Immune-mediated mechanism of AA and clonal evolution. (A) AA is thought to be initiated by recognition and destruction of HSCs by CTLs, which recognize some unknown antigen present on HSCs via their HLA class I molecule. Supporting this hypothesis is a limited usage of T-cell receptor Vβ subsets at diagnosis, suggestive of the presence of oligoclonal expansion of CD8+CD28− T cells, which diminish or disappear with successful IST.1-3 Overproduction of inflammatory cytokines, including interferon γ (IFNγ) and tumor necrosis factor α (TNFα), from aberrantly activated immune cells and stromal microenvironments is also suggested to make a significant contribution to BM failure, in which the role of FAS-mediated apoptosis has been implicated.4 (B) During and/or after immune-mediated BM destruction, a rapid expansion of residual cells (which escaped destruction) occurs, whereby cells carrying mutations achieve clonal dominance and may progress to malignant proliferation. CTL, cytotoxic T cell; HSC, hematopoietic stem cell; IST, immunosuppressive therapy.
