Ocular tuberculosis:Immunological insights, clinical management, and future directions

Uveitis, a potentially sight-threatening intraocular inflammation, can be caused by tuberculosis (TB). This thesis advances our understanding of ocular TB (OTB) by integrating immunological insights, clinical observations, and innovative diagnostic strategies. It combines findings from laboratory studies and patient registries in both Indonesia, a high TB-endemic country, and the Netherlands, a low TB-endemic country. <br/>This work demonstrates that retinal endothelial cells are permissive to Mycobacterium tuberculosis (Mtb) infection and induced the activation of the interferon signalling pathway. Using targeted proteomics on patient serum samples, the thesis shows that OTB and ocular sarcoidosis share many immunological features, but also identifies distinct markers that can help differentiate them. In many patients with uveitis of undetermined cause but positive TB immunoreactivity, confirming active TB is challenging. A randomised controlled trial presented here confirms that antitubercular treatment (ATT) in such cases improves uveitis resolution and reduces relapse, particularly in high-endemic settings. The thesis identifies promising blood-based protein biomarkers (serum CXCL9 and BAFF) that can aid in diagnosing OTB and guiding ATT decisions. Artificial intelligence (AI) analysis of standard fundus photographs showed potential in distinguishing active TB-related uveitis from other causes. In addition, a proof-of-concept study demonstrated that metformin can reduce Mtb growth and inflammation in vitro, opening possibilities for host-directed therapy in OTB. Finally, a novel in vitro OTB model using induced pluripotent stem cell-derived retinal pigment epithelial cells was developed, providing a robust platform for future research. Together, these findings move the field closer to precision medicine for OTB.<br/><br/>