A Potential Biomarker for AMD Progression

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A team of researchers, building on the knowledge that chronic local inflammation underlies the pathogenesis of age-related macular degeneration (AMD), report that interleukin-4 (IL-4), an immunomodulatory cytokine, is significantly elevated in patients with geographic atrophy (GA).¹ The finding suggests that IL-4 may be a marker for GA in the evolution of AMD progression. The finding also moves the University of Colorado Retina Research Group one step closer to answering a question underpinning their ongoing research: Do patients with intermediate AMD (iAMD) who progress to advanced AMD have a differ­ent profile of systemic inflammatory disease markers compared with iAMD patients who do not progress to advanced AMD?

The investigation is part of a longitudinal cohort study that analyzes data from the University of Colorado Age-Related Macular Degeneration Registry, established to study the effect of multiple systemic inflammatory pathways and their influence on the development and progression of AMD.

“Our findings of elevated IL-4 in GA compared to iAMD patients suggest that IL-4 is a marker for system­ic immunological differences between GA and iAMD,” said lead author Vivian Rajeswaren, MS.

Methodology. To determine whether systemic IL-4 is recruited to the retina to reduce the inflammation that underlies AMD, the researchers analyzed IL-4 plasma levels in patients with iAMD (n=199) and GA (n=97) and in healthy controls (n=139), using data collected between 2014 and 2021. They found that dramatically elevated IL-4 levels in the GA cohort may indicate alterations in the cytokine network in AMD patients that function to regulate inflammation.

The researchers also evaluated whether IL-4 levels are moderated by sex and found slightly higher IL-4 levels in male subjects among GA cases. Although not statistically significant, the finding suggests sex may also be a biologic modifier in chronic inflammatory disease.

Pro- or anti-inflammatory? It’s not yet clear whether an elevated concentration of IL-4 indicates a protective or destructive effect against inflammation. One theory holds that IL-4 mediates mast cell production and degranulation, which leads to inflammation, and possibly contributes to retinal or choroidal degeneration, said senior author Alan G. Palestine, MD.

Another theory posits that IL-4 recruits specialized cells—M2 phenotype macrophages—to the retina to clear damaged cells. IL-4 is often considered an anti-inflammatory cytokine, and so activation of this pathway may inhibit further inflammation, said Ms. Rajeswaren.

“At this stage, it is difficult to determine which explanation is more plausible, or if both pathways are activated concomitantly,” Dr. Palestine said. “Our findings suggest an important but yet to be fully defined role for systemic IL-4 in targeted control of inflammation in the pathogenesis of GA. Our next step is to extend our findings to a larger cohort including neovascular AMD patients to better understand underlying disease mechanisms and potential systemic biomarkers.”

—Miriam Karmel

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1 Rajeswaren V et al. Transl Vis Sci Technol. 2023;12(8):1.

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Relevant financial disclosures: Dr. Palestine—Tarsier Pharma: C. Ms. Rajeswaren—None.

For full disclosures and the disclosure key, see below.

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