History of the decline and repositioning of the H-Y antigen: From sex determination to reproductive immunology.

Sex determination is a fundamental process in mammalian biology whose conceptual interpretation has evolved with advances in experimental science. Classical thought, influenced by Aristotelian philosophy, viewed femaleness as an incomplete manifestation of maleness, implicitly characterizing ovarian differentiation as passive. Although modern genetics has rejected this paradigm, its influence persisted into the twentieth century. The H-Y antigen, proposed as a primary sex-determining factor, was identified in transplantation immunology when female recipients rejected male tissues. As it was empirically detectable and linked to the Y chromosome, it was incorporated into hypotheses that a Y-linked antigenic signal induced testicular differentiation. During the 1970s and 1980s, this hypothesis gained prominence, reflecting the experimental accessibility of antigenicity compared with transcriptional regulation. The identification of SRY, a DNA-binding protein encoded within the sex-determining region, shifted this framework. Functional studies established SRY as the testis-determining factor, while ovarian differentiation emerged as an active genetic program involving WNT4, RSPO1, and FOXL2. Within this paradigm, the developmental role attributed to the H-Y antigen became untenable. Reproductive immunology has provided a domain in which H-Y antigens remain relevant as Y chromosome-encoded minor histocompatibility antigens. Their significance is increasingly recognized in maternal-fetal immune interactions and pregnancy disorders, with placental biology revealing sex-dependent differences in immune regulation. In this short review, we reassess the conceptual development of the H-Y antigen and its significance in maternal-fetal immunology and the vertical transmission of infectious diseases.