Gut-licensed β7
            <sup>+</sup>
            CD4
            <sup>+</sup>
            T cells contribute to progressive retinal ganglion cell damage in glaucoma

He, Chong; Xiu, Wenbo; Chen, Qinyuan; Peng, Kun; Zhu, Xiong; Wang, Zuo; Xu, Xiang; Chen, Yang; Zhang, Gao; Fu, Jing; Dong, Qiwei; Wu, Xiaoqiong; Li, An; Liu, Donghua; Gao, Yanping; Wang, Jinxia; Wang, Zhao; Deng, Bolin; Shuai, Ping; Gao, Caiping; Chen, Yilian; Yu, Ling; Lu, Fang

doi:10.1126/scitranslmed.adg1656

Cited by 15 publications

(5 citation statements)

References 42 publications

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“…Previous reports implicate a T-cell response in glaucoma pathogenesis ( 20 , 44 , 45 ). Hence, we aimed to determine whether the pan T-cell marker CD3 could be detected in the retinae of the experimental groups via immunohistology.…”

Section: Resultsmentioning

confidence: 91%

In a novel autoimmune and high-pressure glaucoma model a complex immune response is induced

Reinehr,

Wulf,

Theile

et al. 2024

Front. Immunol.

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BackgroundThe neurodegenerative processes leading to glaucoma are complex. In addition to elevated intraocular pressure (IOP), an involvement of immunological mechanisms is most likely. In the new multifactorial glaucoma model, a combination of high IOP and optic nerve antigen (ONA) immunization leads to an enhanced loss of retinal ganglion cells accompanied by a higher number of microglia/macrophages in the inner retina. Here, we aimed to evaluate the immune response in this new model, especially the complement activation and the number of T-cells, for the first time. Further, the microglia/macrophage response was examined in more detail.MethodsSix-week-old wildtype (WT+ONA) and βB1-connective tissue growth factor high-pressure mice (CTGF+ONA) were immunized with 1 mg ONA. A wildtype control (WT) and a CTGF group (CTGF) received NaCl instead. Six weeks after immunization, retinae from all four groups were processed for immunohistology, RT-qPCR, and flow cytometry, while serum was used for microarray analyses.ResultsWe noticed elevated numbers of C1q+ cells (classical complement pathway) in CTGF and CTGF+ONA retinae as well as an upregulation of C1qa, C1qb, and C1qc mRNA levels in these groups. While the complement C3 was only increased in CTGF and CTGF+ONA retinae, enhanced numbers of the terminal membrane attack complex were noted in all three glaucoma groups. Flow cytometry and RT-qPCR analyses revealed an enhancement of different microglia/macrophages markers, including CD11b, especially in CTGF and CTGF+ONA retinae. Interestingly, increased retinal mRNA as well as serum levels of the tumor necrosis factor α were found throughout the different glaucoma groups. Lastly, more T-cells could be observed in the ganglion cell layer of the new CTGF+ONA model.ConclusionThese results emphasize an involvement of the complement system, microglia/macrophages, and T-cells in glaucomatous disease. Moreover, in the new multifactorial glaucoma model, increased IOP in combination with autoimmune processes seem to enforce an additional T-cell response, leading to a more persistent pathology. Hence, this new model mimics the pathomechanisms occurring in human glaucoma more accurately and could therefore be a helpful tool to find new therapeutic approaches for patients in the future.

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Section: Resultsmentioning

confidence: 91%

In a novel autoimmune and high-pressure glaucoma model a complex immune response is induced

Reinehr,

Wulf,

Theile

et al. 2024

Front. Immunol.

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“…While the innate immune system has long been linked to glaucoma through glial cells and oxidative stress, the findings support the role of the adaptive immune system [ 64 ]. Studies have shown that CD4+ T cells can facilitate RGC death [ 65 ], and an imbalance in Treg cells/T17 cells has been observed in experimental autoimmune optic neuritis, a condition sharing similarities with glaucoma [ 66 ]. Studies indicate a correlation between immune potency and resistance to RGC death, suggesting immune dysfunction as a potential condition for glaucoma development [ 67 ].…”

Section: Discussionmentioning

confidence: 99%

Exploring the Ocular Surface Microbiome and Tear Proteome in Glaucoma

Spörri,

Uldry,

Kreuzer

et al. 2024

IJMS

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Although glaucoma is a leading cause of irreversible blindness worldwide, its pathogenesis is incompletely understood, and intraocular pressure (IOP) is the only modifiable risk factor to target the disease. Several associations between the gut microbiome and glaucoma, including the IOP, have been suggested. There is growing evidence that interactions between microbes on the ocular surface, termed the ocular surface microbiome (OSM), and tear proteins, collectively called the tear proteome, may also play a role in ocular diseases such as glaucoma. This study aimed to find characteristic features of the OSM and tear proteins in patients with glaucoma. The whole-metagenome shotgun sequencing of 32 conjunctival swabs identified Actinobacteria, Firmicutes, and Proteobacteria as the dominant phyla in the cohort. The species Corynebacterium mastitidis was only found in healthy controls, and their conjunctival microbiomes may be enriched in genes of the phospholipase pathway compared to glaucoma patients. Despite these minor differences in the OSM, patients showed an enrichment of many tear proteins associated with the immune system compared to controls. In contrast to the OSM, this emphasizes the role of the proteome, with a potential involvement of immunological processes in glaucoma. These findings may contribute to the design of new therapeutic approaches targeting glaucoma and other associated diseases.

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“… 12 Another study demonstrated the significant role of gut-homing β7 + CD4 + T cells in retinal ganglion cell damage in glaucoma in both human and mouse models. 13 14 This finding highlights the complex interplay of the gut-retina axis in the pathophysiology of glaucoma. While emerging evidence from some observational studies suggests an association between GM dysregulation and glaucoma, whether there is a causal relationship between GM composition and glaucoma risk remains to be established.…”

Section: Introductionmentioning

confidence: 86%

Effect of the gut microbiome in glaucoma risk from the causal perspective

Wu,

Shi,

Chen

et al. 2024

BMJ Open Ophth

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ObjectiveEvidence from observational studies has reported possible associations between the gut microbiome (GM) and glaucoma. However, the causal effect of GM on glaucoma risk remains to be determined.Methods and analysisWe conducted two-sample bidirectional Mendelian randomisation (MR) analyses to explore the causal association between GM and glaucoma. Genome-wide association study summary statistics of 196 GM taxa (n=18 340) and glaucoma (18 902 cases and 358 375 controls) were obtained from MiBioGen and FinnGen Consortium. Inverse variance weighted, MR-Egger, weighted median, weighted mode, Mendelian Randomisation Pleiotropy Residual Sum and Outlier, MR-Egger intercept and Cochran’s Q statistical analyses were used to supplement MR results and sensitivity analysis. An independent cohort from the Medical Research Council (MRC) Integrative Epidemiology Unit at the University of Bristol (MRC-IEU) Consortium (1715 cases and 359 479 controls) was used to validate causal effects.ResultsResults of the MR analysis suggested that the familyOxalobacteraceae(OR 0.900, 95% CI 0.843 to 0.961, p=0.002) and the genusEggerthella(OR 0.881, 95% CI 0.811 to 0.957, p=0.003) had a negative effect on glaucoma, whereas the genusBilophila(OR 1.202, 95% CI 1.074 to 1.346, p=0.001),LachnospiraceaeUCG010(OR 1.256, 95% CI 1.109 to 1.423, p=0.0003) andRuminiclostridium 9(OR 1.258, 95% CI 1.083 to 1.461, p=0.003) had a positive effect on glaucoma. Among these, the positive causal effect ofLachnospiraceaeUCG010(OR 1.002, 95% CI 1.000 to 1.004, p=0.033) on glaucoma was replicated in an independent cohort.ConclusionThis MR analysis from large population studies demonstrated the causal effect of GM on glaucoma risk and supported the role of GM in influencing glaucoma susceptibility.

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Gut-licensed β7 ⁺ CD4 ⁺ T cells contribute to progressive retinal ganglion cell damage in glaucoma

Cited by 15 publications

References 42 publications

In a novel autoimmune and high-pressure glaucoma model a complex immune response is induced

In a novel autoimmune and high-pressure glaucoma model a complex immune response is induced

Exploring the Ocular Surface Microbiome and Tear Proteome in Glaucoma

Effect of the gut microbiome in glaucoma risk from the causal perspective

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Gut-licensed β7 + CD4 + T cells contribute to progressive retinal ganglion cell damage in glaucoma

Cited by 15 publications

References 42 publications

In a novel autoimmune and high-pressure glaucoma model a complex immune response is induced

In a novel autoimmune and high-pressure glaucoma model a complex immune response is induced

Exploring the Ocular Surface Microbiome and Tear Proteome in Glaucoma

Effect of the gut microbiome in glaucoma risk from the causal perspective

Contact Info

Product

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Gut-licensed β7 ⁺ CD4 ⁺ T cells contribute to progressive retinal ganglion cell damage in glaucoma