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E. Medof, N. Muqim, K. G. Shadrach, J. W. Crabb, J. G. Hollyfield, L. Kuttner-Kondo; AMD Is an Autoimmune Disorder in Which Amplification of Complement Activation Triggered by Anti-CEP Autoantibodies Occurs as a Result of Diminished Factor H Function. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2179.
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While fH polymorphisms have been linked to AMD susceptibility, AMD’s age-dependency and pathogenic mechanism remain unclarified. Our group has shown that CEP protein adducts are elevated in AMD Bruch’s membrane, and in AMD plasma both CEP adducts and anti-CEP autoantibodies are increased. To test whether anti-CEP autoantibodies can induce complement activation on Bruch’s membrane and to determine how AMD relevant fH polymorphisms affect control of Bruch’s membrane-associated complement activation, we prepared fH CCPs 1-10 containing each substitution and compared their C3 convertase regulatory activities to native CCPs 1-10 in the fluid phase and on Bruch’s membrane.
For assaying fluid phase DAA, each recombinant fH module was mixed with C3b, C3, fB, and fD, and C3a generation quantitated. For CF activity, each fH module was mixed with C3b and fI, and C3 cleavage assessed. For assaying alternative pathway activation on Bruch’s membrane, anti-CEP mAb or AMD patients’ sera, C1, C4, C2, and C3 were sequentially added, C1/C2 decayed, then C3, fB, fD, and each fH module added, and C3a generation quantitated. The binding of each fH module to CRP was assessed by ELISA.
In the fluid phase, fH I62V, but not Y402H, showed diminished fI cofactor and decay accelerating activity. AMD Bruch’s membranes sensitized with anti-CEP mAb or patients’ sera showed (1) greater C3a generation than age matched control membranes in the presence of native fH CCPs 1-10, and (2) with both fH variants exhibited impaired C3 convertase control, the former due to diminished C3bBb decay and the latter to less avid binding to Bruch’s membrane. The Y402H variant showed diminished binding to CRP.
Taken together, the findings provide 1) a mechanistic explanation for the genetic association of these two fH polymorphisms with AMD and 2) because CEP adducts accumulate gradually, provide an explanation for the age-dependency of the disease.
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