Management of Feline Hyperthyroidism and the Need to Prevent Oxidative Stress: What Can We Learn from Human Research?

Feline hyperthyroidism is a clinical syndrome related to an excessive production of thyroid hormones, and it is considered as a spontaneous animal model for human thyrotoxicosis. Many shared features between the feline and the human disease have been identified so far, including pathogenesis, clinical signs, and treatment options. Although methimazole is considered the first-choice drug in both species, several side effects have been described. Furthermore, methimazole could interfere with the oxidative status, already perturbated by the disease. It has been reported in humans that dietary management, mainly through antioxidant supplementation, could mitigate this oxidative burden. The purpose of the review is to describe current therapeutic options in the course of feline hyperthyroidism and to summarize the state of the art relationship between dietary antioxidants administration and the reduction of methimazole side-effects in humans to support the use of this approach also in cats.

Altered Metabolic Phenotype of Immune Cells in a Spontaneous Autoimmune Uveitis Model

As one of the leading causes of blindness worldwide, uveitis is an important disease. The exact pathogenesis of autoimmune uveitis is not entirely elucidated to date. Equine recurrent uveitis (ERU) represents the only spontaneous animal model for autoimmune uveitis in humans. As the metabolism of immune cells is an emerging field in research and gains more and more significance to take part in the pathogenesis of various diseases, we conducted experiments to investigate the metabolism of immune cells of ERU cases and healthy controls. To our knowledge, the link between a deviant immunometabolism and the pathogenesis of autoimmune uveitis was not investigated so far. We showed that PBMC of ERU cases had a more active metabolic phenotype in basal state by upregulating both the oxidative phosphorylation and the glycolytic pathway. We further revealed an increased compensatory glycolytic rate of PBMC and CD4+ T cells of ERU cases under mitochondrial stress conditions. These findings are in line with metabolic alterations of immune cells in other autoimmune diseases and basic research, where it was shown that activated immune cells have an increased need of energy and molecule demand for their effector function. We demonstrated a clear difference in the metabolic phenotypes of PBMC and, more specifically, CD4+ T cells of ERU cases and controls. These findings are another important step in understanding the pathogenesis of ERU and figuratively, human autoimmune uveitis.

NEU1 is more abundant in uveitic retina with concomitant desialylation of retinal cells

Desialylation of cell surface glycoproteins carried out by sialidases affects various immunological processes. However, the role of neuraminidase 1 (NEU1), one of the four mammalian sialidases, in inflammation and autoimmune disease is not completely unraveled to date. In this study, we analyzed the retinal expression of NEU1 in equine recurrent uveitis (ERU), a spontaneous animal model for autoimmune uveitis. Mass spectrometry revealed significantly higher abundance of NEU1 in retinal Müller glial cells (RMG) of ERU-diseased horses compared to healthy controls. Immunohistochemistry uncovered NEU1 expression along the whole Müller cell body in healthy and uveitic states and confirmed higher abundance in inflamed retina. Müller glial cells are the principal macroglial cells of the retina and play a crucial role in uveitis pathogenesis. To determine whether higher expression levels of NEU1 in uveitic RMG correlate with the desialylation of retinal cells, we performed lectin-binding assays with sialic acid-specific lectins. Through these experiments, we could demonstrate a profound loss of both α2-3- and α2-6-linked terminal sialic acids in uveitis. Hence, we hypothesize that the higher abundance of NEU1 in uveitic RMG plays an important role in the pathogenesis of uveitis by desialylation of retinal cells. As RMG become activated in the course of uveitis and actively promote inflammation, we propose that NEU1 might represent a novel activation marker for inflammatory RMG. Our data provide novel insights in the expression and implication of NEU1 in inflammation and autoimmune disease.

Interaction of septin 7 and DOCK8 in equine lymphocytes reveals novel insights into signaling pathways associated with autoimmunity

ABSTRACTThe GTP-binding protein septin 7 is involved in various cellular processes, including cytoskeleton organization, migration and the regulation of cell shape. Septin 7 function in lymphocytes, however, is poorly characterized. Since the intracellular signaling role of septin 7 is dependent on its interaction network, interaction proteomics was applied to attain novel knowledge about septin 7 function in hematopoietic cells. Our previous finding of decreased septin 7 expression in blood-derived lymphocytes in ERU, a spontaneous animal model for autoimmune uveitis in man, extended the role of septin 7 to a potential key player in autoimmunity. Here, we revealed novel insights into septin 7 function by identification of DOCK8 as an interaction partner in primary blood-derived lymphocytes. Since DOCK8 is associated with important immune functions, our finding of significantly decreased DOCK8 expression and altered DOCK8 interaction network in ERU might explain changes in immune response and shows the contribution of DOCK8 in pathomechanisms of spontaneous autoimmune diseases. Moreover, our analyses revealed insights in DOCK8 function, by identifying the signal transducer ILK as a DOCK8 interactor in lymphocytes. Our finding of the enhanced enrichment of ILK in ERU cases indicates a deviant influence of DOCK8 on inter- and intracellular signaling in autoimmune disease.