HLA-DRB1*15:01 drives sex- and age-dependent microglial immune phenotypes and neuroimmune signaling

IntroductionThe major histocompatibility complex class II (MHC-II) pathway is central to adaptive immunity and immune tolerance, and its age-related dysregulation is increasingly linked to chronic neuroinflammation. The HLA-DRB1*15:01 allele, the strongest genetic risk factor for multiple sclerosis, has been implicated in shaping pathogenic CD4+ T-cell responses and broader neuroimmune vulnerability, yet how this allele modulates age- and sex-dependent neuroimmune processes within the central nervous system (CNS) remains poorly defined.MethodsWe investigated the impact of HLA-DRB1*15:01 expression using a humanized mouse model (HLA mice) and wild-type (WT) controls.

Male and female mice were analyzed at 6, 9, and 15 months of age, with endocrine stratification in females. Behavioral testing, flow cytometry, immunofluorescence, and multiplex cytokine analyses were used to assess cognitive performance, glial immune-associated changes and oxidative stress, astrocyte–microglia IL-3/IL-3R signaling, endothelial activation, selective immune cell accumulation at CNS borders, tissue organization, and hippocampal cytokine profiles.ResultsHLA mice developed age- and sex-dependent cognitive impairment, most pronounced in aged females.