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    • Basic and Clinical Science Course - Excerpt
  • 2020–2021 BCSC Basic and Clinical Science Course™

    Go to Academy Store Learn more and Purchase.

    9 Uveitis and Ocular Inflammation

    Chapter 3: Ocular Immune Responses

    Immune Responses of the Retina, Retinal Pigment Epithelium, Choriocapillaris, and Choroid

    Features of the Immunologic Microenvironment

    The immunologic microenvironments of the retina, RPE, choriocapillaris, and choroid have not been well characterized. The retinal circulation establishes an inner blood–ocular barrier at the level of tight junctions between adjacent endothelial cells, while tight junctions between the cells of the RPE provide an outer barrier between the choroid and the retina. The vessels of the choriocapillaris are highly permeable to macromolecules and allow transudation of most plasma macromolecules into the extravascular spaces of the choroid and choriocapillaris. Well-developed lymphatic channels are absent, although both the retina and the choroid have abundant potential APCs. In the retina, resident microglia (bone marrow–derived cells related to dendritic cells) are interspersed within all layers and can undergo physical changes and migration in response to various stimuli. The choriocapillaris and choroid contain an abundance of certain potential APCs, especially macrophages and dendritic cells.

    The RPE can be induced to express major histocompatibility complex (MHC) class II molecules, suggesting that the RPE may interact with T lymphocytes in some circumstances. The presence of T lymphocytes or B lymphocytes within the normal posterior segment has not been carefully studied, but effector cells appear to be absent from the normal retina. Similar to macrophages, RPE cells also express toll-like receptors (TLRs). These special pattern recognition receptors are critical in recognition of pathogens and in the initiation of innate and adaptive immune responses, forming an initial line of defense against invading microorganisms. A moderate density of mast cells is also present in the choroid, especially around the arterioles, but lymphocytes are present only in very low number. Eosinophils and neutrophils appear to be absent. Under various clinical or experimental conditions, however, a large number of T lymphocytes, B lymphocytes, macrophages, and neutrophils can infiltrate the choroid, choriocapillaris, and retina. The RPE and various cell types within the retina and the choroid (eg, pericytes) can synthesize many different cytokines (eg, transforming growth factor-β) that may alter the subsequent immune response. Local immune processing does not seem to occur. (See also BCSC Section 12, Retina and Vitreous.)

    • Detrick B, Hooks JJ. Immune regulation in the retina. Immunol Res. 2010;47(1–3):153–161.

    CLINICAL EXAMPLE 3-2

    Retinal gene therapy Retinal gene therapy is the intentional transfection of neural retina cells or RPE with a replication-defective virus that has been genetically altered to carry a replacement gene of choice. This gene becomes expressed in any cell infected by the virus. Immune clearance of the virus can cause loss of expression of the transferred gene in other body sites. Applications of gene therapy in humans have been successfully completed. The United States Food and Drug Administration has approved treatment of biallelic RPE65 mutation–associated retinal dystrophy (Leber congenital amaurosis) using adeno-associated virus (AAV) vector to replace the defective RPE65 gene. The agent (voretigene neparvovec-rzyl) is administered via subretinal injection. Despite the relative immune privilege of the eye, immunogenicity of viral vectors is an ongoing area of investigation. In animal models, intravitreal delivery has lead to a humoral response, while subretinal delivery has not. Intraocular inflammation was observed in approximately 5% of patients receiving voretigene neparvovec-rzy. Use of systemic corticosteroids is recommended, starting 3 days prior to injection of voretigene neparvovec-rzyl. Ocular injection of AAV for the treatment of various inherited retinal dystrophies is under investigation. Areas of study include achromatopsia, choroideremia, Leber hereditary optic neuropathy, X-linked retinoschisis, and X-linked retinitis pigmentosa.

    • Mancuso K, Hauswirth WW, Li Q, et al. Gene therapy for red-green colour blindness in adult primates. Nature. 2009;461(7265):784–787.

    • Moore NA, Morral N, Ciulla TA, Bracha P. Gene therapy for inherited retinal and optic nerve degenerations. Expert Opin Biol Ther. 2018;18(1):37–49.

    Excerpted from BCSC 2020-2021 series: Section 9 - Uveitis and Ocular Inflammation. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.

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