The Cellular Composition of the Uveal Immune Environment

Abstract

The uveal tract consists of the iris, the ciliary body and the choroid; these three distinct tissues form a continuous layer within the eye. Uveitis refers to inflammation of any region of the uveal tract. Despite being grouped together anatomically, the iris, ciliary body and choroid are distinct functionally, and inflammatory diseases may affect only one part and not the others. Cellular structure of tissues direct their function, and understanding the cellular basis of the immune environment of a tissue in health, the “steady state” on which the perturbations of disease are superimposed, is vital to understanding the pathogenesis of those diseases. A contemporary understanding of the immune system accepts that haematopoietic and yolk sac derived leukocytes, though vital, are not the only players of importance. An array of stromal cells, connective tissue cells such as fibroblasts and endothelial cells, may also have a role in the inflammatory reaction seen in several immune-mediated diseases. In this review we summarise what is known about the cellular composition of the uveal tract and the roles these disparate cell types have to play in immune homeostasis. We also discuss some unanswered questions surrounding the constituents of the resident leukocyte population of the different uveal tissues, and we look ahead to the new understanding that modern investigative techniques such as single cell transcriptomics, multi-omic data integration and highly-multiplexed imaging techniques may bring to the study of the uvea and uveitis, as they already have to other immune mediated inflammatory diseases.

A single-cell transcriptomic atlas of the human ciliary body

“…2B). In agreement with previous immunohistological studies [ 9 ], we found that myeloid cells including monocytes, macrophages, neutrophils and mast cells contributed to the majority of the immune cell population in the ciliary body (Fig. 1 A, B , Suppl.…”

“…One of the major cell types identified was the macrophage population, supporting the notion that cells of the myeloid lineage primarily make up the immune repertoire of the healthy uveal tract [ 9 ]. The ciliary body has been recognized to have an immunosuppressive environment [ 9 , 66 ], and the anti-inflammatory (M2) macrophages are important for the maintenance of such an immune status.…”

“…Other immune cell types such as monocytes, plasma and mast cells were identified in human ciliary body but were absent in the mouse datasets [ 38 ], possibly attributable to their comparatively low density in the ciliary body/retina. Interestingly, the presence of dendritic cells is well-documented within the entire uveal tract including the iris, ciliary body and choroid in a number of species [ 9 , 10 , 48 – 50 ], but others’ and our scRNAseq analyses failed to identify dendritic cell population in both human and mouse ciliary body with or without the mixture of other ocular tissues [ 16 , 38 , 47 ]. This could be due to the difficulties in completely dissociating/capturing the dendritic cells that reside between the firmly attached ciliary epithelium layers [ 9 , 48 , 49 ].…”

“…Like the brain, the eye is one of the few immune privileged sites of the body. Due to the segregated state from the peripheral immune system, the eye contains various myeloid cells that respond to foreign and self-antigens, and locally, tissue-resident macrophages or microglia are the well-characterized immune cell types that mediate baseline immunity in the intraocular tissues [ 7 – 9 ]. Extensive studies from rodent eyes have revealed that the immune cell populations of the healthy ciliary body consist primarily of cells of the myeloid lineage such as monocytes and macrophages; however, comparatively little work has been focused on the immune environment of the human ciliary body [ 9 ].…”

Ocular Lymphatic and Glymphatic Systems: Implications for Retinal Health and Disease

“…The presence of ciliary body lymphatics has also been investigated by several other groups; however, the results were conflicting. One consistent finding of these studies was the presence of LYVE1-positive cells in the ciliary body stroma and processes [ 74 , 75 , 76 , 77 ]. Interestingly, the majority of these cells was also immunoreactive for CD68 (a well-known macrophage marker), indicating that these cells might belong to the macrophage lineage [ 75 ].…”