Immunology of the eye
Human autoimmune uveitis is a major cause of blindness. Commensals may be involved as a trigger and/or modulator of the disease. In the model of experimental autoimmune uveitis (EAU) induced by immunization with the retinal antigen IRBP, conflicting findings were published by us (PMID:26287682) and by others (PMID:27415793) concerning disease amelioration by antibiotic treatment (ABX). Since the main variable between the studies appeared to be duration of ABX, we set out to examine whether short-term vs. long-term ABX differentially affected EAU development, gut microbiota and host immune responses.
EAU-susceptible B10.RIII mice were given continuous ABX starting 12 weeks (long-term) or 1 week (short-term) before EAU challenge. Short-term ABX ameliorated EAU, whereas long-term ABX had no effect on disease onset or severity vs. untreated controls. Metagenomic analyses revealed ABX-duration-dependent depletion of gut microbial communities, including differential effects on Lactobacillus and other taxa. Interestingly, ABX duration was also associated with progressive disappearanceof CD4+ and CD4+CD8+ intraepithelial lymphocytes (IELs). Notably, these IELs, which are thought to regulate gut barrier integrity, exhibited cytotoxic activity in vitro against autologous immune cells and were modulaed at the transcriptomic level by ABX.
We propose that microbiota play a dual role in uveitis development: they provide a stimulus for uveitogenic effector cells, but also maintain a “regulatory” IEL population, whose progressive loss reverses the protective effect of short-term ABX. Our findings may have implications for extended use of antibiotics in clinical situations and may lead to a better understanding of the role of IELs in the microbiota-gut-eye axis.