Abstract
Autoimmune and autoinflammatory diseases cause morbidity in multiple organ systems including the ocular anterior segment. Genetic disorders of the innate and adaptive immune system present an avenue to study more common inflammatory disorders and host-pathogen interactions. Many of these Mendelian disorders have ophthalmic manifestations. In this review, we highlight the ophthalmic and molecular features of disorders of the innate immune system. A comprehensive literature review was performed using PubMed and the Online Mendelian Inheritance in Man databases spanning 1973–2020 with a focus on three specific categories of genetic disorders: RIG-I-like receptors and downstream signaling, inflammasomes, and RNA processing disorders. Tissue expression, clinical associations, and animal and functional studies were reviewed for each of these genes. These genes have broad roles in cellular physiology and may be implicated in more common conditions with interferon upregulation including systemic lupus erythematosus and type 1 diabetes. This review contributes to our understanding of rare inherited conditions with ocular involvement and has implications for further characterizing the effect of perturbations in integral molecular pathways.
Highlights
Autoimmune and autoinflammatory disorders [1] are frequent causes of morbidity and mortality [2, 3] and are increasing in incidence [4, 5]. ey are caused by dysregulation of various components of the innate and adaptive immune response, but their molecular pathogenesis has not been fully elucidated. e immunological continuum hypothesis [6] proposes that monogenic autoinflammatory disorders and autoimmune diseases are on a spectrum
Phrases that were used in PubMed database searches for the literature review included “interferonopathy,” “ocular features,” “ocular immunity,” “ectodermal dysplasia,” “Singleton–Merten syndrome,” “dyskeratosis,” “inflammasome,” “Aicardi–Goutieres syndrome,” “autoimmune,” “autoinflammatory,” “monogenic interferonopathy,” “type I interferonopathy,” “cryopyrin-associated periodic syndromes,” and “limbal stem cell deficiency.”
Multiple de novo and inherited dominant missense variants in interferon-induced with helicase C domain 1 (IFIH1) clustering within the two helicase domains and C-terminal domain involved in RNA recognition have been associated with Aicardi–Goutieres syndrome 7 (AGS, MIM: 615846) [47, 48]. is condition is an autosomal dominant inflammatory disorder characterized by severe neurologic impairment, with most patients presenting in infancy with delayed psychomotor development, axial hypotonia, spasticity, and brain imaging changes, including basal ganglia calcification, cerebral atrophy, and deep white matter abnormalities along with upregulated interferon signaling and interferon-stimulated gene expression (AGS, MIM: 615846)
Summary
Autoimmune and autoinflammatory disorders [1] are frequent causes of morbidity and mortality [2, 3] and are increasing in incidence [4, 5]. ey are caused by dysregulation of various components of the innate and adaptive immune response, but their molecular pathogenesis has not been fully elucidated. e immunological continuum hypothesis [6] proposes that monogenic autoinflammatory disorders and autoimmune diseases are on a spectrum. We describe recent advances in our understanding of four classes of genes involved in innate immunity: retinoic acidinducible gene I (RIG-I)-like receptors, RIG-I-like downstream signaling pathways, inflammasomes, and RNA processing genes. We highlight their clinical associations with an emphasis on ocular features, human phenotypic associations, and relevant animal model/functional work. A subsequent complementary PubMed search for each gene and any noted clinical associations and animal model work was performed to identify any associations that may not have been included in the OMIM database. Pan-tissue plots were generated for DDX58 grouped with the other genes of its class (RIG-I-like receptors: IFIH1 and DHX58)
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