Argyle, D. A. | bioRxiv Science

bioRxiv2025

Sex differences in human IgG1-mediated angiogenesis inhibition depend on Y chromosome-encoded DDX3Y

Prevalent diseases of angiogenesis such as age-related macular degeneration (AMD) exhibit sex-specific prevalence, with female sex being an independent risk factor for the advanced neovascular form of AMD. The basis for these sex differences is poorly understood. Here, we quantify the impact of sex on suppression of aberrant choroidal angiogenesis by human immunoglobulin 1 (hIgG1), which possesses class-wide, antigen-independent anti-angiogenic activity. Males exhibited significantly more robust hIgG1-induced chemotaxis inhibition in primary human and mouse macrophages and anti-angiogenic activity in mouse laser-induced choroidal neovascularization (CNV). Four core genotypes and XY* Turner Syndrome mouse models revealed the Y chromosome as a sex-biasing factor contributing to hIgG1 responses. Transcriptomic and RNAi screening identified DEAD-Box Helicase 3 Y-Linked (DDX3Y) as necessary for the robust inhibitory effects of hIgG1 in males. Male mice as well as human and mouse macrophages lacking DDX3Y exhibited blunted hIgG1 responses in CNV and macrophage chemotaxis, resembling those of females. These results unveil a novel mechanism through which sex chromosome complement differences can impact key processes involved in AMD, carrying implications for various sex-related disorders and conditions involving angiogenesis.

pathology↗

bioRxiv2023

Survey of commercial antibodies targeting Y chromosome-encoded genes

Commercial antibodies are both a mainstay of biomedical research and subject to increasingly widespread scrutiny for their specificity. We evaluated the specificity of commercially available research grade antibodies by investigating those whose antigen targets are encoded by the Y chromosome. We assessed vendor-provided validation data such as immunoblotting and identified 65 commercial research grade antibodies that exhibited positive reactivity in female-derived tissues and/or cell lines. A thorough analysis of 30 commercial antibodies marketed as targeting the Y chromosome-encoded protein DDX3Y found that 16 (53%) provided no marketing data on specificity, 9 (30%) provided positive data in female or likely female materials, 4 (13%) provided only positive data in male materials, and 1 (3%) provided positive data in male materials and negative data in female materials. Together, these findings suggest that many commercial antibodies may be unsuitable to distinguish between related X and Y chromosome-encoded gene pairs and should instill caution in researchers using these tools to investigate sex chromosome-encoded proteins.

molecular biology↗