Autoimmune diseases, including OLP, have multifactorial pathogenesis. Genetic, hormonal and environmental factors seem to play a role in the development of diseases. Physical and emotional stresses are the main environmental factors in etiology of autoimmune diseases[16]. The two main hormonal pathways that are activated in response to stress alone or together are the Hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic nervous system (SNS). The SNS activation directly and indirectly releases epinephrine and norepinephrine through adrenal medulla[17]. Several studies have shown a positive and significant relationship between psychogenic stress and OLP[18-21], while others did not find a meaningful relationship [22, 23]. The adrenergic receptors bind to the catecholamines secreted in response to stress, and lead to their effects in various cells of the body. Change in the level and/or the type of expressed receptor on the cell surface plays an important role in the etiopathogenesis of the disease[17]. Based on the results of this study, the levels of α1- and β1-adrenergic receptors were significantly higher in unstimulated saliva of OLP patients compared to control group. In addition, the stimulated and unstimulated salivary flow rates were significantly lower in OLP patients to controls. Various types of autoimmune diseases such as rheumatoid arteritis, systemic lupus erythematous can be associated with dysfunction of salivary glands (regardless of the presence or absence of Sjogren's syndrome)[24]. The occurrence of hyposalivation as a common finding in OLP patients have been confirmed in various studies [4-7, 24, 25]. The autonomic nervous system has a critical role in the secretion of saliva. The β-receptor, mediated by cAMP, has high and very high performance in protein and mucin concentrations of saliva respectively. The stimulation of these receptors leads to low, foamy and viscous saliva. Stimulation of α-receptors leads to increased protein concentrations due to the induction of intracellular Ca2+. The α-receptors have low effect on volume, mucin and viscosity of the saliva[14]. In pathogenesis of autoimmune diseases, including OLP, chronic stress and increased SNS tone seems to be involved in reducing the salivary flow rate by increasing salivary mucin production (β1-adrenergic receptor), increasing protein secretion (α1- and β1-adrenergic receptors), vasoconstriction and decreasing blood supply of salivary gland parenchyma. Although the increase in salivary protein components can increase partially the salivary volume, but elevated salivary concentrations and viscosity highly decline the salivary flow rate (volume/min). As we know, the salivary flow rate is the main criterion to evaluation of hyposalivation, not the volume of saliva. The changes in the quality of saliva (increased mucin and protein) are one of the most effective factors in the development of xerostomia even in cases where the patient has no hyposalivation[13]. The high production of protein in the secretory cell requires a lot of energy and leads to stress in the endoplasmic reticulum (ER). The secretory cell response to ER stress by activating hypoxic signals, producing reactive oxygen species (ROS), autophagy, and cell death through internal apoptotic processes. This phenomenon, if chronic, leads to less secretion units in the salivary glands, resulting in reduced saliva production. During apoptosis, the production of inflammatory cytokines, such as IL-6 and type-1 IFNs, and the release and secretion of endogenous antigens and chaperon proteins via apoptotic buds of salivary cells can even be involved in the pathogenesis of OLP[16].
Despite the lack of previous studies on the correlation between adrenergic receptors and OLP pathogenesis, down regulation of muscarinic receptors in OLP patients have been confirmed [25]. It seems that the main role in reducing the salivary flow rate in the OLP patients is due to upregulation of SNS and downregulation of PNS. These two systems are not antagonists to each other in salivary secretion, but function together. The SNS has synergistic effects on secretory cells receiving parasympathetic fibers[9, 14]. It should be noted that the variable concentration of norepinephrine during SNS stimulation can differently stimulate the α1- and β1-adrenergic receptors[26]. In the present study β1-adrenergic receptor in the unstimulated saliva significantly increased and decreased in the stimulated saliva among the OLP patients. Several studies have also shown the contradictory effects of adrenergic agonist and antagonist drugs on the salivary flow rate [27-29]. Also lowering entrance of sympathetic nerve fibers to the parotid gland in comparison with other major salivary glands that cause to less expression of adrenergic receptors on the surface of the secretory cells of parotid gland [13], stimulation of saliva secretion through chewing instead of taste triggers that cause to preferably stimulation of PNS to SNS and more time opportunity for the exchange of acinar cells and ducts in unstimulated saliva to stimulated saliva [10, 16] justify lower levels of adrenergic receptors in the stimulated saliva compared to the unstimulated saliva in both control and OLP groups. Upregulation of salivary adrenergic receptor in OLP patients, probably source both receptors in the secretory cells of salivary gland and elevated level of these receptors in blood cells. However, this phenomenon has not yet been investigated in the OLP patients, such Studies have shown increased expression of the α1-adrenergic receptor in peripheral blood mononuclear cells (PBMCs) during chronic inflammation in patients with juvenile RA, which led to an increase in IL-6 levels in these patients. These receptors are not expressed normally on the surface of the PBMCs [29-31]. Another study revealed that the adrenergic receptors on the surface of immune cells shifted from β2 to α1 in autoimmune diseases [29]. In healthy condition SNS, balance the pre-inflammatory and anti-inflammatory responses by stimulating different receptors. Chronic stress in genetically susceptible individuals led to an imbalance in the levels of adrenergic receptors on the surface of the immune and salivary cells that can be effective in reduced salivary flow rate and pathogenesis of autoimmune diseases such as OLP.