## 4 Discussion
\begin{table}
\begin{tabular}{c c c c c c} \hline  & **Cut-Off** & **AUC (95\% CI)** & **Youden Index** & **Sensitivity\%** & **Specificity\%** & \(p\)**-Value** \\ \hline IL-6 & 8.576 pg/mL & 0.7083 & 0.5417 & 87.50 & 66.67 & 0.1968 \\ \hline IL-1\(\beta\) & 16.62 pg/ml & 0.7083 & 0.5833 & 75.00 & 83.33 & 0.1968 \\ \hline CRP & 218.4 pg/ml & 0.7083 & 0.5417 & 87.50 & 66.67 & 0.1968 \\ \hline \end{tabular}  
Significance level established at \(p<0.05\). Abbreviations: ROC—receiver operating characteristic; AUC—area under the Curve; CL—confidence interval; IL-6—interleukin:6; IL-1\(\beta\)—interleukin:19; CRP—C-reactive protein.  
\end{table} 
Table 5: ROC logistic regression analysis of salivary IL-6, IL-1\(\beta\), and CRP as potential diagnostic biomarkers for differentiating between children with a severe degree of PIG and those without plaque-induced gingival inflammation. pathogenic microflora in the children with a severe degree of gingivitis, which would have led to an increase in the severity of the inflammatory response, increased gingival inflammation, and increased production of inflammatory mediators, such as IL-6 and IL-1\(\upbeta\)[21]. The qualitative and quantitative content of plaque is different as a result of plaque maturation [29; 30]. The significant difference between moderate and severe PIG only seems reasonable because in patients with a low degree of PIG, host protective mechanisms (e.g., cell immunity) could still be not active enough. In patients with a moderate degree of PIG, the immunological mechanism differs from that of the severe form. The transition from a moderate to severe degree of gingivitis has been reported to be characterized by a shift from the innate immune response to the acquired immune response [31]. Macrophages, which predominate in the innate phase, have a reduced capacity for pro-inflammatory cytokine production compared to B-cells, which represent the acquired immune response [31]. We did not establish a statistical significance between IL-6, IL-1\(\upbeta\), and CRP levels in the control group and the group with a mild degree of PIG because the PIG in the latter group was characterized as an initial phase of plaque-induced gingivitis. This initial phase of PIG is characterized by the formation of so-called initial lesions, where the appearance of gingival inflammation is low and characterized by hyperemia and slight edema, without bleeding upon probing [32]. The observed cytokine levels in the saliva in our study were also low, and not statistically different compared to those of the control group. The innate immune mechanisms are active during this stage and cytokine production is very low. The rate of collagen destruction also is low [32]. The moderate degree of gingivitis is characterized by hyperemia, edema, provoked bleeding, and the formation of early lesions. The inflammatory cells which are involved in this stage are lymphocytes and macrophages. The collagen degradation rate is higher than that in mild-degree PIG but lower than in severe-degree PIG [32]. The observed lowest levels of IL-6, IL-1\(\upbeta\), and CRP in moderate-degree PIG could be due to the resolution of macrophages from M1 (classical) into M2 (alternative) phenotypes [33]. The M1 phenotype is the pro-inflammatory phenotype which is characterized by increased IL-6 production [34; 35]. The M2 phenotype is involved in tissue repair and is characterized by decreased IL-6 production [36; 37]. Probably, the anti-inflammatory M2 phenotype involved in active tissue repair is the distinctive immune response, a compensatory mechanism in moderate-degree PIG [36; 37]. This explains the lowest cytokine levels that were found in moderate-degree PIG. [PERSON] et al. (2019) discuss in their study the transition of macrophages from M1 to M2 phenotypes in patients with gingivitis and periodontitis. Interestingly, they also did not find statistically significant differences between the M1 and M2 polarization of macrophages in healthy tissues and tissues with periodontitis [33].