## 1 Introduction  
As the prevalence of orthodontic malocclusion and the need for treatment increases, more and more patients are indicated for orthodontic treatment with fixed orthodontic appliances (brackets). These appliances are composed of metal alloys of nickel (Ni), cobalt (Co), chromium (Cr), titanium (Ti), iron (Fe), and copper (Cu) [1]. During mastication, pressure and temperature fluctuations and electrochemical reactions with nutrients in the mouth cause the release of metal ions into saliva and, if these processes last for a longer time, they create a medium for long-term corrosion [2]. Research has shown that fixed orthodontic appliances release nickel and chromium ions into saliva through electrochemical decomposition, which leads to the production of free radicals and chemical changes in the DNA base [3]. Nickel and its compounds form arsenic and sulfide complexes, which are known allergens, mutagens, and carcinogens [4]. These ions can penetrate the mucous membrane and activate epithelial cells, which produce various cytokines or chemokines. An immune response is then triggered, during which antigen and T cells are activated. Some cytokines activate antigen-presenting cells, such as Langerhans cells or dendritic cells. The activated antigens migrate to the lymph nodes, where they release allergens to T cells. Subsequent re-exposure to the same allergen triggers the activation of specific T cells, which subsequently enter the bloodstream and cause visible signs of hypersensitivity after 48-72 h. However, the exact molecular mechanisms that mediate the interaction between epithelial and immune cells in nickel allergy are unknown [5, 6].  
Epidemiological studies have found hypersensitivity reactions to nickel and chromium, with 15.7% of the population being allergic to metal in general, 14.5% of the population being specifically allergic to nickel, and 0.8% being specifically allergic to chromium. hypersensitivity to nickel is found in many countries around the world, with varying frequencies of sensitivity, but the risk of developing allergies remains high [6]. Allergic sensitivity to chromium is lower than that to nickel, but studies have shown that hypersensitivity reactions to chromium occur in about 10% of men and 3% of women [4; 7]. The most common oral pathologies associated with nickel allergy are gingivitis and desquamative oral lesions, as well as complaints, such as a burning sensation, a metallic taste in the mouth, and pain, mostly related to the release of nickel and chromium ions from fixed orthodontic appliances [8; 9; 10; 11].  
In recent years, there has been a debate about the influence of metals in fixed orthodontic appliances (brackets) on allergic reactions. Clinical studies are being conducted in order to assess the release of nickel and chromium ions from fixed orthodontic appliances, the intensity of the release of the ions, the changes in the levels of the ions during orthodontic treatment, and the relationship between the levels of chromium and nickel ions and changes in the health status of patients [12]. The nickel and chromium content of saliva is usually measured using an atomic absorption spectrometer by taking saliva samples before orthodontic treatment and at specific time points during the treatment period (from 1 month to 1.5 years). Many studies have been conducted in the past, but not all researchers have agreed that nickel and chromium ions released from brackets have an effect on human health. However, the absence of summarized evidence in the literature concerning the effect of metal ions leaves considerable uncertainty. Hence, the present systematic literature review was conducted in order to evaluate and present the newest information about the influence of nickel and chromium ions in saliva in patients with fixed orthodontic appliances (brackets). Manufacturing and brand-related metallurgical features of the brackets are ignored.