Is the HLA System Really Involved in Implantation, Pregnancy, or Abortion of the Fetus?: Strengths, Weaknesses, and Controversial Points

PROBLEMS: Pregnancy is a sensitizing event for human leukocyte antigen (HLA) alleles, as the fetus, acting as a semi-allograft, expresses maternal and paternal haplotypes in a codominant manner. Consequently, the mother may develop anti-HLA antibodies directed against the paternal haplotype. However, unlike in organ transplantation, this sensitization is not usually associated with fetal rejection in multiparous women, raising a central question in reproductive immunology: How is maternal-fetal tolerance achieved and maintained? METHOD OF STUDY: This review examines the influence of the HLA system on the immunological mechanisms underlying maternal-fetal tolerance. RESULTS: Accumulating evidence suggests that this phenomenon results from a complex network of cellular and molecular interactions. The roles of non-classical HLA molecules, particularly HLA-G, the modulation of NK activity via KIR receptors, and the expansion of regulatory T cells, which contribute to the maintenance of systemic immunological tolerance, are highlighted. In parallel, the relevance of anti-HLA antibodies and polymorphisms in HLA regulatory regions in susceptibility to gestational complications has been investigated. CONCLUSION: It considers how insights from reproductive immunology may inform related fields such as transplantation and oncology.