*4.1. Candida Infection Affecting Salivation*

In the early stages of oral candidiasis, *Candida* attaches to the oral mucosa and begins to multiply [64, 70]. Several proteins, such as secretory IgA, lactoferrin, histatins, and defensins, downregulate adhesion and multiplication of *Candida* [10,71–73]. Among the proteins, histatins and defensins are particularly effective as antifungal factors, which are produced in epithelial cells and salivary glands [74]. Histatins 1, 3, and 5 are present within saliva, accounting for about 80% of total salivary histatins [75]. Human β-defensin-1 was isolated from both the major and minor salivary glands, especially from ductal cells and not acinar cells [76]. Therefore, when salivation or the antifungal agent levels of saliva are reduced, oral microbial hyperproliferation is permitted and oral candidiasis can more easily manifest [73].

Salivary flow showed a significantly negative correlation between stimulated salivary flow rates and *Candida* colony-forming units (CFUs) in the patients with xerostomia [77]. This trend also appeared in patients with reduced salivation after radiation therapy [78]. Antifungal therapy for candidiasis patients can expect to relieve pain, redness, and oral mucosa atrophy. Notably, antifungal therapy often increases the amount of saliva by removing *Candida*. A clinical study investigated the effects of *Candida* elimination on stimulating whole salivary flow rate [79]. The patients with successful elimination of *Candida* showed significantly increased stimulated whole salivary flow rate, whereas patients with unsuccessful elimination of *Candida* did not show increased stimulated whole salivary flow rate. Sympathetic stimuli, like acute pain and stress from *Candida* infection, can reduce salivary flow rate. In other words, parasympathetic stimuli result in increased saliva flow rate; on the other hand, sympathetic stimuli result in more viscous saliva secretions [24,80]. On the basis of this evidence, researchers have suggested that the increased stimulated whole salivary flow rate after treatment was the result of reduced sympathetic stimulation by oral pain reduction [79]. The study states that a decrease in sympathetic stimulation could lead to changed watery salivary secretion. However, 13.5% of the patients with successful elimination of *Candida* did not show increased stimulated whole salivary flow rate [79]. The unrestored salivary flow rate may be a result of salivary gland destruction from the *Candida* infection, and the salivary glands could not restore function even after successful *Candida* treatment [20,62].

#### *4.2. Candida Infection and Host Immune Response*

Oral *Candida* infection on salivary glands causes host immune responses by activation of T lymphocytes. The T cells mediate inflammation by stimulating the production of inflammatory cytokines, such as TNF-α, IL-1ß, and IL-6. These T cells also stimulate the production of inflammatory chemokines and recruit neutrophils and macrophages. The rapid and localized induction of these cytokines form the first line of defense that limits the transmission of invading *Candida*. However, recurrent or chronic infections can provide an elevated inflammatory environment, leading to organ dysfunction [81]. TNF-α and IL-1ß play well-known roles in the pathogenesis of chronic inflammatory diseases. These cytokines may affect salivary gland damage [82–84]. The role of these cytokines in the etiology has been determined experimentally in Sjögren's syndrome with dry mouth [85]. TNF-α suppresses the transcription of Aquaporin-5 and destroys human salivary gland acinar cells. Aquaporin-5 is critical for saliva production and a specific channel protein found in the acinar cells that allows for rapid transcellular migration of water in response to an hydrostatic/osmotic pressure gradient [86,87]. There is a cycle of destruction where *Candida* causes immune mediated salivary gland destruction, following reduced salivary flow and consequent *Candida* infection.

#### **5. Diagnosis of Oral Candidiasis**
