Antibody-mediated pathogenesis of chronic GVHD through DBY/HLA class II complexes and induction of a GVL effect

•Specific HLA class II alleles are risk factors for cGVHD in HLA-identical female-to-male transplantat relying on full-length DBY presenting capability.•Full-length DBY complexed with HLA class II on vascular endothelium directly contribute to the antibody-mediated pathogenesis of cGVHD. [Display omitted] Chronic graft-versus-host disease (cGVHD) is a multiorgan syndrome with clinical features resembling those of autoimmune diseases. Thus, understanding commonalities in the pathophysiology of cGVHD and autoimmune diseases, such as the presence of disease-risk HLA alleles, is imperative for developing novel therapies against cGVHD. Alloantibodies against H-Y antigens encoded on the Y-chromosome are well-described risk factors for cGVHD in female-to-male transplantation. However, because H-Y antigens generally localize intracellularly in the male reproductive organs, how they emerge at affected organ levels remains elusive. Here, by analyzing nationwide registry data stratified per donor–recipient sex, we identified specific HLA class II alleles that contributed to susceptibility to male cGVHD after transplantation from HLA-identical female siblings (HLA-DRB1∗15:02: hazard ratio, 1.28; 95% confidence interval, 1.03-1.58; P = .025). Coexpression of HLA-DRB1∗15:02 efficiently transported full-length H-Y antigens, especially DBY, to the surface. The presence of alloantibodies against DBY/HLA class II complexes significantly predicted the occurrence of cGVHD (68.8% vs 31.7% at 1 year; P = .002). Notably, the ability of HLA class II molecules to transport and present DBY to alloantibodies was closely associated with the susceptibility of HLA class II alleles to cGVHD. DBY specifically colocalized with HLA class II molecules on the dermal vascular endothelium in cGVHD and provoked complement-dependent cytotoxicity. Moreover, these complexes were observed in some male leukemic cells. Altogether, these findings suggest that vascular endothelial cells facilitate alloantibody-mediated cGVHD and highlight that alloantibodies against DBY/HLA class II complexes could be common targets for cGVHD and a graft-versus-leukemia effect. Chronic graft-versus-host disease (cGVHD) has many features resembling autoimmune diseases such as scleroderma. Alloantibodies against H-Y antigens, encoded on the Y chromosome, are a risk factor for cGVHD in female-into-male transplantation. Umino and colleagues investigated the link between these 2 observations and demonstrate that, although H