Altered Expression of CD46 and CD59 on Leukocytes in Neovascular Age-Related Macular Degeneration

Singh, Amardeep; Faber, Carsten; Falk, Mads Krüger; Nissen, Mogens Holst; Hviid, Thomas Vauvert F.; Sørensen, Torben Lykke

doi:10.1016/j.ajo.2012.01.036

Cited by 48 publications

(44 citation statements)

References 40 publications

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“…A recent study showed that the monocytes of wet AMD patients had significantly lower expression levels of the complement regulators CD46 and CD59 [73]. Taken together, the findings suggest that the levels of circulating complement proteins increase with aging.…”

Section: Raised Complement In the Blood Of Amd Patientssupporting

confidence: 62%

Age-Related Macular Degeneration: A Complementopathy?

Kijlstra¹,

Berendschot²

2015

Ophthalmic Res

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Age-related macular degeneration (AMD) is a progressive eye disease affecting many elderly individuals. It has a multifactorial pathogenesis and is associated with numerous environmental (e.g. smoking, light and nutrition) and genetic risk factors. A breakthrough in the mechanisms causing AMD is emerging; the involvement of the alternative pathway of the complement system appears to play a pivotal role. This has led to the statement that AMD is a disease caused by a hyperactive complement system, allowing the term ‘complementopathy' to define it more precisely. Abundant evidence includes: the identification of drusen components as activators of complement, immunohistochemical data showing the presence of many species of the complement system in the retinal pigment epithelium-Bruch's membrane-choroidocapillary region of AMD eyes, a strong association of AMD with certain genetic complement protein variants, raised complement levels in blood from AMD patients and the preliminary successful treatments of geographic atrophy with complement factor D (FD) inhibitors. FD is the rate-limiting enzyme of the alternative complement pathway, and is produced by adipose tissue. Recent findings suggest that nutrition may play a role in controlling the level of FD in the circulation. Addressing modifiable risk factors such as smoking and nutrition may thus offer opportunities for the prevention of AMD.

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Section: Raised Complement In the Blood Of Amd Patientssupporting

confidence: 62%

Age-Related Macular Degeneration: A Complementopathy?

Kijlstra¹,

Berendschot²

2015

Ophthalmic Res

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“…In addition, we demonstrated that this polymorphism is associated with a risk of BOS development. CD59 expression is important in various diseases, including age-related macular degeneration (20). Furthermore, hyperexpression of CD59 on ECs is suggested to be crucial in graft accommodation following transplantation (1,5,7).…”

Section: Discussionmentioning

confidence: 99%

A Promoter Polymorphism in the CD59 Complement Regulatory Protein Gene in Donor Lungs Correlates With a Higher Risk for Chronic Rejection After Lung Transplantation

Budding

Graaf

Kardol‐Hoefnagel

et al. 2016

American Journal of Transplantation

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Complement activation leads primarily to membrane attack complex formation and subsequent target cell lysis. Protection against self-damage is regulated by complement regulatory proteins, including CD46, CD55, and CD59. Within their promoter regions, singlenucleotide polymorphisms (SNPs) are present that could influence transcription. We analyzed these SNPs and investigated their influence on protein expression levels. A single SNP configuration in the promoter region of CD59 was found correlating with lower CD59 expression on lung endothelial cells (p ¼ 0.016) and monocytes (p ¼ 0.013). Lung endothelial cells with this SNP configuration secreted more profibrotic cytokine IL-6 (p ¼ 0.047) and fibroblast growth factor b (p ¼ 0.036) on exposure to sublytic complement activation than cells with the opposing configuration, whereas monocytes were more susceptible to antibody-mediated complement lysis (p < 0.0001). Analysis of 137 lung transplant donors indicated that this CD59 SNP configuration correlates with impaired long-term survival (p ¼ 0.094) and a significantly higher incidence of bronchiolitis obliterans syndrome (p ¼ 0.046) in the recipient. These findings support a role for complement in the pathogenesis of this posttransplant complication and are the first to show a deleterious association of a donor CD59 promoter polymorphism in lung transplantation.

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“…In support of this, systemic virus infection in mice resulting in acute complement activation induced a transient 2-fold decrease in Cd59a expression in RPE/choroid (Faber C. unpublished data) and a decreased density of CD59 on peripheral monocytes have been reported in patients with neovascular AMD. 35 Collectively, the retinal damage in AMD could be the result of a local decrease in CD59 expression in response to increased systemic complement activation.…”

Section: Figurementioning

confidence: 99%