On one hand, resistant dogs develop a robust Th1 immune response, resulting in the production of proinflammatory cytokines, such as IFN- and TNF-, which limit the infection and associated inflammation by increasing the leishmanicidal activity of macrophages. a valuable tool in vaccine development and new immunotherapy strategies to prevent or control disease outcome. Keywords:canine leishmaniasis, circulating immune complexes, biomarkers, diagnostic,Leishmania infantum, vaccines == 1. Introduction == Leishmaniases are a group of parasitic diseases caused by different species of theLeishmaniaparasite. Among them, canine visceral leishmaniasis (CanL), caused byLeishmania infantum(L. infantum), is a global zoonotic disease that is potentially fatal for dogs and, due to its potential transmission, to humans. The role of dogs as the main vertebrate reservoir is well-established, making visceral leishmaniasis (VL) a prime example of the importance of embracing a One Health approach for efficient surveillance and control of canine and human disease [1,2,3,4]. In CanL, one of the main determinants for the establishment of the infection is the hosts BMS 299897 immune systems ability to control the parasite. Two well-recognized types of host immune response are induced as a consequence of infection. On one hand, resistant dogs develop a robust Th1 immune response, resulting in the production of proinflammatory cytokines, such as IFN- and TNF-, which limit the infection and associated inflammation by BMS 299897 increasing the leishmanicidal activity of macrophages. In contrast, susceptible dogs develop a systemic immune response dominated by Th2 cells, regulatory T-cells (Tregs) and regulatory B cells [5,6]. The cytokines released by Th2 cells, which include interleukins IL-4 and IL-13, and the activity of Tregs and regulatory B cells via IL-10, downregulates the protective Th1 immune response, promoting inappropriate humoral immune responses [7,8,9,10,11,12,13]. The uncontrolled concentration of antibodies and the presence ofLeishmaniaantigens induce the formation of circulating immune complexes (CIC) [14], composed of aggregatedLeishmaniaproteins, anti-LeishmaniaIgG and IgM and, to a lesser extent, complement system fractions [15]. Macrophages activated by these immune complexes inhibit IL-12 biosynthesis, and, therefore, IFN- production, and secrete high levels of IL-10 [16], thus impeding the establishment of cell-mediated immunity and reducing the macrophages ability to kill the parasite [14]. Macrophages lose their ability to eliminate immune complexes, resulting in a deposition of CIC in the vascular walls of specific organs that leads to inflammation and tissue BMS 299897 injury [14,17]. This deposition is responsible for some of the clinical manifestations of CanL [18], including glomerulonephritis, considered to be the most severe complication of CanL. It has variable clinical presentations, depending on the disease stage [12,14,19] and is the most frequent cause of renal failure and death. BMS 299897 CanL has a broad range of nonspecific clinical manifestations, ranging between subclinical, chronic and severe, sometimes reaching an acute stage that may kill the animal [20]. Therefore, the management of Rabbit polyclonal to BNIP2 CanL is complex, and it is important to establish a standardized clinical staging system [12,21]. Veterinarians should use information from multiple sources, such as clinical history; examination findings; clinicopathological abnormalities; molecular tests to detect the parasite, such as the Polymerase Chain Reaction (PCR); and serological tests to evaluate the host immune response, such as the immunofluorescence antibody test (IFAT) or the Enzyme-Linked ImmunoSorbent Assay (ELISA). This evaluation is necessary to characterize the severity of the disease and determine the clinical stage, BMS 299897 enabling the selection of an adequate treatment or to predict progression toward more serious and irreversible stages [19,20]. Although there are a wide variety of diagnostic techniques for CanL, none of them offers 100% sensitivity or specificity [22,23], and new diagnostic tools are needed to improve detection, especially in asymptomatic dogs. In this sense, Parody et al. recently described a method to isolate CIC and quantify their levels in serum samples obtained from dogs infected withL. infantum[15]. Furthermore,.