Clusterin and complement activation in exfoliation glaucoma

Ivo Doudevski, Agueda Rostagno, Mary Cowman, Jeffrey Liebmann, Robert Ritch, Jorge Ghiso

Research output: Contribution to journalArticle

Abstract

PURPOSE. The study was done to better understand the biological significance of clusterin colocalization with the exfoliation deposits (XF deposits), and provide insight into a pathogenic mechanism involving activation of the complement system and its pro-inflammatory consequences in patients with exfoliation glaucoma. METHODS. Exfoliation lens deposits were analyzed by high resolution atomic force microscopy imaging and confocal immunofluorescence. Levels of clusterin and vitronectin, as well as of the complement activation products C3a and soluble C5b-9, were assessed via ELISA. RESULTS. Atomic-force microscopy examination of lenses with exfoliation syndrome (XFS) revealed a dense fibrillar network on the anterior, aqueous-bathed surface of the lens, while the epithelial side displayed no discernible structural features at the same resolution. Clusterin colocalized with XF deposits, demonstrating integral association with the fibrils. Levels of activation-derived complement components C3a and soluble C5b-9, as well as the complement inhibitors clusterin and vitronectin, were found significantly elevated (1.7-fold, P < 0.05; 4.1-fold, P < 0.05; 1.8-fold, P < 0.01; and 3.0-fold, P < 0.01, respectively) in aqueous humor from glaucoma patients with XFS compared to non-XFS glaucoma controls. CONCLUSIONS. The data provide compelling evidence for the activation of the complement system in XFS, highlighting the generation of subproducts with potent proinflammatory activity, which are capable of triggering and chronically maintaining levels of subclinical inflammation, suggesting novel targets for therapeutic intervention. The colocalization of clusterin in exfoliation fibrils suggests a failed attempt to prevent tissue accumulation of protein aggregates, as seen in other protein folding disorders, likely due to the abnormal high levels of misfolded proteins overwhelming its chaperone capacity.

Original languageEnglish (US)
Pages (from-to)2491-2499
Number of pages9
JournalInvestigative Ophthalmology and Visual Science
Volume55
Issue number4
DOIs
StatePublished - Feb 18 2014

Fingerprint

Exfoliation Syndrome
Clusterin
Complement Activation
Lenses
Complement Membrane Attack Complex
Vitronectin
Atomic Force Microscopy
Complement Inactivating Agents
Glaucoma
Complement C3a
Proteostasis Deficiencies
Aqueous Humor
Fluorescent Antibody Technique
Enzyme-Linked Immunosorbent Assay
Inflammation
Proteins

Keywords

  • Complement system
  • Exfoliation syndrome
  • Extracellular chaperones
  • Protein misfolding disorders

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

Cite this

Clusterin and complement activation in exfoliation glaucoma. / Doudevski, Ivo; Rostagno, Agueda; Cowman, Mary; Liebmann, Jeffrey; Ritch, Robert; Ghiso, Jorge.

In: Investigative Ophthalmology and Visual Science, Vol. 55, No. 4, 18.02.2014, p. 2491-2499.

Research output: Contribution to journalArticle

Doudevski, I, Rostagno, A, Cowman, M, Liebmann, J, Ritch, R & Ghiso, J 2014, 'Clusterin and complement activation in exfoliation glaucoma', Investigative Ophthalmology and Visual Science, vol. 55, no. 4, pp. 2491-2499. https://doi.org/10.1167/iovs.13-12941
Doudevski, Ivo ; Rostagno, Agueda ; Cowman, Mary ; Liebmann, Jeffrey ; Ritch, Robert ; Ghiso, Jorge. / Clusterin and complement activation in exfoliation glaucoma. In: Investigative Ophthalmology and Visual Science. 2014 ; Vol. 55, No. 4. pp. 2491-2499.
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AU - Doudevski, Ivo

AU - Rostagno, Agueda

AU - Cowman, Mary

AU - Liebmann, Jeffrey

AU - Ritch, Robert

AU - Ghiso, Jorge

PY - 2014/2/18

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N2 - PURPOSE. The study was done to better understand the biological significance of clusterin colocalization with the exfoliation deposits (XF deposits), and provide insight into a pathogenic mechanism involving activation of the complement system and its pro-inflammatory consequences in patients with exfoliation glaucoma. METHODS. Exfoliation lens deposits were analyzed by high resolution atomic force microscopy imaging and confocal immunofluorescence. Levels of clusterin and vitronectin, as well as of the complement activation products C3a and soluble C5b-9, were assessed via ELISA. RESULTS. Atomic-force microscopy examination of lenses with exfoliation syndrome (XFS) revealed a dense fibrillar network on the anterior, aqueous-bathed surface of the lens, while the epithelial side displayed no discernible structural features at the same resolution. Clusterin colocalized with XF deposits, demonstrating integral association with the fibrils. Levels of activation-derived complement components C3a and soluble C5b-9, as well as the complement inhibitors clusterin and vitronectin, were found significantly elevated (1.7-fold, P < 0.05; 4.1-fold, P < 0.05; 1.8-fold, P < 0.01; and 3.0-fold, P < 0.01, respectively) in aqueous humor from glaucoma patients with XFS compared to non-XFS glaucoma controls. CONCLUSIONS. The data provide compelling evidence for the activation of the complement system in XFS, highlighting the generation of subproducts with potent proinflammatory activity, which are capable of triggering and chronically maintaining levels of subclinical inflammation, suggesting novel targets for therapeutic intervention. The colocalization of clusterin in exfoliation fibrils suggests a failed attempt to prevent tissue accumulation of protein aggregates, as seen in other protein folding disorders, likely due to the abnormal high levels of misfolded proteins overwhelming its chaperone capacity.

AB - PURPOSE. The study was done to better understand the biological significance of clusterin colocalization with the exfoliation deposits (XF deposits), and provide insight into a pathogenic mechanism involving activation of the complement system and its pro-inflammatory consequences in patients with exfoliation glaucoma. METHODS. Exfoliation lens deposits were analyzed by high resolution atomic force microscopy imaging and confocal immunofluorescence. Levels of clusterin and vitronectin, as well as of the complement activation products C3a and soluble C5b-9, were assessed via ELISA. RESULTS. Atomic-force microscopy examination of lenses with exfoliation syndrome (XFS) revealed a dense fibrillar network on the anterior, aqueous-bathed surface of the lens, while the epithelial side displayed no discernible structural features at the same resolution. Clusterin colocalized with XF deposits, demonstrating integral association with the fibrils. Levels of activation-derived complement components C3a and soluble C5b-9, as well as the complement inhibitors clusterin and vitronectin, were found significantly elevated (1.7-fold, P < 0.05; 4.1-fold, P < 0.05; 1.8-fold, P < 0.01; and 3.0-fold, P < 0.01, respectively) in aqueous humor from glaucoma patients with XFS compared to non-XFS glaucoma controls. CONCLUSIONS. The data provide compelling evidence for the activation of the complement system in XFS, highlighting the generation of subproducts with potent proinflammatory activity, which are capable of triggering and chronically maintaining levels of subclinical inflammation, suggesting novel targets for therapeutic intervention. The colocalization of clusterin in exfoliation fibrils suggests a failed attempt to prevent tissue accumulation of protein aggregates, as seen in other protein folding disorders, likely due to the abnormal high levels of misfolded proteins overwhelming its chaperone capacity.

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KW - Extracellular chaperones

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