Predicted Indirectly Recognizable HLA Epitopes Presented by HLA‐DRB1 Are Related to HLA Antibody Formation During Pregnancy

Pregnancy can prime maternal immune responses against inherited paternal HLA of the fetus, leading to the production of child‐specific HLA antibodies. We previously demonstrated that donor‐specific HLA antibody formation after kidney transplantation is associated with donor‐derived HLA epitopes presented by recipient HLA class II (predicted indirectly recognizable HLA epitopes presented by HLA class II [PIRCHE‐II]). In the present study, we evaluated the role of PIRCHE‐II in child‐specific HLA antibody formation during pregnancy. A total of 229 mother–child pairs were HLA typed. For all mismatched HLA class I molecules of the child, we subsequently predicted the number of HLA epitopes that could be presented by maternal HLA class II molecules. Child‐specific antigens were classified as either immunogenic or nonimmunogenic HLA based on the presence of specific antibodies and correlated to PIRCHE‐II numbers. Immunogenic HLA contained higher PIRCHE‐II numbers than nonimmunogenic HLA. Moreover, the probability of antibody production during pregnancy increased with the number of PIRCHE‐II. In conclusion, our data suggest that the number of PIRCHE‐II is related to the formation of child‐specific HLA antibodies during pregnancy. Present confirmation of the role of PIRCHE‐II in antibody formation outside the transplantation setting suggests the PIRCHE‐II concept is universal. This study provides new insights into the role of indirectly recognizable HLA epitopes presented by HLA‐DRB1 in the generation of humoral immune responses to HLA during pregnancy. See the editorial from Duquesnoy on page 3019.