Abstract
Equine recurrent uveitis (ERU) is a common ocular disease of horses and described as a model for human autoimmune uveitis. This immune-mediated, inflammatory condition progressively destroys the eye, ultimately leading to blindness. Genetic and autoimmune factors, next to infections with Leptospira, are discussed as key factors in the pathogenesis. Furthermore, a release of neutrophil extracellular traps (NETs) by activated neutrophils is involved. NETs are composed of decondensed chromatin and proteins that can immobilize invading pathogens. However, if NETs accumulate, they can contribute to detrimental autoimmune processes. Thus, we aimed to investigate the impact of NETs in ERU patients. Therefore, we quantified several NET-markers (cell-free DNA, nucleosomes, citrullinated histone H3, histone-myeloperoxidase complexes, interleukin-17, equine cathelicidin 1 and DNase I activity) and NET-autoantibodies in sera and vitreous body fluids (VBF) of ERU-diseased horses and correlated the data with the disease status (signalment, ERU scores and Leptospira infection status). NET markers were detected to varying degrees in VBF of diseased horses, and partially correlated to disease severity and the presence of Leptospira spp. Cell-free DNA and nucleosomes as NET markers correlate with ERU severity in total and VBF scores, despite the presence of active DNases. Additionally, a significant correlation between fundus affection in the eye and NET autoantibodies was detectable. Therefore, we further investigated the influence of VBF samples from equine patients and isolated NETs on the blood-retina barrier in a cell culture model. VBF of diseased horses significantly induced cytotoxicity in retinal pigment epithelial cells. Moreover, partially digested NETs also resulted in cytotoxic effects. In the presence of lipopolysaccharide (LPS), the main component of the leptospiral surface, both undigested and completely digested NETs were cytotoxic. Correlations between the ERU-scores and Leptospira were also calculated. Detection of leptospiral DNA, and antibody titers of the serovar Grippotyphosa correlated with disease severity. In addition, a correlation between Leptospira and several NET markers was observed in VBF. Altogether, our findings suggest a positive correlation between NET markers with disease severity and involvement of Leptospira in the VBF of ERU-diseased horses, as well as a cytotoxic effect of NETs in eyes.
Highlights
Equine recurrent uveitis (ERU) is a common, inflammatory disease of eyes in horses
These two NET markers were significantly elevated in vitreous body fluid (VBF) of ERU patients
Besides a latent activation of these immune cells even in the quiescent state of disease [33], NETs were found in eyes of ERU patients by our group [34]
Summary
Equine recurrent uveitis (ERU) is a common, inflammatory disease of eyes in horses. Horses are used as a research model because of numerous similarities in clinical signs and pathogenesis with human autoimmune uveitis [1, 2]. Autoimmune uveitis does not occur naturally, and experimentally induced forms are rarely recurrent, in contrast to human and equine disease [1, 3]. The spontaneous disease clinically appears with repetitive inflammatory episodes of the eye without systemic findings. Typical clinical pictures are synechiae, cataracts, lens luxation, liquefication and inflammatory deposits inside the vitreous, chorioretinopathies up to retinal detachment, and phthisis bulbi [6,7,8,9]. One common surgery for horses suffering of ERU is vitrectomy, a minimally invasive replacement of the vitreous body fluid (VBF) by buffered salt solution [8, 10]
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