Adaptive immune crosstalk and complement dysregulation in the aging retina.

Abstract

The eye, long viewed as immune-privileged, is now recognized as a dynamic immunological environment where innate and adaptive mechanisms intersect to maintain retinal homeostasis. In aging and age-related retinal diseases such as age-related macular degeneration (AMD), this balance deteriorates as chronic, low-grade inflammation replaces immune quiescence. Adaptive immune involvement in AMD is reflected by increased antiretinal autoantibodies and systemic immune changes, including accelerated aging of CD8⁺ T-cells. Complement activation further amplifies adaptive responses; C5a stimulates T-cell secretion of proinflammatory cytokines, such as interleukin-17 (IL-17) and IL-22, which contribute to retinal injury. Retinal cells exhibit context-dependent immune plasticity. Retinal pigment epithelial (RPE) cells upregulate major histocompatibility complex molecules in response to stress and can express the regulatory transcription factor forkhead box p3 (FOXP3), indicating an intrinsic immunomodulatory capacity. Myeloid populations are likewise heterogeneous: Resident microglia maintain immune surveillance, whereas infiltrating monocyte-derived macrophages often drive maladaptive inflammation and lesion progression. The complement system also contributes to age-related synaptic remodeling, with C1q and C3 tagging synapses for elimination. This pathway is normally limited by Complement Factor H (CFH), whose regulatory function is strengthened by binding to apolipoprotein E (APOE). However, the neurodegeneration-associated APOE ε4 isoform shows reduced CFH affinity, promoting excessive complement activity. Sex-specific immune aging further modifies complement signaling, microglial behavior, and APOE-dependent susceptibility. Together, these insights illustrate how adaptive immunity shifts from protective surveillance to chronic, pathological inflammation, driving the initiation and progression of age-related retinal degeneration.