Studies over the past decade have revealed a central role for innate immune sensors in autoimmune and autoinflammatory diseases. cGAS, a cytosolic DNA sensor, detects both foreign and host DNA and generates a second-messenger cGAMP, which in turn binds and activates stimulator of IFN genes (STING), leading to induction of type I interferons and inflammatory cytokines. Recently, gain-offunction mutations in STING have been identified in patients with STING-associated vasculopathy with onset in infancy (SAVI). SAVI patients present with early-onset systemic inflammation and interstitial lung disease, resulting in pulmonary fibrosis and respiratory failure. Here, we describe two independent SAVI mouse models, harboring the two most common mutations found in patients. A direct comparison of these strains reveals a hierarchy of immune abnormalities, lung inflammation and fibrosis, which do not depend on either IFN-α/β receptor signaling or mixed lineage kinase domainlike pseudokinase (MLKL)-dependent necroptotic cell death pathways. Furthermore, radiation chimera experiments reveal how bone marrow from the V154M mutant mice transfer disease to the WT host, whereas the N153S does not, indicating mutation-specific disease outcomes. Moreover, using radiation chimeras we find that T cell lymphopenia depends on T cell-intrinsic expression of the SAVI mutation. Collectively, these mutant mice recapitulate many of the disease features seen in SAVI patients and highlight mutation-specific functions of STING that shed light on the heterogeneity observed in SAVI patients. STING | SAVI | type I interferonopathies | T cells | cell death N ucleic acids are readily detected by nucleic acid sensors that survey cells for signs of infection or tissue damage. Engagement of a diverse collection of RNA and DNA sensors trigger host-defense responses to curb pathogen replication and initiate beneficial repair responses to tissue injury. The DNA sensor cGAS (cGMP-AMP synthase) is a nucleotidyl transferase that detects double-stranded DNA and generates a novel secondmessenger 2′-5′cGMP-AMP (cGAMP). cGAMP binds stimulator of IFN genes (STING), causing its dimerization leading to activation of TBK1/IRF3 and IKK/NF-κB, pathways resulting in the induction of type I IFNs and proinflammatory cytokines, respectively (1). DNases outside cells (DNase I), within the phagolysosomal compartment (DNase II) or cytosol (DNase III/Trex1), ensure that in healthy individuals self nucleic acids do not trigger DNA sensors (2). Inappropriate clearance of DNA and its subsequent detection by DNA sensors underlies the pathogenesis of debilitating human diseases, such as Aicardi-Goutiéres syndrome (3). A subset of Aicardi-Goutiéres syndrome patients have mutations in Trex1, a 3′-5′ exonuclease that degrades DNA, which accumulates from endogenous retroelements (4, 5).Gain-of-function (GOF) mutations in components of RNA and DNA sensing pathways can also result in severe autoinflammatory and autoimmune diseases. Examples include the GOF mutations in DDX58 (RIG-I) and ...

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Background Red blood cell (RBC) alloantibodies to non-self antigens may develop following transfusion or pregnancy, leading to morbidity and mortality in the form of hemolytic transfusion reactions or hemolytic disease of the newborn. A better understanding of the mechanisms of RBC alloantibody induction, or strategies to mitigate the consequences of such antibodies, may ultimately improve transfusion safety. However, such studies are inherently difficult in humans. Study Design and Methods We recently generated transgenic mice with RBC specific expression of the human KEL glycoprotein, with the KEL2 or KEL1 antigens. Herein, we investigate recipient alloimmune responses to transfused RBCs in this system. Results Transfusion of RBCs from KEL2 donors into wild type recipients (lacking the human KEL protein but expressing the murine KEL orthologue) resulted in dose dependent anti-KEL glycoprotein IgM and IgG antibody responses, enhanced by recipient inflammation with poly (I:C). Boostable responses were evident upon repeat transfusion, with morbid appearing alloimmunized recipients experiencing rapid clearance of transfused KEL2 but not control RBCs. Although KEL1 RBCs were also immunogenic following transfusion into wild type recipients, transfusion of KEL1 RBCs into KEL2 recipients or vice versa failed to lead to detectable anti-KEL1 or anti-KEL2 responses. Conclusions This murine model, with reproducible and clinically significant KEL glycoprotein alloantibody responses, provides a platform for future mechanistic studies of RBC alloantibody induction and consequences. Long term translational goals of these studies include improving transfusion safety for at risk patients.