Immune Privilege: The Microbiome and Uveitis

Abstract

Immune privilege (IP), a term introduced to explain the unpredicted acceptance of allogeneic grafts by the eye and the brain, is considered a unique property of these tissues. However, immune responses are modified by the tissue in which they occur, most of which possess IP to some degree. The eye therefore displays a spectrum of IP because it comprises several tissues. IP as originally conceived can only apply to the retina as it contains few tissue-resident bone-marrow derived myeloid cells and is immunologically shielded by a sophisticated barrier – an inner vascular and an outer epithelial barrier at the retinal pigment epithelium. The vascular barrier comprises the vascular endothelium and the glia limitans. Immune cells do not cross the blood-retinal barrier (BRB) despite two-way transport of interstitial fluid, governed by tissue oncotic pressure. The BRB, and the blood-brain barrier (BBB) mature in the neonatal period under signals from the expanding microbiome and by 18 months are fully established. However, the adult eye is susceptible to intraocular inflammation (uveitis; frequency ~200/100,000 population). Uveitis involving the retinal parenchyma (posterior uveitis, PU) breaches IP, while IP is essentially irrelevant in inflammation involving the ocular chambers, uveal tract and ocular coats (anterior/intermediate uveitis/sclerouveitis, AU). Infections cause ~50% cases of AU and PU but infection may also underlie the pathogenesis of immune-mediated “non-infectious” uveitis. Dysbiosis accompanies the commonest form, HLA-B27–associated AU, while latent infections underlie BRB breakdown in PU. This review considers the pathogenesis of uveitis in the context of IP, infection, environment, and the microbiome.

Immune responses to injury and their links to eye disease

“…Uveitis is a multifactorial inflammatory disease that has destructive effects in both anterior and posterior segments of the eye [148,[199][200][201]. It is characterized by inflammation within the uvea, the middle layer of the eye that contains most of its vasculature.…”

Uveitis: Molecular Pathogenesis and Emerging Therapies

“…Immune privilege was then viewed as a unique feature of the eye and failure to reject an allograft or alloantigen was attributed to the lack of blood vessels in retina (9). A modern explanation of immune privilege is that proteins in immune privileged tissues of the CNS are sequestrated from the peripheral immune system by the blood-retina barrier (BRB), blood-brain-barrier (BBB) and the neurovascular unit (NVU) comprised of pericytes, perivascular macrophages, neuronal dendrites, glia limitans of the Müler/microglia and tightly bound endothelial cells that surround the NVU (10,11). The avascular immunosuppressive environment of the retina lacks lymphatic drainage, contains resident regulatory cells that secrete neuropeptides and anti-inflammatory cytokines and also contributes to immunological sequestration of the retina (10).…”

“…A modern explanation of immune privilege is that proteins in immune privileged tissues of the CNS are sequestrated from the peripheral immune system by the blood-retina barrier (BRB), blood-brain-barrier (BBB) and the neurovascular unit (NVU) comprised of pericytes, perivascular macrophages, neuronal dendrites, glia limitans of the Müler/microglia and tightly bound endothelial cells that surround the NVU (10,11). The avascular immunosuppressive environment of the retina lacks lymphatic drainage, contains resident regulatory cells that secrete neuropeptides and anti-inflammatory cytokines and also contributes to immunological sequestration of the retina (10). In addition, the RPE and resident retinal cells that express inhibitory cell surface associated proteins (TGF-b, FAS/FAS ligand, CD46 and CD59) limit inflammation in the retina by inactivating lymphocytes (12)(13)(14).…”

“…Mice treated with IL-35 containing exosomes (i35-Exosomes) were protected from developing severe uveitis and disease protection correlated with expansion of IL-10 and IL-35 secreting Treg cells with concomitant suppression of Th17 responses (93) (Figure 3). i35-Exosome therapy thus overcomes the technically difficult and laborintensive effort required to produce sufficient amounts of IL-35-producing i35-Bregs for immunotherapy: as much as 32x10 10 exosomes can be isolated from a mouse and 2x10 10 i35-exosomes contain~15ng IL-35. Another advantage of i35-Exosomes therapy is that IL-12p35/Ebi3 heterodimers are confined in the same vesicle which obviates the dosing issue of determining the precise amount of bioactive IL-35 administered to the subject (93).…”

A Role for Folate in Microbiome-Linked Control of Autoimmunity

“…Immune privilege is a relative property of all tissues reflecting various degrees of tissue-based immunological tolerance [ 47 ] and has particular relevance for the large intestine, now considered a secondary immune organ [ 48 , 49 ]. “Unconventional” IP of the gut [ 50 ] tolerates trillions of commensals and has two components, a physicochemical barrier and an immunological barrier [ 51 ]. The physical barrier is provided by the two cellular barriers which prevent translocation of pathobionts from the intestine to the general circulation (reviewed in [ 47 ]).…”