Complement factor H Y402H polymorphism results in diminishing CD4+ T cells and increasing C-reactive protein in
Marie Krogh Nielsen1, Yousif Subhi2,3, Mads Falk1
1Clinical Eye Research Division, Department of Ophthalmology, Zealand University Hospital, Roskilde, Denmark.
Insights
The CFH Y402H risk genotype is linked to lower CD4+ T cells and higher CRP levels in healthy individuals, suggesting immune changes precede age-related macular degeneration (AMD). This finding sheds light on AMD
Area of Science:
- Immunology
- Genetics
- Ophthalmology
Background:
- Age-related macular degeneration (AMD) is a leading cause of vision loss in older adults.
- Genetic variants in complement factor H (CFH) are associated with AMD risk, but the underlying mechanisms are unclear.
- Low-grade inflammation and immune system dysregulation are implicated in AMD pathogenesis.
Purpose of the Study:
- To investigate the association between the CFH Y402H genotype and markers of low-grade inflammation.
- To explore the relationship between the CFH Y402H genotype, immune cell profiles, and AMD stages.
- To elucidate the role of complement dysregulation in the development of AMD.
Main Methods:
- Recruited healthy individuals, dry AMD, and neovascular AMD participants.
- Performed retinal examinations, lifestyle interviews, and blood sample analysis for C-Reactive Protein (CRP) and T cell subsets (CD4+, CD8+).
- Conducted CFH Y402H genotyping and analyzed splenocytes from wild type and Cfh null mutant mice.
Main Results:
- Healthy individuals with the risk HH genotype showed higher CRP and lower CD4+ T cell proportions compared to YH/YY genotypes.
- The HH genotype was associated with an age-related decrease in CD4+ T cells in healthy individuals and in dry AMD patients.
- Cfh null mutant mice also exhibited lower CD4+ T cell proportions, supporting a role for complement in T cell regulation.
Conclusions:
- The risk-associated CFH genotype is linked to an age-related decrease in CD4+ T cells and elevated CRP levels in healthy individuals.
- These findings suggest that impaired complement regulation leads to immune alterations that may precede AMD development.
- The study highlights the intricate interplay between genetic predisposition, immune dysregulation, and the pathogenesis of age-related macular degeneration.
Abstract:
Age-related macular degeneration (AMD) is a common cause of visual loss among the elderly. Genetic variants in the gene encoding complement factor H (CFH) have been identified as an AMD susceptibility gene, however, the mechanistic link is debated. Here, we investigated the link between the CFH Y402H genotype and low-grade inflammation. We recruited 153 healthy individuals, 84 participants with dry stages of AMD, and 148 participants with neovascular AMD. All participants were subjected to detailed retinal examination, and interview regarding comorbidities and lifestyle. Blood samples were analyzed for level of C-Reactive Protein (CRP), white blood cell differential count, and stained with fluorescent antibodies to differentiate CD4+ and CD8+ T cells. CFH Y402H genotyping was performed using an allele-specific polymerase chain reaction genotyping assay. Splenocytes from young and aged wild type and Cfh null mutant C57BL/6J mice were examined for CD4+ and CD8+ T cells. Healthy individuals with the CFH Y402H at-risk polymorphism HH had higher levels of CRP and lower proportions of CD4+ T cells compared to persons with the YH or YY polymorphism (P = 0.037, Chi-square). Healthy individuals with the HH polymorphism displayed lower proportions of CD4+ T cells with ageing (P < 0.01, one-way ANOVA), whereas both young and aged Cfh null mutant mice displayed lower proportions of CD4+ T cells (P < 0.001 and P < 0.05; unpaired t test). Participants with dry AMD and the HH polymorphism had similarly lower proportions of CD4+ T cells (P = 0.024, one-way ANOVA), but no difference in CRP-levels. In the neovascular stage of AMD, there was no difference in proportion of CD4+ cells or CRP levels according to genotype. The risk-associated CFH genotype is associated with an age-related decrease in proportion of CD4+ T cells and increased levels of CRP in healthy individuals. This indicates that decreased complement regulation results in extensive changes in innate and adaptive immune compartments that precede development of AMD.
