Beyond the Complement Cascade: Insights into Systemic Immunosenescence and Inflammaging in Age-Related Macular Degeneration and Current Barriers to Treatment

Khan, Ameer; Chowers, Itay; Lotery, Andrew

doi:10.3390/cells12131708

Cited by 8 publications

(4 citation statements)

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“…Inflammaging and immunosenescence have received substantial attention in ocular disease in recent years, including age-related macular degeneration ( 53 ) and uveitis ( 54 ). While evidence on the humoral immune response with age is limited, an increasing cellular-immune dysfunction, a vanning proliferation of antigen-specific lymphocytes, a reduced cytokine production, and a lower activation level of cytotoxic and natural killer cells ( 55 , 56 ) have been demonstrated.…”

Section: Discussionmentioning

confidence: 99%

The role of age in ocular toxoplasmosis: clinical signs of immunosenescence and inflammaging

Eraghi,

Garweg,

Pleyer

2024

Front. Med.

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PurposeThis study aimed to investigate the association between age, immune response, and clinical presentation of ocular toxoplasmosis (OT).DesignThis was a monocentric, retrospective, observational cohort study.MethodsA review of the medical records of patients with active OT at the Uveitis Center, Charité Universitätsmedizin, was conducted. Baseline parameters included age at presentation, visual acuity, intraocular pressure (IOP), size and location of active lesions, inflammatory activity, antibody index (AI), and complications of intraocular inflammation. The data were presented as the mean ± standard deviation (SD). The level of significance was set at a p-value of <0.05.ResultsBetween 1998 and 2019, 290 patients with active OT were diagnosed at our tertiary reference center. The mean age of the participants was 37.7 ± 17.1 years, 53.8% of them were female individuals, and 195 patients (70.9%) showed recurrent disease. Older age was associated with lower baseline visual acuity (p = 0.043), poor visual outcome (p = 0.019), increased inflammatory activity (p < 0.005), and larger retinal lesions (p < 0.005). Older patients presented a lower AI (<35 years: 45.1 ± 82.7, median: 12.1; ≥35 years: 18.6 ± 50.5, median: 5.8; p = 0.046), confirmed by a decrease in AI with increasing age (R2 = 0.045; p = 0.024). Finally, AI was correlated with lesion size (multiple linear regression analysis: p = 0.043). Macular involvement (24.3% of patients) was positively correlated with complications (macular/peripapillary edema and retinal detachment, p < 0.005) and poor visual outcome (p < 0.005) and was negatively correlated with inflammatory activity (p < 0.005).ConclusionWe found a strong and clinically relevant impact of age on the clinical presentation and course of OT. While an unspecific inflammatory response increased with age, the specific, local humoral immune response declined. These findings are well in line with the concept of immunosenescence and inflammaging in uveitis.

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Section: Discussionmentioning

confidence: 99%

The role of age in ocular toxoplasmosis: clinical signs of immunosenescence and inflammaging

Eraghi,

Garweg,

Pleyer

2024

Front. Med.

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“…Research on aging choroidal endothelial cells in rhesus monkeys reveals high levels of SA-β-Gal and abnormal cytoskeletal activity, sensitizing choriocapillaris to MAC-induced endothelial dysfunction [73]. Increasing evidence suggests that mitochondrial dysfunction plays a critical role in microvascular aging, and the accumulation of DNA damage in the aging vasculature may contribute to replicative senescence [27,[74][75][76].…”

Section: Molecular Insights Into Choroidal Vascular Agingmentioning

confidence: 99%

Aging in Ocular Blood Vessels: Molecular Insights and the Role of Oxidative Stress

Cui,

Buonfiglio,

Pfeiffer

et al. 2024

Biomedicines

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Acknowledged as a significant pathogenetic driver for numerous diseases, aging has become a focal point in addressing the profound changes associated with increasing human life expectancy, posing a critical concern for global public health. Emerging evidence suggests that factors influencing vascular aging extend their impact to choroidal and retinal blood vessels. The objective of this work is to provide a comprehensive overview of the impact of vascular aging on ocular blood vessels and related diseases. Additionally, this study aims to illuminate molecular insights contributing to vascular cell aging, with a particular emphasis on the choroid and retina. Moreover, innovative molecular targets operating within the domain of ocular vascular aging are presented and discussed.

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“…Although the etiology is incompletely understood, evidence suggests a role for inflammation in AMD pathogenesis and progression . Chronic low-level local inflammation is indicated by the presence of inflammatory mediators in drusen and inflammatory cell infiltrates in affected ocular tissues . Polymorphism has been identified in several immune-related genes associated with the risk of AMD .…”

Section: Introductionmentioning

confidence: 99%

“…[5][6][7] Chronic low-level local inflammation is indicated by the presence of inflammatory mediators in drusen 8 and inflammatory cell infiltrates in affected ocular tissues. 9 Polymorphism has been identified in several immune-related genes associated with the risk of AMD. 10 A recent transcriptomewide association study reported marked upregulation of genes associated with complement system activation in advanced AMD (ocular and nonocular tissues).…”

mentioning

confidence: 99%

Janus Kinase Inhibitor Therapy and Risk of Age-Related Macular Degeneration in Autoimmune Disease

Hallak,

Abbasi,

Goldberg

et al. 2024

JAMA Ophthalmol

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ImportanceThe involvement of chronic inflammation in the pathogenesis of age-related macular degeneration (AMD) opens therapeutic possibilities to AMD management.ObjectiveTo determine whether Janus kinase inhibitors (JAKis) are associated with a reduced risk of AMD development in patients with autoimmune diseases.Design, Setting, and ParticipantsThis retrospective observational cohort study used administrative claims data from Merative MarketScan research databases (Commercial and Medicare Supplemental) and Optum Clinformatics Data Mart databases between January 1, 2010, and January 31, 2022. Patients with autoimmune diseases satisfying study eligibility criteria and who received JAKi treatment (9126 in MarketScan and 5667 in Optum) were propensity score matched (1:1) to identical numbers of study-eligible patients who received non–JAKi-based immunotherapy.ExposureTreatment duration of 6 months or longer.Main Outcomes and MeasuresIncidence rates of AMD (exudative and nonexudative) over the first 6 to 18 months of treatment were determined, and bayesian Poisson regression models were used to estimate incidence rate ratios, 95% CIs, and posterior probabilities of AMD.ResultsAfter matching, female sex represented the majority of the patient population in both MarketScan and Optum (14 019/18 252 [76.6%] and 8563/3364 [75.2%], respectively in the JAKi patient population). More than 60% of the patient population was older than 55 years of age in both cohorts. Over the specified treatment period, a 49% relative reduction in incidence of AMD was observed among patients who received JAKi therapy (10/9126 events; adjusted incidence rate ratio [AIRR], 0.51; 95% CI, 0.19-0.90) vs those who received non-JAKi therapy (43/9126 events; AIRR, 1 [reference]) in MarketScan, and a 73% relative reduction in incidence of AMD was observed among patients who received JAKi therapy (3/5667 events; AIRR, 0.27; 95% CI, 0.03-0.74) vs those who received non-JAKi therapy (21/5667 events; AIRR, 1 [reference]) in Optum. The absolute percentage reductions were 0.36% (MarketScan) and 0.32% (Optum), favoring patients who received JAKi therapy. Posterior probabilities of the adjusted risk being less than unity were 97.6% (MarketScan) and 98.9% (Optum) for those who received JAKi therapy vs those who received non-JAKi therapy in MarketScan and Optum, respectively.Conclusions and RelevanceJAKi use may be associated with a reduced risk of incident AMD in US adults with major autoimmune diseases. The absolute percentage reduction is consistent with a potential role for JAKi in this population. Future studies with long-term follow-up are recommended to investigate the association between JAKi use and incident AMD in other disease indications. Investigation into the role of systemic inflammation and JAK–signal transducers and activators of transcription signaling in AMD may improve understanding of the pathophysiology of AMD and lead to new treatment options.

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Beyond the Complement Cascade: Insights into Systemic Immunosenescence and Inflammaging in Age-Related Macular Degeneration and Current Barriers to Treatment

Cited by 8 publications

References 205 publications

The role of age in ocular toxoplasmosis: clinical signs of immunosenescence and inflammaging

The role of age in ocular toxoplasmosis: clinical signs of immunosenescence and inflammaging

Aging in Ocular Blood Vessels: Molecular Insights and the Role of Oxidative Stress

Janus Kinase Inhibitor Therapy and Risk of Age-Related Macular Degeneration in Autoimmune Disease

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