receptor itself when recognizing its related antigen and a costimulatory signal by professional antigenpresenting cells (APCs) [22]. In gingivitis, the predominant APCs are CD14+

dendritic cells. While in the periodontitis, the predominant APCs are CD19+

B lymphocytes [38]. Therefore, the activation of adaptive immunity

RANKL is a cytokine member of the TNF family that can be bound or secreted to the membrane and stimulates the differentiation of osteoclasts, cell fusion, and activation that leads to bone resorption [40, 41]. Osteoblasts and stromal cells of the bone marrow predominantly express RANKL bound to the membrane, which induces osteoclastogenesis through cell contact with osteoclast precursors. Likewise, activated T and B cells produce both the membrane-bound and soluble RANKL forms. Soluble RANKL can induce osteoclastogenesis independently of direct contact between infiltrating lymphocytes and osteoclast precursors on the bone surface. However, 17 T-helper cells expressing RANKL, but not T-helper 1 cells, activate osteoclasts also by direct cell-cell contact [42]. In the alveolar bone, the RANKL/OPG/RANK system controls the balance of the bone metabolism [43]. RANKL is the osteoclasts activator and the molecular signal directly responsible for the bone resorption, which interacts with its associated receptor RANK on the surface of osteoclast and osteoclast precursors, which triggers its recruitment on the bone surface and cell fusion and activation [44]. Osteoprotegerin (OPG) is a soluble protein that has the ability to block the biological functions of RANKL by competitive inhibition [45]. In periodontitis, the increase in RANKL/OPG promotes the recruitment of osteoclast precursors, their

has a great influence on the bone loss in periodontitis, associated with B and T lymphocytes, since several studies have shown that these cells are the main cellular sources of activator of the κB ligand receptor of the nuclear factor (RANKL) during

fusion, and subsequent activation, leading to bone resorption [46].

cytes are capable to tilt bone metabolism favoring bone resorption [50].

On the other hand, Th1 lymphocytes have a fundamental role in the establishment and progression of periodontitis, through the increase of IFN-γ levels [18]. Studies have shown that mice IFN-γ-deficient showed low levels of inflammatory cytokines and chemokines, as well as macrophages infiltrated in periodontal tissue, developing a less severe phenotype of alveolar bone destruction [47]. IL-1β and TNF-α are cytokines secreted by Th1 lymphocytes. TNF-α and IL-1β produce vasodilation, stimulate the activation of endothelial cells to increase the recruitment of immune cells, increase the chemokines production in most cell types, participate in the activation of neutrophils, and stimulate secretion and tissue activation of MMPs, among other functions. Although neither IL-1β nor TNF-α is directly involved in the stimulation of bone resorption, they indirectly promote bone destruction by stimulating sustained inflammation of the periodontal tissue [48]. Th2 lymphocytes are the main cellular source of IL-4, which promotes the change of class to the secretion of IgE in B cells and favors the alternative activation of macrophages in an IFN-γindependent pathway. These effector functions of the Th2 lymphocytes negatively regulate the inflammatory and Th1 lymphocyte responses, so that the polarization of a Th2-type immune response in periodontitis may represent a damaged adaptive immune response [18, 49]. Finally, RANKL can also be secreted by Th17 lymphocytes, which in cooperation with inflammatory cytokines derived from Th1 lympho-

and

*3.2.2 Adaptive immune response in periodontal disease*

**10**

CD83<sup>+</sup>

and CD83+

periodontal inflammation [39].

The main etiological factor of periodontal disease is the bacteria, which are capable of activating the innate immune response of the host inducing an inflammatory response. The evolution of this inflammatory response culminates in the destruction of periodontal tissues. For this reason, it is important to understand the different molecular and cellular mechanisms of the pathogenesis of periodontal disease, with the purpose of making an opportune diagnosis and appropriate treatment and prognosis.
