Tibor Károly Fábián

There are numerous defense proteins present in the saliva. Although some of these molecules are present in rather low concentrations, their effects are additive and/or synergistic, resulting in an efficient molecular defense network of the oral cavity. Moreover, local concentrations of these proteins near the mucosal surfaces (mucosal transudate), periodontal sulcus (gingival crevicular fluid) and oral wounds and ulcers (transudate) may be much greater, and in many cases reinforced by immune and/or inflammatory reactions of the oral mucosa. Some defense proteins, like salivary immunoglobulins and salivary chaperokine HSP70/HSPAs (70 kDa heat shock proteins), are involved in both innate and acquired immunity. Cationic peptides and other defense proteins like lysozyme, bactericidal/permeability increasing protein (BPI), BPI-like proteins, PLUNC (palate lung and nasal epithelial clone) proteins, salivary amylase, cystatins, prolin-rich proteins, mucins, peroxidases, statherin and others are primarily responsible for innate immunity. In this paper, this complex system and function of the salivary defense proteins will be reviewed.

Spondyloarthropathies consist of chronic inflammatory disorders genetically linked with each other through HLA-B27 molecules, and are connected with the destruction of periarticular bone and also with systemic bone loss in many cases. Expected molecular mechanisms behind these conditions overlap the functions of Hsp70s, a group of major molecular chaperones and cytokines. Hsp70s may control disease progression via inhibition of unfolded HLA-B27 protein accumulation and alteration of ER stress signaling. Further, Hsp70s may improve disease related malfunction of antigen presentation, and may induce nitric oxide (NO) release from macrophages which probably protective against spondyloarthropaties as well. Considering premised possible influence of Hsp70s on core mechanisms of spondyloarthropaties it may be expected that, increased expression of Hsp70s advantageously retards disease progress, or may lead to remission. On the other hand Hsp70s as danger signals induces the secretion of proinflammatory cytokines playing major role in the progression of spondyloarthropaty induced bone loss. Consequently, the effect of Hsp70s on the progression of spondyloarthropathic bone loss is "Janus-faced" in some respect: increase of Hsp70s' level is likely advantageous regarding to the core of disorder; but it may facilitate existing bone resorption processes.

Heat shock proteins of the 70kDa family (HSPAs/HSP70s) are major molecular chaperones and cytokines of most cells and microbes, extracellular and interstitial fluids, blood, synovial fluids and secretory body fluids like saliva. The induction of human HSPAs plays an important role at cellular level under most stress conditions; whereas microbial HSPAs improve microbial tolerance to environmental changes, and improve virulence and resistance against antimicrobial peptides. Extracellular HSPAs reveal cytoprotective properties and are involved in numerous physiological and pathological events, including modulation of cytokine release and immunity. Accordingly, HSPAs play a role in the maintenance of pulpal health, and the repair of injured dental hard tissues. HSPAs also play a role in stress adaptation of periodontal tissues, and in the maintenance of periodontal and mucosal health including defense against microbes, prevention of mucosal allergic reactions, and facilitation of healing of ulcers and wounds. Despite their advantageous effects maintaining health of several oral tissues, HSPAs are likely to play a role in the disadvantageous amplification of pulpal inflammatory response to bacteria, and in the formation of several periapical inflammatory lesions. HSPAs may also induce gingivitis under certain conditions, and play a role in the progression of periodontal bone defects. HSPAs may also play a role in atopic-type allergic reactions, autoimmune disorders, and haptenation in certain cases. Based on the above data, it can be assumed that HSPAs play an important role in oral defense under healthy conditions; however, their role is somewhat “Janus-faced” under pathological conditions.

The possible influence of fear of death and attitude toward death were studied related to dental anxiety in Hungarian elementary and secondary school subjects (n = 277; 114 males, 163 females; age between 8 and 18 years). Dental fear and anxiety scores were DAS: 10.8 +/- 3.6; DFS: 40.6 +/- 15.6; STAI-S: 38.0 +/- 11.0; STAI-T: 40.3 +/- 10.0. Lester's Attitude Toward Death Scale scores were 6.3 +/- 1.3. Girls scored higher on DAS, STAI-S, and STAI-T scales (P <= 0.05). Age influenced STAI-S, STAI-T, and Lester's Scale scores (P <= 0.05). Lester's Scale scores influenced the expectations of the subjects about the dental fear of their surrounding people (parents, brother, sister, friends) (P <= 0.05). A percentage of 7.22 of the subjects indicated a rather strong connection between dental fear and fear of death. These subjects had significantly higher dental fear and anxiety scores as compared to others (P <= 0.01). Death-related content was found in 4.3% of drawings and in 10.5% of free associations (couplings) related to teeth (in 12.6% either in drawings or in couplings). The appearance of death-related content was higher with higher age, and higher expected dental fear of surrounding people (P <= 0.01). Our data indicate a detectable influence of fear of death on dental fear, especially in subjects with higher dental fear scores.

Molecular chaperones were considered to be intracellular, but there is increasing evidence demonstrating their cytoprotective and immune modulator properties outside the cell. The major extracellular chaperone (Hsp70) was also found in saliva, indicating a possible effect of Hsp70 on mucosal surfaces. Here we summarize the immune-modulatory role of the 70-kDa stress protein family, with special attention on the potential impact of salivary Hsp70 on oral defense mechanisms. There are three major facets of Hsp70-induced immune activation: 1) the appearance of Hsp70 on the surface of certain tumor cells or virally infected cells, leading to their phagocytosis and subsequent lysis; 2) the role of extracellular uncomplexed Hsp70 as a danger signal, leading to the secretion of proinflammatory cytokines from antigen-presenting cells and T lymphocytes and of nitric oxide from macrophages as well as to complement activation; 3) receptor-mediated uptake of peptide-loaded Hsp70 to antigen-presenting cells and cross-presentation of the Hsp70-peptide complex as an antigen to cytotoxic T cells and natural killer lymphocytes. The immune-activating effect of salivary Hsp70 may also be highly important in oral defense, especially in areas where molecular and cellular participants of the immune response appear on the surface of the oral cavity (i.e. several lesions of the mucosa and the periodontal tissues).