Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent muscular dystrophy that presents with asymmetric progressive weakening of muscles in the face, upper body and shoulder girdle, progressing to loss of ambulation and profound physical disabilities. Misexpression of the transcription factor DUX4 is associated with FSHD muscle pathology, but clinical onset and severity are highly variable. We hypothesize that this clinical variability is associated with DUX4 transcriptome disruptions which produce neoantigens that initiate an FSHD patient-specific innate immune response. To investigate the role of innate immunity in FSHD muscle pathology, we have developed a human immune/FSHD muscle double xenograft model in an immune deficient mouse strain that is genetically engineered for the selective expansion of innate immune cells, and for engraftment and differentiation of patient-derived FSHD or healthy control myoblasts when transplanted into the tibialis anterior (TA) muscle. Our findings show that human CD45+ innate immune cells preferentially home to and destroy FSHD xenoengrafted muscle relative to control muscle. Further, NanoString RNA analysis reveals a selective upregulation of complement genes in FSHD xenograft muscle, also observed in FSHD muscle biopsies suggesting activation of the classical complement innate immunity pathway mediated by infiltration of macrophages, dendritic cells and monocytes. These findings support our hypothesis that innate immunity plays a central role in FSHD muscle pathology and establishes an FSHD muscle/immune xenograft model to investigate the mechanisms underlying the FSHD innate immunity response and to develop innate immunity therapeutics.
Support: Friends of FSHD Research, NINDS and NICHD UMMS Wellstone MDCRC