Pathogenesis of PRCA. Various mechanisms may lead to PRCA. (1) Viral infections (eg, B19 parvovirus) and a variety of drugs may have a direct cytotoxic effect against erythroid precursors or also exert an indirect pathogenic effect via a molecular mimicry mechanism. The resulting cross-reactive TCR recognition may lead to a breach of tolerance with polyclonal CTL responses. (2) This latter phenomenon may also be triggered by alteration of immune tolerance because of the presence of thymoma (or thymic dysfunction) with subsequent LGL clonal expansion (in some cases carrying STAT3 mutations). (3) Lack of viral clearance from immunodeficiency (eg, hypoglobulinemia) may be the cause of elicitation of aberrant CTLs responses. Alternatively, in the context of immunodeficiency antibody responses or the inability of TCR recognition may lead to generation of autoreactive T cells with alterations of TCR repertoires evading immune-tolerance mechanisms. For instance, the presence of T-cell subsets with predominant expression of γδ⁺ TCR rearrangements lacking HLA class I restriction could explain the attack of erythroid progenitors, which physiologically present downregulation of HLA class I antigens. GS, Good syndrome; STAT3, signal transducer and activator of transcription 3.