Microbiome and Autoimmune Uveitis

Abstract

Commensal microbes affect all aspects of immune development and homeostasis in health and disease. Increasing evidence points to the notion that the gut commensals impact not only intestinal diseases but also diseases in tissues distant from the gut. Autoimmune or non-infectious uveitis is a sight-threatening intraocular inflammation that affects the neuroretina. It is strongly T cell driven, but the precise causative mechanisms are not fully understood. We and others observed that depletion of gut microbiota in animal models of uveitis attenuated disease. Using a spontaneous model of the disease, we questioned how retina-specific uveitogenic T cells are primed when their cognate antigens are sequestered within the immune privileged eye. The data suggested that gut commensals provide a signal directly through the retina-specific T cell receptor and cause these autoreactive T cells to trigger uveitis. This activation of retina-specific T cells in the gut appears to be independent of the endogenous retinal antigen. Rather, the findings point to the notion that gut microbiota may mimic retinal antigen(s), however, the actual mimic has not yet been identified. Microbiota may also serve as an "adjuvant" providing innate signals that amplify and direct the host immune response for development of uveitis. In contrast, spontaneous uveitis that develops in AIRE^-/- mice appears to be independent of gut microbiota. To date, available data on human microbiota in association with uveitis are very limited and causative relationships are difficult to establish. This review will summarize the current knowledge on the role of microbiome in uveitis and its underlying mechanisms, and discuss unresolved questions and issues in an attempt to explore the concept of gut-retina axis.

Keywords: autoimmune uveitis; autoreactive T cells; commensal microbiota; gut; retina.

Figure 1

Induced and spontaneous models of autoimmune uveitis. Experimental Autoimmune Uveitis (EAU) is induced by active immunization of WT B10.RIII mice with the retinal autoantigen IRBP in complete Freund's adjuvant (CFA). Histology pictures show healthy and uveitic retina (H&E). A uveitogenic T cell line was established from draining LN cells of EAU-induced WT mice by several rounds of in vitro activation with uveitogenic peptide IRBP161-180. This cell line is highly pathogenic when adoptively transferred to naïve WT mice. The most highly antigen-responsive TCRαβ cloned from this cell line was used for generation of IRBP-specific TCR transgenic mice. A TCR transgenic line, R161H, develops spontaneous uveitis around weaning age.

Figure 2

Fundus images of R161H mice under germ-free (GF) or specific pathogen-free (SPF) conditions. Fundus images were taken by Micron II. WT mice (SPF or GF) do not develop spontaneous uveitis and show normal fundus. SPF R161H mice develop moderate to severe uveitis and inflammation peaks between 2–3 months of age. Diffuse lesions and inflammation along the vessels and away from the vessels are present. GF R161H mice develop milder uveitis with focal inflammation/lesions. Photos were taken at 11 weeks old except for GF WT mice at 7 weeks old.

Figure 3

Microbiota-dependent activation of retina-specific autoreactive T cells triggers uveitis. A high frequency of retina-specific autoreactive T cells is present in the periphery including gut LP of R161H mice (1). Gut microbiota-derived products, which may mimic Ag to these T cells, are presented by antigen presenting cells (2). Retina-specific T cells become activated, migrate to the eye (3), and cross the blood retinal barrier to cause inflammation in the retina (4).