Recent studies showed that gain-of-function mutations of MDA5 (GOF MDA5) lead to aberrant activation of its signaling, resulting in a variety of immune disorders, such as Aicardi-Goutières syndrome (AGS) and systemic lupus erythematosus (SLE).127–129 Further study indicates that the Alu: Alu hybrids formed of inverted repeats (IRs) which are abundant in the cytosol, are the primary ligands for GOF MDA5, while wild type MDA5 has limited ability to recognize Alu: Alu hybrids. This evidence concerns the gene IFIH1 and Aicardi-Goutières syndrome.