Bisretinoid-mediated complement activation on retinal pigment epithelial cells is dependent on complement factor H...

Area of Science:

• Ophthalmology
• Immunology
• Genetics

Background:

• Age-related macular degeneration (AMD) is a leading cause of vision loss in the elderly.
• Genetic variants in complement factor H (CFH), specifically Y402H and I62V substitutions, are strongly linked to AMD risk.
• Stargardt maculopathy, another blinding disease, involves mutations in ABCA4, leading to toxic bisretinoid accumulation.

Purpose of the Study:

• To investigate the link between CFH haplotype in human retinal pigment epithelium (hRPE) cells, exposure to bisretinoid-laden photoreceptor outer segments (OS), and complement activation.
• To determine if specific CFH haplotypes influence complement system response to bisretinoid stress in hRPE cells.

Main Methods:

• Cultured human RPE (hRPE) cells with different CFH haplotypes (AMD-predisposing HH402/VV62 and AMD-protective YY402/II62) were exposed to outer segments (OS) from Abca4(-/-) mice (containing bisretinoids) and wild-type OS.
• Complement activation, including factor B dependence and membrane attack complex (MAC) deposition, was assessed in response to OS exposure.

Main Results:

• hRPE cells with the AMD-predisposing CFH haplotype (HH402/VV62) exhibited complement activation, dependent on factor B, when exposed to bisretinoid-containing Abca4(-/-) OS.
• In contrast, hRPE cells with the AMD-protective CFH haplotype (YY402/II62) showed no complement activation after exposure to either type of OS.
• HH402/VV62 hRPE cells demonstrated significant MAC deposition after ingesting Abca4(-/-) OS, indicating increased vulnerability compared to YY402/II62 cells.

Conclusions:

• Accumulation of bisretinoids within hRPE cells can trigger complement system activation and dysregulation.
• hRPE cells with reduced complement inhibitory function due to specific CFH variants are susceptible to complement-mediated damage.
• These findings highlight the role of complement dysregulation in AMD pathogenesis, particularly in the context of bisretinoid accumulation.