Cytokines in autoimmune uveitis

Abstract

Autoimmune uveitis is a complex group of sight-threatening diseases that arise without a known infectious trigger. The disorder is often associated with immunological responses to retinal proteins. Experimental models of autoimmune uveitis targeting retinal proteins have led to a better understanding of the basic immunological mechanisms involved in the pathogenesis of uveitis and have provided a template for the development of novel therapies. The disease in humans is believed to be T cell-dependent, as clinical uveitis is ameliorated by T cell-targeting therapies. The roles of T helper 1 (Th1) and Th17 cells have been major topics of interest in the past decade. Studies in uveitis patients and experiments in animal models have revealed that Th1 and Th17 cells can both be pathogenic effectors, although, paradoxically, some cytokines produced by these subsets can also be protective, depending on when and where they are produced. The major proinflammatory as well as regulatory cytokines in uveitis, the therapeutic approaches, and benefits of targeting these cytokines will be discussed in this review.

FIG. 1.

Histological appearance of uveitis in human and mouse (a) Healthy mouse retina. V, vitreous; G, ganglion cell layer; P, photoreceptor cell layer; R, retinal pigment epithelium; C, choroid; S, sclera. (b) EAU in the B10.RIII mouse induced by immunization with IRBP. Note disorganized retinal architecture and damage to ganglion and photoreceptor cell layers, retinal folds, subretinal exudate, vasculitis, focal damage to the retinal pigment epithelium, and choroidotos. (c) Uveitis in human (ocular sarcoidosis). Note gross similarity in pathological picture between b and c. (Photographs are provided by Dr. Chi-Chao Chan, Laboratory of Immunology, National Eye Institute.) (Reprinted from Caspi .) EAU, experimental autoimmune uveitis; IRBP, interphotoreceptor retinoid-bindin protein.

FIG. 2.

Cytokines and differentiation of effector T cell lineages associated with uveitis. Shown are CD4 T cell differentiation scheme based on currently available information from the literatures and role(s) of each subset in the animal models of EAU. IL, interleukin; TGF-β, transfoming growth factor β; Ag, antigen; TNF-α, tumor necrosis factor α; IFN-γ, interferon-γ; Th cells, T helper cells; Treg cells, regulatory T cells; APC, antigen presenting cells.

FIG. 3.

Innate stimulation of APC determines Th1/Th17 balance. Dendritic cells (DC) cultured from bone marrow (BM) using accepted methods were incubated overnight with LPS, Mycobacterium tuberculosis (MTB) extract, or the yeast polysaccharide zymosan. After washing the DC monolayers, sorted naive T cells were added in presence of anti-CD3 Ab for 6 days. Cells were stained for CD4 and intracellularly for IL-17A and IFN-γ after a 4 h PMA: phorbol myristic acetate/Ionomycin and brefeldin A pulse. Shown is cytokine production by CD4+ cells (Isabelle Suffia and others, unpublished data). LPS, lipopolysaccharide; PMA, phorbol myristic acetate.

FIG. 4.

Cytokine networks in pathogenesis of uveitis. Presentation of Ag in the periphery in the presence of cytokines and innate (environmental) stimuli induces T cell activation, differentiation, and clonal expansion. Activated effector (uveitogenic) T cells then migrate and extravasate into the eye. Upon breakdown of blood–retinal barrier (BRB), leukocytes and lymphocytes (Th1 and Th17) that are recruited from circulation, as well as inflammatory cytokines, amplify the inflammation, resulting in uveitis. RPE, retinal pigment epithelium; ONL, outer nuclear layer; OPL, outer plexiform layer; INL, inner nuclear layer; IPL, inner plexiform layer; GCL, ganglion cell layer.