JAMA neurology · 2024
Multimodal Neuroimaging Reveals and Guides Treatment of a Middle Cerebral Artery Web.
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Martinez Thomas L, Zacharias Zeb R, Lee Kyungmoo, Han Ian C, Jiao Chunhua, Bach Bernardo B, Roos Benjamin, Chava Srinivas, McCormick Mary M, Sinkey Christine, Wu Amy P, Mukhopadhyay Chirantan, Coussa Razek G, Russell Jonathan, Binkley Elaine M, Boldt H Culver, Folk James C, Russell Stephen R, Mullins Robert F, Fingert John H, Wang Kai, Abramoff Michael D, Stone Edwin M, Scheetz Todd E, Houtman Jon C D, Sonka Milan, Sohn Elliott H
Аннотация
PURPOSE: Genetic studies implicate the matrix metalloproteinase-9 (MMP9) locus in neovascular age-related macular degeneration (nvAMD) risk but genotype-phenotype associations of MMP9 with nvAMD are lacking. This study aimed to investigate the influence of MMP9 genotype and T-cell subset frequency on structural and functional treatment outcomes in nvAMD.
METHODS: We reanalyzed single-cell RNA sequencing data and used ELISA and flow cytometry in THP-1-derived monocytes to measure immune cell expression of MMP9 within human choroids. In a clinical nvAMD cohort of 38 patients, we genotyped the nvAMD risk single nucleotide polymorphism (SNP; rs4810482) and quantified retinal fluid using deep-learning-based optical coherence tomography (OCT) image analysis. On a subset of nine patients, we performed high-dimensional immunophenotyping.
RESULTS: MMP9 is predominantly expressed in mature THP-1-derived dendritic-like cells (ELISA, P = 0.009; flow cytometry, P = 0.001). Patients with the TC genotype of MMP9 exhibited greater disease severity compared to CC or TT genotypes with a significantly higher total retinal fluid volume (P = 0.009). Immunophenotyping revealed that higher proportions of circulating CD8+ effector memory T cells re-expressing CD45RA (TEMRA) were associated with increased residual subretinal fluid (P = 0.03), indicating persistent disease activity.
CONCLUSIONS: MMP9 genotype affects structural and functional outcomes in patients with nvAMD. Along with the observed systemic immune dysregulation, these findings support the role of a MMP9-dendritic-T-cell axis in nvAMD immunopathogenesis and highlight this as a potential therapeutic target.
METHODS: We reanalyzed single-cell RNA sequencing data and used ELISA and flow cytometry in THP-1-derived monocytes to measure immune cell expression of MMP9 within human choroids. In a clinical nvAMD cohort of 38 patients, we genotyped the nvAMD risk single nucleotide polymorphism (SNP; rs4810482) and quantified retinal fluid using deep-learning-based optical coherence tomography (OCT) image analysis. On a subset of nine patients, we performed high-dimensional immunophenotyping.
RESULTS: MMP9 is predominantly expressed in mature THP-1-derived dendritic-like cells (ELISA, P = 0.009; flow cytometry, P = 0.001). Patients with the TC genotype of MMP9 exhibited greater disease severity compared to CC or TT genotypes with a significantly higher total retinal fluid volume (P = 0.009). Immunophenotyping revealed that higher proportions of circulating CD8+ effector memory T cells re-expressing CD45RA (TEMRA) were associated with increased residual subretinal fluid (P = 0.03), indicating persistent disease activity.
CONCLUSIONS: MMP9 genotype affects structural and functional outcomes in patients with nvAMD. Along with the observed systemic immune dysregulation, these findings support the role of a MMP9-dendritic-T-cell axis in nvAMD immunopathogenesis and highlight this as a potential therapeutic target.