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Natasha Buchanan, John Demirs, Steve Louie, Sassan Azarian, Karen Anderson, Bruce Jaffee, Sha-Mei Liao; Low-grade Ocular Inflammation Is Chronically Present In Complement Factor H-deficient Mice. Invest. Ophthalmol. Vis. Sci. 2011;52(14):978.
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There is a strong association between complement dysregulation, age-related macular degeneration (AMD), and membranoproliferative glomerulonephritis (MPGN). To explore the basis for this association, we characterized complement factor H-deficient mice.
We evaluated C57Bl/6 wild-type, CFH(+/-), and CFH(-/-) mice from 2 to 23 months of age. Plasma complement levels were measured by western blots. Eyes and kidneys were evaluated histologically. Urine albumin was assessed monthly. Neutrophils were evaluated by a myeloperoxidase assay, and inflammatory cytokines were evaluated by multiplex ELISA or Taqman. Ocular A2E levels were evaluated by LC-MS.
CFH(-/-) mice had continuous complement activation as measured by low plasma complement components C3α and factor B (~5% of normal; p<0.001) and increased complement breakdown byproducts iC3b and Factor Ba (~250%, p<0.001). At 23 months, the retina, RPE, and choroid in CFH(-/-) mice were histologically similar to controls, but neutrophils and pro-inflammatory mediators MCP1, TNFa, and CD11b were increased by 50% (p<0.001). Complement C3 of RPE cells and ocular A2E levels were modestly elevated (~20% increase, p<0.001) in the aged CFH(-/-) mice. Histologically, C3 in glomerular basement membranes (GBM) and the severity of kidney pathology (mesangial matrix expansion, crescent formation, and GBM segmentation) increased with age in CFH(-/-) mice. Albuminuria in CFH(-/-) mice was evident by 5 months of age. Neutrophils and inflammatory cytokines SDF1b, IL6, and MMP9 were increased by 50% (p<0.001) in CFH(-/-) mouse kidneys. CFH(+/-) mice had no significant changes.
Neutrophils and inflammatory cytokines are present in the posterior segments of mice with complement dysregulation due to lack of CFH. In addition, features associated with AMD, such as elevated A2E and C3, are found in ocular tissue of aged CFH (-/-) mice. Kidneys had impaired function and elevated neutrophils, inflammatory cytokines, and C3; these are features characteristic of humans with MPGN. CFH deficiency may induce continuous, low-grade ocular and kidney inflammation that may play a role in the pathogenesis of AMD and MPGN.
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