Models for clonal expansion in PNH. (a) In the first model, the PIG-A mutation sufficiently affects cellular function to cause an intrinsic growth advantage. (b) Extrinsic factors are invoked for other models; immune effects are illustrated, but differential responses to hematopoietic growth factors, inhibitory cytokines, or stromal cells are also possible. (c) GPI-anchor deficiency might produce a global deficit in immune recognition, as for example through absence of a costimulatory molecule on the target, providing a general selective advantage to the mutated cells. (d) Alternatively, a GPI-anchor protein might be antigenic, by resemblance to an exogenous antigen or after antigenic spread. (e) Finally, altered protein processing due to the absence of anchor structures might change the nature and quantity of peptides derived from normally GPI-anchored proteins, as well as their MHC presentation. As illustrated, cell surface proteins are normally recycled to the membrane or degraded by lysosomes for class II presentation; in PNH, anchorless proteins likely are processed by the proteasome for class I presentation. Differences in immune response to normal and PNH cells should follow.