Mapping the pathogenesis of immune-mediated aplastic anemia: filling the gaps

Immune-mediated aplastic anemia (AA) is a rare and life-threatening bone marrow failure disorder caused by autoimmune-mediated destruction of hematopoietic stem and progenitor cells in the bone marrow, resulting in severely reduced peripheral blood counts. Although immunosuppressive therapy can restore hematopoiesis in some patients, the immune mechanisms underlying disease development and treatment response remain incompletely understood. This thesis aimed to elucidate the immune response underlying the pathogenesis of AA by comprehensively characterizing the immune landscape in the bone marrow, the primary site of disease. Using advanced single-cell and spatial profiling technologies, immune cells were analyzed in bone marrow samples obtained from patients with AA before and after treatment. The findings demonstrate that AA is driven by a coordinated immune response involving a broad spectrum of immune cell phenotypes. Several cell subpopulations, including CCR6-expressing B-cells and T-cells, were identified as potentially pathogenic subpopulations. In addition, this thesis provides new insights into the mechanisms of action of immunosuppressive therapy and the biological processes that may contribute to leukemic evolution. Collectively, this thesis provides a comprehensive atlas of the immune landscape in AA, advances our understanding of AA pathogenesis, and identifies potential targets for the development of more precise and effective therapies.