Whole-Exome Sequencing of Patients With Posterior Segment Uveitis

Li, Angela S.; Vélez, Gabriel; Darbro, Benjamin W.; Toral, Marcus A.; Yang, Jing; Tsang, Stephen H.; Ferguson, Polly J.; Folk, James C.; Bassuk, Alexander G.; Mahajan, Vinit B.

doi:10.1016/j.ajo.2020.07.021

Cited by 13 publications

(10 citation statements)

References 102 publications

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“…Our data suggest a crucial role of the NLR signal transduction pathway in the EAU pathology in the iris region, which has not been identified as one of the most prominent pathways when using other uveal tissues, such as choroid/RPE samples. Notably, in a genetic association cohort study, exome sequencing analysis of the peripheral blood DNA samples of 164 patients with posterior segment uveitis identified NOD2 , NLRP1 , NLRP3 , and NLRC4 variants ( Li et al, 2021 ). These findings add evidence to the conclusion that the NLR signaling pathway plays a key role in uveitis pathogenesis, and the molecules in this pathway could be novel therapeutic targets for autoimmune uveitis.…”

Section: Discussionmentioning

confidence: 99%

Integrated Transcriptome Analysis of Iris Tissues in Experimental Autoimmune Uveitis

Chang

Han

et al. 2022

Front. Genet.

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Uveitis is a severe ocular inflammatory disease that affects the uvea and frequently results in visual impairment, even irreversible blindness. The current treatments for uveitis have exhibited adverse side effects. To find novel targets of this disease, we perform comparative transcriptome analysis using normal (n = 4) and experimental autoimmune uveitis (EAU) (n = 4) rat iris samples. We mainly focus on the expression profiles of mRNAs and long non-coding RNAs, and identify NOD-like receptor signaling pathway as the one that plays a key role in the pathological changes of the EAU irises. Our work demonstrates that the EAU iris transcriptome can be mined to uncover novel targetable pathways for uveitis. The molecules in NOD-like receptor signaling pathway could be novel therapeutic targets for autoimmune uveitis.

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Section: Discussionmentioning

confidence: 99%

Integrated Transcriptome Analysis of Iris Tissues in Experimental Autoimmune Uveitis

Chang

Han

et al. 2022

Front. Genet.

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“…NLRP1 is known to be an inflammasome sensor in humans. To our knowledge, certain neuropsychiatric disorders [e.g., multiple sclerosis (40), Alzheimer's disease (41), autism spectrum disorder (42), schizophrenia (43)], ophthalmic diseases [e.g., uveitis (44), corneal intraepithelial dyskeratosis (45,46)], colorectal adenomatous polyposis (47), respiratory papillomatosis (48), orthopedic diseases [e.g., rheumatoid arthritis (49)], endocrine disorders [e.g., autoimmune Addison's disease (50,51), type 1 diabetes (51)] and skin disorders [e.g., NAIAD (23), multiple selfhealing palmoplantar carcinoma (1), keratosis lichenoides chronica (1), vitiligo (50)(51)(52)(53)] have been reported as NLRP1-related diseases. Thus, NLRP1 is one of the most important molecules for various systemic disorders, including inflammatory diseases.…”

Section: Discussionmentioning

confidence: 99%

UVB-Induced Skin Autoinflammation Due to Nlrp1b Mutation and Its Inhibition by Anti-IL-1β Antibody

et al. 2022

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NLRP1 (NACHT and leucine-rich repeat-containing protein family, pyrin domain-containing protein 1) is an innate immune sensor that is involved in the formation of inflammasome complexes. NLRP1 hyperactivity has been reported to cause inherited autoinflammatory diseases including familial keratosis lichenoides chronica and NLRP1-associated autoinflammation with arthritis and dyskeratosis. We generated Nlrp1b (the mouse homologue of human NLRP1) gain-of-function knock-in (Nlrp1b KI) mice with UVB irradiation-induced autoinflammatory skin lesions. We demonstrated that UVB irradiation induces IL-1β upregulation and IL-1β-dependent inflammation via caspase-1 activation in these Nlrp1b KI mice. RNA sequencing revealed the upregulation of inflammasome pathway-related genes, keratinocyte stress marker genes, and keratinocyte differentiation marker genes in the Nlrp1b KI mice after UVB irradiation. The skin inflammation and hyperkeratosis from UVB irradiation in the Nlrp1b KI mice were inhibited by both intraperitoneal and subcutaneous administration of anti-IL-1β antibodies before UVB irradiation. UVB irradiation and the IL-1β pathway are important in the pathogenesis of NLRP1-associated autoinflammatory skin lesions.

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“…Genetic testing was performed with retinal testing panels (Blueprint) and by whole exome sequencing. 8 Additionally, we utilized the AIR diagnostic criteria set forth by Fox et al 9 Based on these guidelines, patients enrolled in our study met the following criteria: (1) no history or examination findings indicative of another apparent cause of visual function abnormality; (2) the presence of synaptic signaling abnormalities on ERG; (3) the presence of serum antiretinal antibodies (ARAs); and (4) the absence of overt intraocular inflammation. Additional supportive criteria included signs/symptoms of photoreceptor dysfunction, personal/family history of autoimmune disease or uveitis, and the rapid onset of vision changes.…”

Section: Methodsmentioning

confidence: 99%

Proteomic Analysis of Autoimmune Retinopathy Implicates Neuronal Cell Adhesion Molecule as a Potential Biomarker

Al-Moujahed

Vélez

et al. 2022

Ophthalmology Science

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Whole-Exome Sequencing of Patients With Posterior Segment Uveitis

Cited by 13 publications

References 102 publications

Integrated Transcriptome Analysis of Iris Tissues in Experimental Autoimmune Uveitis

Integrated Transcriptome Analysis of Iris Tissues in Experimental Autoimmune Uveitis

UVB-Induced Skin Autoinflammation Due to Nlrp1b Mutation and Its Inhibition by Anti-IL-1β Antibody

Proteomic Analysis of Autoimmune Retinopathy Implicates Neuronal Cell Adhesion Molecule as a Potential Biomarker

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