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Review
. 2021 Apr 30:12:623725.
doi: 10.3389/fimmu.2021.623725. eCollection 2021.

Uveitis: Molecular Pathogenesis and Emerging Therapies

Charles E Egwuagu  1 , Sahar A Alhakeem  1   2 , Evaristus C Mbanefo  1
Affiliations
Review

Uveitis: Molecular Pathogenesis and Emerging Therapies

Charles E Egwuagu et al. Front Immunol. .

Abstract

The profound impact that vision loss has on human activities and quality of life necessitates understanding the etiology of potentially blinding diseases and their clinical management. The unique anatomic features of the eye and its sequestration from peripheral immune system also provides a framework for studying other diseases in immune privileged sites and validating basic immunological principles. Thus, early studies of intraocular inflammatory diseases (uveitis) were at the forefront of research on organ transplantation. These studies laid the groundwork for foundational discoveries on how immune system distinguishes self from non-self and established current concepts of acquired immune tolerance and autoimmunity. Our charge in this review is to examine how advances in molecular cell biology and immunology over the past 3 decades have contributed to the understanding of mechanisms that underlie immunopathogenesis of uveitis. Particular emphasis is on how advances in biotechnology have been leveraged in developing biologics and cell-based immunotherapies for uveitis and other neuroinflammatory diseases.

Keywords: EAU; autoimmunity; cellular therapies; immunobiology; molecular therapies; uveitis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Structure of the Vertebrate Eye. The eye is composed of: (i) the outer tunic of the eye comprised of the sclera and cornea (ii) the uvea comprised of the choroid, the iris and the ciliary body; (iii) the neural retina comprised of five types of neurons (ganglion cell, amacrine cells, bipolar cells, horizontal cells and photoreceptors (rods and cones); (iv) Muller cell; (v) RPE.
Figure 2
Figure 2
Immunopathogenic Mechanisms of experimental autoimmune uveitis (EAU). (A) Central tolerance mechanism: Bone marrow derived lymphoid-primed multipotent progenitors (LMPPs) and common lymphoid progenitors (CLPs) enter the thymus near the cortico-medullary junction. Thymus-settling progenitors cells give rise to early T cell progenitors (ETPs), double negative 1 (DN1), DN2 and DN3 thymocytes that then migrate to the subcapsular zone for further development (42). DN3 thymocytes that express functional pre-T cell receptor and CXCR4 receive survival signals that promote proliferation and eventual differentiate to DN4 and then double positive (DP) thymocytes. The DP thymocytes (CCR9Hi) undergoing positive selection interact with self-peptide/MHC complexes on cortical thymic epithelial cells, upregulate CCR7 and mature into single positive (SP) mature T cells that migrate to the thymic medulla (42). The medullary thymic epithelial cells (mTEC) in collaboration with the AIRE transcription factor (autoimmune regulator) in the medulla, promiscuously express tissue-restrictive antigens of major proteins in peripheral tissues. AIRE also contributes to mechanism of negative selection, which eliminates self-reactive T cells that would cause autoimmune diseases. T cells with normal low affinity/avidity recognition of self-antigens are induced to upregulate sphingosine-1-phosphate receptor 1 (S1P1), exit the thymus and enter the blood and peripheral lymphoid tissues. (B) Peripheral tolerance mechanisms mediated by nTregs render potentially autoreactive T cells anergic or “ignorant”. Naïve T cells that enter the circular or peripheral tissues differentiate to various T-helper subsets in response to PAMPs (pathogen associated molecular patterns) or molecular mimicry mechanism. During EAU, active immunization with ocular antigens (e.g. IRBP or S-Ag) in CFA emulsion induces clonal expansion of Th1 and Th17 resulting in disease by day 14-20 followed by Treg and Breg-mediated resolution of the acute inflammatory response between days 25-32 after disease induction. However, few autoreactive memory T cells expressing IL-7Rα persist and they eventually migrate to the bone marrow (BM) where they reside and can be reactivated to mediate recurrent uveitis. (C) Schematic representation of early events associated with loss of immune privilege of the eye and induction of retinal protective mechanism in rodent model of uveitis. Effector molecules such as Granzyme B and proinflammatory cytokines secreted by Th17 cells facilitate breakdown of blood retina barrier (BRB), resulting in the influx of other inflammatory cells such as Th1, Th2, and monocytes. The inflammatory cells entering the eye encounter hostile environment of the neuroretina consisting of anti-inflammatory molecules as well as regulatory T and B cells secreting IL-10 and/or IL-35. RPE, retinal pigment epithelium; OPN, optic nerve; CON, control retina; EAU, OCT image of mouse with uveitis.
Figure 3
Figure 3
Emerging Therapies for Uveitis. (A) Regulation of STAT3 pathway. Cytokines such as IL-6 or IL-23 bind their cognate receptor on lymphocytes and activate receptor-associated JAK kinases. Following the recruitment of latent STAT3 proteins to the activated receptor complex, the STAT3 protein is Tyrosine-phosphorylated, forms pSTAT3:pSTAT3 homodimers that translocate to the nucleus and activate STAT3-responsive genes. SOCS (SOCS1, SOCS3) proteins are immediate early genes activated by pSTAT3 and they are negative feedback regulators of JAK/STAT pathway. They inhibit or terminate JAK/STAT signals by binding to Tyrosine-phosphorylated JAKs or cytokine receptors, targeting them for degradation in the proteosome. PIAS3 protein also inhibits STAT3 transcriptional activities by binding STAT3 DNA binding domain and physically preventing STAT3 binding to target genes. (B) Other emerging therapies for the treatment of uveitis include: (i) Immunotherapy with IL-35-producing Breg cells (i35-Breg) (ii) Administration of biologics (IL-35, IL12p35); (iii) Exosome treatment with IL-35-containing exosomes (i35-Exosomes).
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