Billiar, T. | bioRxiv Science

bioRxiv2025

Aicardi-Goutieres Syndrome Associated ADAR G1007R mutation dominantly induces neuroinflammation in mouse brain

The ADARG1007Rmutation is one of the most frequent mutations found in type six Aicardi-Goutieres Syndrome (AGS), a severe inflammatory encephalopathy in pediatric patients. We report here a mouse model bearing an human equivalent ADARG1007R mutation, and the heterozygous mice recapitulated some pathologic features of ADARG1007R AGS patients, including early-onset brain inflammation in heterozygous individuals and interferon-stimulated gene (ISG) expression within deep brain areas. Furthermore, we demonstrated that brain inflammation could be reversed by deletion of the cellular RNA receptor MDA5, which blocks the cellular RNA sensing signaling pathway. This model provides a unique tool for studying the molecular mechanisms underlying the heterozygous ADARWT/G1007R mutation in AGS brain pathogenesis. It may also be a valuable platform for developing personalized therapies for patients with this specific mutation.

neuroscience↗

bioRxiv2025

Liver transplant rejection features memory cell priming, spatially differentiated networks and novel drug targets.

Acute T-cell-mediated transplant rejection, the earliest contributor to immunological graft failure responds variably to T-cell suppression. Early rejection can co-exist with donor-specific antibodies which also shorten graft survival, without affecting graft histology visibly. Here, during early liver transplant rejection, blood leukocytes manifest primed T-cells with heat shock protein (HSP) signaling and transcriptional programs for memory cell expansion. Corresponding biopsies demonstrate upregulated immune synapse and proteasomal genes in T-cell-infiltrated portal and central regions of the liver lobule. With donor-specific antibodies, the intervening intralobular region demonstrates a germinal-center-like allograft response with upregulated CD40, chemokine, T-follicular and complement signaling, which intensifies along the direction of sinusoidal blood flow from portal to central regions. Proteasomal and HSP90 inhibitors suppress donor-specific alloresponses of T- and B-cells in blood samples from patients with early rejection. The molecular injury spectrum of early rejection is complex, spatially differentiated and reveals novel early immunosuppressive strategies to extend graft survival.

immunology↗