Vitamin A, systemic T-cells, and the eye: Focus on degenerative retinal disease

Abstract

The first discovered vitamin, vitamin A, exists in a range of forms, primarily retinoids and provitamin carotenoids. The bioactive forms of vitamin A, retinol and retinoic acid, have many critical functions in body systems including the eye and immune system. Vitamin A deficiency is associated with dysfunctional immunity, and presents clinically as a characteristic ocular syndrome, xerophthalmia. The immune functions of vitamin A extend to the gut, where microbiome interactions and nutritional retinoids and carotenoids contribute to the balance of T cell differentiation, thereby determining immune status and contributing to inflammatory disease around the whole body. In the eye, degenerative conditions affecting the retina and uvea are influenced by vitamin A. Stargardt's disease (STGD1; MIM 248200) is characterised by bisretinoid deposits such as lipofuscin, produced by retinal photoreceptors as they use and recycle a vitamin A-derived chromophore. Age-related macular degeneration features comparable retinal deposits, such as drusen featuring lipofuscin accumulation; and is characterised by parainflammatory processes. We hypothesise that local parainflammatory processes secondary to lipofuscin deposition in the retina are mediated by T cells interacting with dietary vitamin A derivatives and the gut microbiome, and outline the current evidence for this. No cures exist for Stargardt's or age-related macular degeneration, but many vitamin A-based therapeutic approaches have been or are being trialled. The relationship between vitamin A's functions in systemic immunology and the eye could be further exploited, and further research may seek to leverage the interactions of the gut-eye immunological axis.

Keywords: Stargardt’s disease; T cell; age - related macular degeneration; carotenoids; gut microbiome; retina; retinoids; vitamin A.

FIGURE 1

The molecular structure of vitamin A in its multiple forms. The chemical group denoted X defines retinol, retinal, retinoic acid, and retinyl esters depending on its composition. Stereoisomeric 11-cis and 11-trans retinoids depend on the three-dimensional arrangement of the vitamin A molecule around the double bond at the eleventh carbon residue, labelled in red. The ß-ionone ring, modified in synthetic forms of vitamin A, is also labelled.

FIGURE 2

The two versions of the visual cycle, classical and intraretinal, a series of chemical reactions, mostly enzyme-catalysed, underlying chromophore regeneration in rods and cones, respectively. Intra- and extra-photoreceptor processes are shaded blue and red, respectively. Rods work with the retinal pigmented epithelium in the classical visual cycle, whereas cones work with Müller cells in the intraretinal visual cycle.

FIGURE 3

Summary of the metabolism of vitamin A, running from different dietary sources through generation of bioactive metabolites, as well as reactions required for clearance. All-trans stereoisomers predominate away from the eye, whereas the eye, and particularly the retina, feature 11-cis and all-trans isomers, crucial for vision.

FIGURE 4

The “flipping” function of ABCA4. 11-cis retinal accumulates in darker conditions as opsins are saturated, whereas all-trans retinal is produced by photoisomerisation in lighter conditions. Retinal associates with membranal phosphatidylethanolamine (PE) to form N-cis-retinylidene-PE (NcRPE) and N-trans-retinylidene-PE (NtRPE), which ABCA4 flips across the membrane at the cost of ATP hydrolysis. NcRPE and NtRPE dissociate, and 11-cis retinal undergoes chemical isomerisation, allowing all-trans retinal to reenter the visual cycle.