Hypothetical role of SIRPα variant mismatch in HSCT with an HLA-matched donor. (A) Matched SIRPα variants between donor and recipient. The interaction between SIRPα and CD47 remains in the balance of activation and inhibition signals without any “non-self” response from monocytes. (B) Mismatched SIRPα variants between donor and recipient elicit a “non-self” signal for monocyte activation. Donor and recipient APCs, including macrophages and DCs, are activated. The enhanced innate immunity may further promote adaptive immunity through specific effector cells, which will lead to a higher risk for cGVHD and other clinical manifestations.